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Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first-line or second-line treatment of patients with hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival in patients in specific clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival results in patients treated with a CDKI and fulvestrant. Methods In this exploratory analysis, we pooled individual patient data from three phase 3 randomised trials of CDKI or placebo in combination with fulvestrant in patients with breast cancer submitted to the US Food and Drug Administration and approved before Aug 1, 2020, in support of marketing applications. All analysed patients were aged at least 18 years, had an Eastern Cooperative Oncology Group performance status of 0–1, had hormone receptor-positive, HER2-negative advanced or metastatic breast cancer, and received at least one dose of CDKI or placebo in combination with fulvestrant. The median overall survival was estimated using Kaplan-Meier methods, and hazard ratios (HRs) with corresponding 95% CIs were estimated using Cox regression models. Patients were analysed collectively, by number of previous lines of systemic endocrine therapy in any disease setting (first-line or endocrine naive vs second-line and later), and in various clinicopathological subgroups of interest. The estimated median overall survival was not reported by group when the pooled population included patients treated across lines of therapy because of potential patient heterogeneity. All results presented are considered exploratory and hypothesis generating. Findings Across the three pooled trials, 1960 patients were randomly assigned between Oct 7, 2013, and June 10, 2016 (12 patients were not treated and 1296 [66%] patients were randomly assigned to CDKI and 652 [33%] to placebo). In all treated patients (n=1948), the estimated HR for overall survival was 0·77 (95% CI 0·68–0·88), with a median follow-up of 43·7 months (IQR 37·8–47·7) and deaths in 935 (48%) of the 1948 patients. The difference in estimated median overall survival was 7·1 months, favouring CDKIs. In patients who received CDKIs or placebo in combination with fulvestrant as first-line systemic endocrine therapy (two trials; n=396), the estimated HR for overall survival was 0·74 (95% CI 0·52–1·07), with a median follow-up of 39·4 months (IQR 37·0–42·2). 123 (31%) of these patients died. The difference in estimated median overall survival could not be calculated because median overall survival was not estimable (95% CI 50·9–not estimable) in the CDKI group and was 45·7 months (95% CI 41·7–not estimable) in the placebo group. In patients who received CDKIs or placebo in combination with fulvestrant as second-line or later systemic endocrine therapy (three trials; n=1552), the estimated HR for overall survival was 0·77 (95% CI 0·67–0·89), with a median follow-up of 45·1 months (95% CI 39·2–48·5). 812 (52%) of these patients died. The difference in estimated median overall survival was 7·0 months, favouring CDKIs. Interpretation The addition of CDKIs to fulvestrant resulted in a consistent overall survival benefit in all pooled patients and within most clinicopathological subgroups of interest. These findings support the existing standard of care of CDKIs plus fulvestrant for the treatment of patients with hormone receptor-positive, HER2-negative, advanced breast cancer. Funding None.

Subgroup analyses are assessments of treatment effects based on certain patient characteristics out of the total study population and are important for interpretation of pivotal oncology trials. However, appropriate use of subgroup analyses results for regulatory decision-making and product labeling is challenging. Typically, drugs approved by the FDA are indicated for use in the total patient population studied; however, there are examples of restriction to a subgroup of patients despite positive study results in the entire study population and also extension of an indication to the entire study population despite positive results appearing primarily in one or more subgroups. In this article, we summarize key issues related to subgroup analyses in the benefit–risk assessment of cancer drugs and provide case examples to illustrate approaches that the FDA Oncology Center of Excellence has taken when considering the appropriate patient population for cancer drug approval. In general, if a subgroup is of interest, the subgroup analysis should be hypothesis-driven and have adequate sample size to demonstrate evidence of a treatment effect. In addition to statistical efficacy considerations, the decision on what subgroups to include in labeling relies on the pathophysiology of the disease, mechanistic justification, safety data, and external information available. The oncology drug review takes the totality of the data into consideration during the decision-making process to ensure the indication granted and product labeling appropriately reflect the scientific evidence to support patient population for whom the drug is safe and effective.

Unblinded trials are common in oncology, but patient knowledge of treatment assignment may bias response to questionnaires. We sought to ascertain the extent of possible bias arising from patient knowledge of treatment assignment.This is a retrospective analysis of data from 2 randomized trials in multiple myeloma, 1 double-blind and 1 open label. We compared changes in patient reports of symptoms, function, and health status from prerandomization (screening) to baseline (pretreatment but postrandomization) across control and investigational arms in the 2 trials. Changes from prerandomization scores at ~2 and 6 months on treatment were evaluated only across control arms to avoid comparisons between 2 different experimental drugs. All scores were on 0- to 100-point scales. Inverse probability weighting, entropy balancing, and multiple imputation using propensity score splines were used to compare score changes across similar groups of patients.Minimal changes from screening were seen at baseline in all arms. In the control arm, mean changes of7 points were seen for all domains at 2 and 6 months. The effect of unblinding at 6 months in social function was a decline of less than 6 points (weighting: -3.09; 95% confidence interval -8.41 to 2.23; balancing: -4.55; 95% confidence interval -9.86 to 0.76; imputation: -5.34; 95% confidence interval -10.64 to -0.04).In this analysis, we did not find evidence to suggest that there was a meaningful differential effect on how patients reported their symptoms, function or health status after knowing their treatment assignment.

The FDA Oncology Center of Excellence (OCE) is a leader within the agency in scientific outreach activities and regulatory science research. On the basis of analysis of scientific workshops, internal meetings, and publications, the OCE identified nine scientific priority areas and one cross-cutting area of high interest for collaboration with external researchers. This article describes the process for identifying these scientific interest areas and highlights funded and unfunded opportunities for external researchers to work with FDA staff on critical regulatory science challenges.

The development and review of combination drug regimens in oncology may present unique challenges to investigators and regulators. For regulatory approval of combination regimens, it is necessary to demonstrate the contribution of effect of each monotherapy to the overall combination. Alternative approaches to traditional designs may be needed to accelerate oncology drug development, for example, when combinations are substantially superior to available therapy, to reduce exposure to less effective therapies, and for drugs that are inactive as single agents and that in combination potentiate activity of another drug. These approaches include demonstration of activity in smaller randomized trials and/or monotherapy trials conducted in a similar disease setting. This article will discuss alternative approaches used in the development of approved drugs in combination, based on examples of recent approvals of combination regimens in renal cell carcinoma.

Background Although the Adjuvant Paclitaxel and Trastuzumab (APT) trial has been adopted clinically, single-arm trials have limitations, and interest remains whether these patients with small node-negative human epidermal growth factor receptor 2 (HER2)-positive early breast cancer (EBC) would benefit from more intensive chemotherapy. This analysis explored whether external controls can contextualize single-arm studies to add to clinical decision making in the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Patients and methods Patient-level data from five randomized trials supporting drug approval in adjuvant HER2-positive EBC were pooled, and patients with low-risk EBC were selected (n = 1770). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane/trastuzumab (ACTH) or taxane/carboplatin/trastuzumab (TCH; n = 1366) were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n = 406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT; n = 374) were also matched (1:1) to those treated with TH. Propensity scores were estimated using covariates of age, tumor stage, estrogen receptor status, progesterone receptor status, and histological grade. Results After matching, the estimated probabilities of invasive disease-free survival (iDFS) at 3 and 5 years were 98.6% and 96.5% in the TH arm, and 96.6% and 92.9% in the ACTH/TCH arm, respectively. The estimated probabilities of overall survival (OS) at 3 and 5 years were 99.7% and 99.3% in the TH arm, and 99.0% and 97.4% in the ACTH/TCH arm, respectively. Comparing the TH arm with the ACT arm in the matched sample, the estimated difference in iDFS was 7.5% (TH 98.8% and ACT 91.3%) at 3 years and 12.6% (TH 96.1% and ACT 83.5%) at 5 years. The estimated difference in OS was 2.6% (TH 100% and ACT 97.4%) at 3 years, and 5.3% (TH 99.3% and ACT 94.0%) at 5 years. Conclusions Our analyses suggest that patients' outcomes in both arms were in general similar, thus providing additional reassurance regarding de-escalation of therapy.

Purpose: Differentiation syndrome (DS) is a serious adverse reaction of isocitrate dehydrogenase (IDH) inhibitors ivosidenib and enasidenib in patients with (IDH)1- and IDH2-mutated acute myeloid leukemia (AML), respectively. Experimental Design: During FDA review of marketing applications for ivosidenib and enasidenib, data from pivotal trials were queried to identify cases of DS in patients with relapsed or refractory (R/R) AML. One hundred seventy-nine patients with R/R AML received ivosidenib and 214 received enasidenib. Adverse events, labs, and vital signs in the first 90 days of treatment were screened per diagnostic criteria, and narratives were reviewed to adjudicate DS cases. Results: We identified 72 of 179 (40%) potential cases for ivosidenib and 86 of 214 (40%) for enasidenib; 34 of 179 (19%) and 41 of 214 (19%) were adjudicated as DS. Leukocytosis was present in 79% and 61% of cases, respectively. Median (range) time to onset was 20 (1–78) and 19 (1–86) days. Grade ≥ 3 adverse reactions occurred in 68% and 66%; 6% and 5% were fatal. Univariate analyses suggested baseline bone marrow blasts ≥ 48% and peripheral blood blasts ≥ 25% and 15% for ivosidenib and enasidenib, respectively, were associated with increased risk of DS. Complete remission (CR) + CR with partial hematologic recovery rates were lower in patients with versus without DS [ivosidenib 18% (95% confidence interval, 7%–35%) vs. 36% (28%–45%); enasidenib 18% (7%–33%) vs. 25% (18%–32%)]. Conclusions: DS is a common and potentially fatal adverse reaction of IDH inhibitors, and use of standardized diagnostic criteria may aid in earlier diagnosis and treatment. See related commentary by Zeidner, p. 4174

On March 8, 2019, the FDA granted accelerated approval to atezolizumab in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 [PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥1% of the tumor area], as determined by an FDA-approved test. Approval was based on data from IMpassion130, which randomized patients to receive atezolizumab or placebo in combination with paclitaxel protein-bound. Investigator-assessed progression-free survival (PFS) in the intent-to-treat (ITT) and PD-L1–positive populations were coprimary endpoints. After 13-month median follow-up, the estimated median PFS in the PD-L1–positive population was 7.4 months in the atezolizumab arm and 4.8 months in the placebo arm [HR = 0.60; 95% confidence interval (CI), 0.48–0.77]. Overall survival (OS) results were immature with 43% deaths in the ITT population, representing 59% of the OS events required to perform the final OS analysis. Adverse reactions occurring in ≥20% of patients receiving atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite. Accelerated approval was appropriate taking into account the unmet medical need along with the immaturity of the OS results and potential for PFS in the PD-L1–expressing population to predict clinical benefit.

On April 4, 2019, the FDA approved a supplemental new drug application for palbociclib (IBRANCE), to expand the approved indications in women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) in combination with an aromatase inhibitor or fulvestrant, to include men. Palbociclib was first approved in 2015 for use in combination with letrozole for the treatment of estrogen receptor–positive, HER2-negative advanced breast cancer as initial endocrine-based therapy in postmenopausal women and subsequently in 2016 in combination with fulvestrant in women with HR-positive, HER2-negative advanced breast cancer with disease progression following endocrine therapy. The current approval was primarily based on the results of the PALOMA-2 and PALOMA-3 trials and, supported by real-world data from electronic health records and insurance claims. To support the safety evaluation in male patients, data from two phase I studies with palbociclib and safety information from the global safety database, were also reviewed. This article summarizes FDA decision-making and data supporting the approval of palbociclib for the treatment of male patients with HR-positive, HER2-negative advanced or MBC.

Background: The Adjuvant Paclitaxel and Trastuzumab (APT) trial was a single-arm trial in patients with small node-negative HER2-positive early breast cancer (EBC). Although the regimen used in the APT trial has been adopted clinically, single-arm trials have limitations, and interest remains if these patients, particularly those with T1c or T2 disease would benefit from more intensive chemotherapy. Methods: Patient-level data from five randomized trials (BCIRG 006, NSABP-B31, HERA, N-9831, and APHINITY) submitted to FDA to support drug approval in adjuvant HER2-positive EBC were pooled (n=19087). Patients treated concurrently with trastuzumab and either anthracycline/cyclophosphamide/taxane (ACTH) (n=932), or taxane/carboplatin (TCH) (n=434), were matched (1:1) to patients treated with paclitaxel and trastuzumab (TH) in the APT trial (n=406) using propensity scores. Patients treated with anthracycline/cyclophosphamide/taxane (ACT) (n=374) were also matched (1:1) to those treated with TH on the APT trial. Propensity score models included age, tumor size (Tim/T1a, T1b, T1c, T2), grade, and hormone receptor status. Invasive disease-free survival (iDFS) and overall survival (OS) were compared between patients treated with ACTH or TCH and patients treated with TH from the APT trial, and between patients treated with ACT and TH. Results: After matching, 305 patients were included from the APT trial and 305 patients from the trastuzumab containing external control (ACTH or TCH). One hundred and sixty-nine patients from the APT trial were also matched to 169 patients from the ACT external control. The propensity score matching adequately balanced the patients’ baseline age and disease characteristics (Table 1). The iDFS and OS results are shown in Table 2. Similar results were observed when comparing patients who received ACTH versus TH, and comparing patients who received TCH versus TH. Similar results were also seen in trastuzumab-based treatment subgroups based on tumor size. Conclusions: External controls can be useful to contextualize single arm studies. These exploratory analyses further support the use of de-escalated therapy in patients with low-risk HER2-positive EBC. Table 1: Demographics and Disease CharacteristicsAPT (TH) N = 305External Control (ACTH/TCH) N = 305Std. Mean Diff (%)Age (Yrs), Mean (Std)54.6 (10.7)54.7 (9.8)1.1Primary Tumor Size (cm), Mean (Std)1.3 (0.6)1.4 (0.6)19.7Tumor Stage, n (%)T1ami16 (5.3)11 (3.6)-8.0T1b93 (30.5)95 (31.2)1.4T1c162 (53.1)166 (54.4)2.6T234 (11.2)33 (10.8)-1.1Grade, n (%)G119 (6.2)20 (6.6)1.3G2107 (35.1)95 (31.2)-8.4G3179 (58.7)190 (62.3)7.4ER+, n (%)198 (64.9)200 (65.6)1.4PR+, n (%)158 (51.8)157 (51.5)-0.7HR+, n (%)204 (66.9)202 (66.2)-1.4 APT (TH) N = 169External Control (ACT) N = 169Std. Mean Diff (%)Age (Yrs), Mean (Std)51.9 (10)52.5 (8.9)6.7Tumor Size (cm), Mean (Std)1.5 (0.6)1.6 (0.6)24.3Tumor Stage, n (%)T1ami6 (3.6)6 (3.6)0T1b30 (17.8)25 (14.8)-8.0T1c103 (61.0)109 (64.5)7.4T230 (17.8)29 (17.2)-1.6Grade, n (%)G13 (1.8)3 (1.8)0G252 (30.8)52 (30.8)0G3114 (67.5)114 (67.5)0ER+, n (%)100 (59.2)93 (55.0)-8.4PR+, n (%)81 (47.9)79 (46.8)-2.4HR+, n (%)103 (61.0)100 (59.2)-3.6 Table 2: iDFS and OSAPT (TH) (%)External Control (ACTH/TCH) (%)iDFS3 yrs98.6 (96.4, 99.5)96.6% (93.7, 98.1)5 yrs96.5 (93.6, 98.1)92.9% (88.2, 95.8)OS3 yrs99.7 (97.6, 100.0)99.0% (96.9, 99.7)5 yrs99.3 (97.2%, 99.8)97.4 (94.5, 98.7)APT (TH) (%)External Control (ACT) (%)iDFS3 yrs98.8 (95.3, 99.7)91.3 (85.7, 94.7)5 yrs96.1 (91.5, 98.2)83.5 (76.5, 88.6)OS3 yrs100 (NA, NA)97.4 (93.3, 99.0)5 yrs99.3 (95.3, 99.9)94.0 (88.8, 96.8) Citation Format: Laleh Amiri-Kordestani, Diqiong Xie, Erik Bloomquist, Shenghui Tang, Richard Pazdur, Rajeshwari Sridhara, Sara M Tolaney, Eric P Winer, Julia A Beaver. An FDA analysis of survival outcomes comparing adjuvant paclitaxel and trastuzumab trial (APT) to an external control from historical clinical trials [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD4-08.

Summary Background Cyclin-dependent kinase 4/6 inhibitors (CDKIs) are indicated with endocrine therapy as first-line or second-line treatment for hormone receptor-positive, HER2-negative, advanced or metastatic breast cancer. We aimed to investigate the benefit of adding CDKIs to endocrine therapy in patients whose tumours might have differing degrees of endocrine sensitivity. Methods We pooled individual patient data from all phase 3 randomised breast cancer trials of CDKIs plus endocrine therapy submitted to the US Food and Drug Administration before Jan 1, 2019, in support of marketing applications. Our pooled analysis included all randomly assigned patients in these trials who received at least one dose of CDKI or placebo with endocrine therapy (an aromatase inhibitor [letrozole or anastrazole] or fulvestrant). We did prespecified subgroup analyses in patients with progesterone receptor-negative disease; patients with a disease-free interval of 12 months or less; patients with de-novo metastases, lobular histology, and bone-only disease; patients with visceral metastases; and patients aged up to 40 years. Patients who were not treated, who received tamoxifen as endocrine therapy, or who were treated with an aromatase inhibitor but who had received previous chemotherapy in the metastatic setting (not first-line) were excluded from our pooled analyses. All studies had a primary endpoint of investigator-assessed progression-free survival, defined as time from date of randomisation to the initial date of documented cancer progression or death, whichever occurred first. Median progression-free survival was estimated with Kaplan-Meier methods. Hazard ratios (HR) with 95% CIs for progression-free survival were estimated by means of Cox regression models. Findings The seven studies meeting this study's inclusion criteria were done between Feb 22, 2013, and Nov 3, 2017, with a median duration of follow-up of 19·7 months (IQR 15·9–25·9). 4200 patients were included in the pooled analysis, of whom 1320 received an aromatase inhibitor plus a CDKI, 932 received placebo plus an aromatase inhibitor, 1296 received fulvestrant plus a CDKI, and 652 received fulvestrant plus placebo. Across all seven pooled trials, the difference in estimated median progression-free survival was 8·8 months in favour of CDKI plus endocrine therapy over placebo plus endocrine therapy (range across the trials 6·8–13·3 months; HR 0·59, 95% CI 0·54–0·64). Progression-free survival results favoured the CDKI group in all prespecified clinicopathological subgroups analysed, with similar HRs to that for the broader intended-use population. In first-line aromatase inhibitor-treated patients (n=2252), the median progression-free survival in the CDKI plus aromatase inhibitor group was 28·0 months (95% CI 25·3–29·1) versus 14·9 months (14·0–16·7) in the placebo plus aromatase inhibitor group (difference 13·1 months; range across the trials 13·0–13·3 months; HR 0·55, 95% CI 0·49–0·62). In first-line fulvestrant-treated patients (n=396), the median progression-free survival was 18·6 months (95% CI 14·8–23·5) in the placebo plus fulvestrant group and not estimable (22·4 to not estimable) in the CDKI plus fulvestrant group (difference not estimable; HR 0·58, 95% CI 0·42–0·80). In the patients treated with fulvestrant in the second-line setting and beyond (n=1552), the difference in estimated median progression-free survival between the CDKI plus fulvestrant group and the placebo plus fulvestrant group was 6·9 months in favour of the CDKI group (range across the trials 5·5–7·3 months; HR 0·56, 95% CI 0·49–0·64). Interpretation Since the addition of CDKI to endocrine therapy seemed to benefit all clinicopathological subgroups of interest in this pooled analysis, further research is needed to identify patient subgroups for whom endocrine therapy alone might be appropriate for first-line or second-line treatment of hormone receptor-positive, HER2-negative metastatic breast cancer. Funding None.

PURPOSE Many older women will be treated with a cyclin-dependent kinase 4/6 (CDK4/6) inhibitor and an aromatase inhibitor (AI), given US Food and Drug Administration approval of three agents in this class. The current pooled analysis examines the efficacy and safety of this combination in older women. PATIENTS AND METHODS We pooled data from three randomized controlled studies (N = 1,827) of different CDK4/6 inhibitors in combination with an AI for initial treatment of postmenopausal women with hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer. The effect of age on progression-free survival was evaluated using Kaplan-Meier estimates and a Cox proportional hazards regression model. RESULTS For patients age 75 years or older (n = 198) who were treated with a CDK4/6 inhibitor and an AI, hazard ratio was 0.49 (95% CI, 0.31 to 0.76) with an estimated median progression-free survival of 31.1 months (95% CI, 20.2 months to not reached) versus 13.7 months (95% CI, 10.9 months to 24.9 months) for those treated with an AI. Incidence of grade 3 to 4 adverse events was 88.8% in patients age 75 years and older and 73.4% in patients younger than age 75 years. Patients age 75 years or older reported a decline in quality-of-life measures using the EQ-5D regardless of treatment with AI alone or with the addition of a CDK4/6 inhibitor. CONCLUSION There was similar efficacy with a CDK4/6 inhibitor in combination with an AI compared with AI alone for first-line treatment of hormone receptor–positive, human epidermal growth factor receptor 2–negative metastatic breast cancer in older women compared with younger patients. Patients older than age 75 years experienced higher rates of toxicity, dose modifications, and a decrease from baseline in quality-of-life measures.

On December 20, 2017, the FDA granted regular approval to pertuzumab in combination with trastuzumab and chemotherapy for the adjuvant treatment of patients with HER2-positive early breast cancer (EBC) at high risk of recurrence. Approval was based on data from the APHINITY trial, which randomized patients to receive pertuzumab or placebo in combination with trastuzumab and chemotherapy. After 45.4-month median follow-up, the proportion of invasive disease-free survival (IDFS) events in the intent-to-treat population was 7.1% (n = 171) in the pertuzumab arm and 8.7% (n = 210) for placebo [hazard ratio (HR), 0.82; 95% confidence interval (CI), 0.67–1.00; P = 0.047]. The proportion of IDFS events in patients with hormone receptor–negative disease was 8.2% (n = 71) and 10.6% (n = 91) in the pertuzumab and placebo arms, respectively (HR, 0.76; 95% CI, 0.56–1.04). The proportion of IDFS events for patients with node-positive disease was 9.2% (n = 139) and 12.1% (n = 181) in the pertuzumab and placebo arms, respectively (HR, 0.77; 95% CI, 0.62–0.96). Adverse reactions in ≥30% of patients receiving pertuzumab were diarrhea, nausea, alopecia, fatigue, peripheral neuropathy, and vomiting. From a regulatory standpoint, the benefits of the addition of pertuzumab to adjuvant treatment outweighed the risks for patients with EBC at high risk of recurrence.

Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as 1st or 2nd line treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival (PFS) of patients in certain clinicopathological subgroups, all of whom received consistent benefit from the addition of a CDKI to hormonal therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI and fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of CDKI in combination with fulvestrant submitted to the US Food and Drug Administration (FDA) in support of marketing applications. All analyzed patients received at least one dose of CDKI or placebo in combination with fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Patients were analyzed collectively, by number of prior lines of systemic endocrine therapy in any disease setting (1st-line or endocrine naive vs. 2nd -line and later), and in various clinicopathologic subgroups of interest. Findings: In all pooled patients (n=1948), the estimated OS HR was 0∙77 (95% CI 0∙68-0∙88), with a median follow-up of 43∙7 months (interquartile range, (IQR): 37∙8, 47∙7) and deaths in 48% of patients. The difference in estimated median OS was 7∙1 months, favoring CDKIs. In patients who were endocrine therapy naive and received CDKIs as 1st -line systemic endocrine therapy (2 trials, n=396), the estimated OS HR was 0∙74 (95% CI 0∙52-1∙07), with a median follow-up of 39∙4 months (IQR: 37∙0, 42∙2) and deaths in 31% of patients. The median OS difference could not be calculated, since median OS was not reached on CDKI arm. In patients who received CDKIs as 2nd-line or later systemic endocrine therapy (3 trials, n=1552), the estimated OS HR was 0∙77 (95% CI 0∙67-0∙89), with a median follow-up of 45∙1 months (IQR: 39∙2, 48∙5) and deaths in 52% of patients. The median OS difference was 7∙0 months, favoring CDKIs. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding CDKI to fulvestrant. Patients with de novo metastatic disease (n=470, OS HR 0∙91 [95% CI 0∙68-1∙21]) and Asian patients (n=394, OS HR 0∙95 [95% CI 0∙81-1∙60]) appeared to benefit relatively less from the addition of CDKI to fulvestrant. Although the estimated OS HR appeared to favor fulvestrant alone in patients age < 40 [HR 1∙5 (95% CI 0∙75-3∙02)], this result must be interpreted with caution, given the small sample size (n=89) and correspondingly wide confidence interval. Evaluation of other age subgroups showed results in favor of the addition of CDKI to fulvestrant. All results presented are considered exploratory and hypothesis-generating. Interpretation: Addition of CDKIs to fulvestrant appears to confer a consistent overall survival benefit across all pooled patients and within most clinicopathological subgroups of interest. Funding: None. Declaration of Interest: All authors declare no competing interests. Ethical Approval: All patients in the included trials were required to provide informed written consent, and all trials had institutional review board or ethical approval.

This review provides a comprehensive assessment of recent literature reports describing atypical response patterns observed with immune checkpoint inhibitors (ICIs), modifications to response evaluation criteria for ICIs, and treatment beyond progression in clinical trials. Certain response patterns such as durable response, pseudoprogression, hyperprogression, and dissociated responses can be seen with ICI treatment. These patterns carry differing prognoses and are associated with varied factors. There are multiple modifications of standard Response Evaluation Criteria in Solid Tumors (RECIST) that have been proposed to better characterize immunotherapy response; however, standard RECIST1.1 remains most commonly used in clinical trials. Treatment beyond progression varies in frequency and benefit depending on assessment criteria and cancer type. Future research incorporating modified imaging criteria and biomarker assessments may serve to clarify who will benefit most from treatment beyond progression.

Tremendous progress has been made in treating patients with metastatic melanoma over the past decade. In that timeframe, the FDA has approved 12 novel treatments for patients with advanced unresectable melanoma, comprising both kinase-targeted therapies and immune checkpoint inhibitors (ICI), and five treatments for adjuvant (postoperative) use in patients with high-risk resectable stage III melanoma. It is not known whether outcomes can be further improved by administering kinase inhibitors or ICI in the neoadjuvant (presurgical) setting in patients with high-risk resectable melanomas. Noting research community interest in exploring the neoadjuvant approach for treating melanoma and recognizing that early harmonization of methodologies may expedite the development of therapeutics in this space, the FDA and Melanoma Research Alliance convened a public workshop on November 6, 2019, in National Harbor, Maryland, to discuss key issues. The workshop consisted of 23 faculty and included more than 250 live participants. Topics discussed included opportunities for advancing novel endpoints for regulatory purposes as well as translational research, clinical trial design considerations, and strategies for optimizing patient selection while mitigating risk.

On December 19, 2018, the U.S. Food and Drug Administration (FDA) granted approval to olaparib monotherapy for first-line maintenance treatment of BRCA-mutated (BRCAm) advanced ovarian cancer and, on May 8, 2020, expanded the indication of olaparib to include its use in combination with bevacizumab for first-line maintenance treatment of homologous recombination deficient (HRD)–positive advanced ovarian cancer. Both these approvals were based on randomized, double-blind, placebo-controlled trials. Approval for olaparib monotherapy was based on the SOLO-1 trial, comparing the efficacy of olaparib versus placebo in patients with BRCAm advanced ovarian, fallopian tube, or primary peritoneal cancer after surgical cytoreduction and first-line platinum-based chemotherapy. Two companion diagnostic (CDx) tests were approved with this indication: BRACAnalysis CDx, for germline BRCA1/2 alterations, and FoundationOne CDx, for BRCA1/2 alterations in tissue specimens. Approval for olaparib in combination with bevacizumab was based on the results of the PAOLA-1 trial that compared olaparib with bevacizumab versus placebo plus bevacizumab in patients with advanced high-grade epithelial ovarian cancer, fallopian tube, or primary peritoneal cancer after first-line platinum-based chemotherapy and bevacizumab. Myriad myChoice CDx was designated as a companion diagnostic device for use of olaparib plus bevacizumab combination for ovarian cancer associated with HRD-positive status. Both trials demonstrated clinically meaningful improvements in progression-free survival and favorable benefit-risk profiles for the indicated populations. This article summarizes the FDA thought process and data supporting the approval of olaparib as monotherapy and in combination with bevacizumab for maintenance therapy in this setting. Implications for Practice These approvals represent the first poly (ADP-ribose) polymerase inhibitor, alone or in combination with bevacizumab, approved in first-line maintenance treatment of women with advanced ovarian cancer after cytoreductive surgery and chemotherapy. In patients with BRCA-mutated tumors, olaparib monotherapy demonstrated a 70% reduction in the risk of disease progression or death compared with placebo, and olaparib in combination with bevacizumab demonstrated a 67% reduction in the risk of disease progression or death compared with bevacizumab alone in homologous recombination deficient–positive tumors. These approvals represent a major advance for the treatment of women with advanced ovarian cancer who are in complete or partial response after their initial platinum-based chemotherapy.

BACKGROUND: The primary endpoint in many registration trials is progression-free survival (PFS), defined as the time from randomization until objective tumor progression or death. In the clinical setting, however, PFS can be difficult to measure and explain, especially in patient-friendly language. For real-world evidence (RWE) based studies, time to treatment discontinuation (TTD), defined as time from randomization to discontinuation of the investigational study drug, may be a more practical endpoint. We hypothesize TTD will correlate with PFS and analyzed registration trials from recently FDA approved cyclin dependent kinase 4/6 inhibitors (CDKIs) to test this hypothesis. TTD was defined as time from randomization to discontinuation of the CDKI. METHODS: We pooled data from five phase III randomized, controlled, registration trials of CDKIs with an aromatase inhibitor (AI) in the first-line or fulvestrant in the second-line setting. The CDKI discontinuation dates used to calculate TTD were derived from the patient-level datasets. We calculated patient-level correlation between TTD and PFS. We also summarized median TTD and PFS as well as the number of TTD and PFS events. RESULTS: A total of 3017 patients were included in the pooled analysis (n=1899 treated with CDKI, n=1118 with placebo). The median PFS and TTD and the number of events are shown in Table 1. The patient-level Spearman correlation coefficient of TTD and PFS ranged from 0.87-0.95. The trial-level association was approximately R2=0.23. Table 1:Primary ResultsTreatment ArmNPFS EventsTTD EventsMedian PFS, in mo (95% CI)Median TTD, in mo (95% CI)Spearman Correlation CoefficientCDKI1899873138320.7 (19.2-22.2)14.3 (13.6-14.9)0.87Placebo111871488311.7 (11.0-13.6)11.0 (9.7-12.0)0.95 CONCLUSION: Patient-level pooled cross-trial analysis show a relationship between TTD and PFS in registration trials of CDKIs. In all trials, the difference in time between median TTD and median PFS appeared greater in the CDKI arm than the placebo arm. This analysis is limited by the relatively small number of studies included. Further research is needed to determine both whether: 1) TTD can serve as a pragmatic endpoint for analyses of RWE, and 2) is a more meaningful endpoint to patients. Citation Format: Gao JJ, Gong Y, Cheng J, Schroeder RJ, Amiri-Kordestani L, Khozin S, Kluetz P, Sridhara R, Pazdur R, Blumenthal G, Beaver JA, Prowell TM. Time to treatment discontinuation as a pragmatic endpoint: A U.S. Food and Drug Administration pooled analysis of CDK 4/6 inhibitors [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-14-02.

On March 29, 2018, the FDA granted accelerated approval for blinatumomab (Blincyto; Amgen, Inc.) for the treatment of adults and children with B-cell precursor acute lymphoblastic leukemia (BCP ALL) in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. Blinatumomab is a CD3xCD19 bispecific antibody approved previously for the treatment of relapsed or refractory BCP ALL. The basis for this accelerated approval was a single-arm trial. For the 86 patients in first and second complete remission with MRD ≥ 0.1%, conversion to MRD < 0.01% was achieved after one cycle of blinatumomab by 85.2% [95% confidence interval (CI): 73.8%, 93.0%] and 72.0% (95% CI: 50.6%, 87.9%), respectively, and the estimated median hematologic relapse-free survivals (RFS) were 35.2 months (95% CI: 0.4–53.5) and 12.3 months (95% CI: 0.7–42.3), respectively. Hematologic RFS was considered substantial independent of whether patients underwent subsequent allogeneic stem cell transplantation. The safety profile for blinatumomab was established in prior studies, and no new safety signals were observed in the new population. Cytokine release syndrome and neurotoxicity remain significant risks. The FDA is requiring confirmation of clinical benefit in a randomized trial.

Among patients with newly diagnosed non-small cell lung cancer (NSCLC), approximately 70% occur in those above 65 years of age and more than half are metastatic or locally advanced NSCLC.Retrospective analyses pooling data across 4 randomized clinical trials comparing programmed death 1 receptor (PD-1) or programmed death ligand 1 (PD-L1) to docetaxel for the treatment of patients with advanced or metastatic NSCLC with disease progression on or after a platinum-containing therapy were conducted. Demographics, efficacy, and safety data from these trials were pooled and aggregated based on age. The relative treatment effects on overall survival (OS) across age groups were evaluated using Kaplan-Meier methodology. A meta-analysis was performed comparing OS across age groups treated with PD-1/PD-L1 blocking antibodies compared with those treated with docetaxel, as a common control arm across trials. A Cox Proportional Hazards model, stratified by clinical trial, was used and a univariate and multivariate adjusted analysis of OS to further identify trends in efficacy across age groups.Among patients treated with PD-1/PD-L1 blocking antibodies enrolled across the 4 clinical trials, 42% were65 years of age, 99% had ECOG performance status of 0-1, 75% had received 1 prior therapy, and 76% were diagnosed with Stage IV disease. In the pooled analysis of 2,824 patients across both arms, the treatment effects in age-defined subgroups were similar, with a hazard ratios (HR), unadjusted or adjusted, for OS of 0.71 (95% confidence interval 0.63, 0.80) in patients65 years and 0.66 (0.57, 0.76) in patients ≥65 years of age. In patients ≥70 years, the HR for OS was 0.67 (0.55. 0.82) and in patients ≥ 75 years, the HR was 0.81 (0.58, 1.13). Estimated median OS in patients receiving PD-1/PD-L1 blocking antibodies versus docetaxel was 14.5 months versus 8.8 months in patients65 years, 14.2 months versus 9 months in patients ≥65 years, 14.1 versus 9.2 months in patients ≥70 years, and 14.7 versus 9.5 months in the patients ≥75years. Grade 3 or 4 treatment-related adverse events with PD-1/PD-L1 blocking antibodies were less frequent in patients ≥75 years (23%) compared to patients65 year ( 49%) and65 years (47%), as were serious adverse events (30%, 32.5%, 15%); however, treatment-emergent adverse events leading to discontinuation of treatment (7%, 7%, and 5%) in those subgroups ≤65 years,65 years, and75 years, respectively, were similar.Patients 65 and older with advanced and metastatic NSCLC, including those ≥75 years, seem to derive similar survival benefits from treatment with PD-1/PD-L1 blocking antibodies as patients65 years of age. Patients 75 and older enrolled on these trials appear to tolerate PD-1/PD-L1 blocking antibodies and have a lower incidence of grade 3 or 4 treatment-emergent adverse events compared to the subgroup of patients65 years of age.

On July 17, 2017, the FDA approved neratinib (NERLYNX; Puma Biotechnology, Inc.) for the extended adjuvant treatment of adult patients with early-stage HER2-overexpressed/amplified breast cancer, to follow adjuvant trastuzumab-based therapy. Approval was based on data from ExteNET, a randomized, double-blind, placebo-controlled multicenter trial. Women with early-stage HER2-positive breast cancer and within 2 years of completing adjuvant trastuzumab were randomized to neratinib (n = 1,420) or placebo (n = 1,420) for 1 year. The primary endpoint was invasive disease-free survival (iDFS), defined as the time between randomization date to first occurrence of invasive recurrence (local/regional, ipsilateral, or contralateral breast cancer), distant recurrence, or death from any cause, with 2 years and 28 days of follow-up. The trial showed a statistically significant treatment effect favoring neratinib with a stratified HR of 0.66 [95% confidence interval (CI), 0.49–0.90, P = 0.008]. The estimated iDFS rate at 2 years was 94.2% (95% CI, 92.6%–95.4%) in patients treated with neratinib versus 91.9% (95% CI, 90.2%–93.2%) in those receiving placebo. Diarrhea was the most common adverse event (AE), with a 40% incidence of grade 3 or 4 diarrhea, and represents the most common AE leading to treatment discontinuation. Other frequent AEs (>10% incidence) were nausea, abdominal pain, fatigue, vomiting, rash, stomatitis, decreased appetite, and muscle spasms. Other than diarrhea, neratinib is associated with a low incidence of severe AEs; toxicities are generally reversible and manageable with dose interruptions, dose reductions, and/or standard medical care. This article summarizes FDA decision-making and data supporting the neratinib approval. Clin Cancer Res; 24(15); 3486–91. ©2018 AACR. See related commentary by Unni et al., p. 3483

Purpose: Both objective response rate (ORR) and progression-free survival as defined by RECIST are weakly associated with overall survival (OS) in trials evaluating immunotherapy drug products. We proposed a novel intermediate response endpoint (IME) for evaluating immunotherapies. Experimental Design: We defined IME response as having no nontarget lesion progression, no new lesion appearance, and reaching a target lesion response determined by baseline tumor burden, tumor reduction depth, and tumor change dynamics within one year after randomization. Database used consisted of data from randomized active-controlled immunotherapy trials. Criterion for IME was developed on the basis of patient-level data from a training dataset, and further evaluated using an independent testing dataset. A patient-level responder analysis comparing OS between patients with and without an IME response was conducted using combined data. Association between trial-level OS hazard ratio (HR) and IME odds ratio (OR) was analyzed using a weighted linear regression model. Results: A total of 5,806 patients from 9 randomized studies were included in the database. At patient level, patients with IME response had improved OS compared with nonresponders (HR = 0.09). At trial level, association between OS and IME was moderate (R2 = 0.68). Conclusions: The IME was moderately associated with OS, and the association appeared to be stronger than the association observed between RECIST-defined ORR and OS. However, the analyses conducted in this research are exploratory and further evaluation is needed before using this endpoint in future studies. Clin Cancer Res; 24(10); 2262–7. ©2017 AACR.

Purpose: With the approval of immunotherapies for a variety of indications, methods to assess treatment benefit addressing the response patterns observed are important. We evaluated RECIST criteria–based overall response rate (ORR) and progression-free survival (PFS) as potential surrogate endpoints of overall survival (OS), and explored a modified definition of PFS by altering the threshold percentage determining disease progression to assess the association with survival benefit in immunotherapy trials. Experimental Design: Thirteen randomized, multicenter, active-control trials containing immunotherapeutic agents submitted to the FDA were analyzed. Associations between treatment effects of ORR, PFS, modified PFS, and OS were evaluated at individual and trial levels. Patient-level responder analysis was performed for PFS and OS. Results: The coefficient of determination (R²) measured the strength of associations, where values near 1 imply surrogacy and values close to 0 suggest no association. At the trial level, the association between hazard ratios (HR) of PFS and OS was R2 = 0.1303, and between the odds ratio (OR) of ORR and HR of OS was R2 = 0.1277. At the individual level, the Spearman rank correlation coefficient between PFS and OS was 0.61. Trial-level associations between modified PFS and OS ranged between 0.07 and 0.1, and individual-level correlations were approximately 0.6. HRs of PFS and OS for responders versus nonresponders were 0.129 [95% confidence interval (CI), 0.11–0.15] and 0.118 (95% CI, 0.11–0.13), respectively. Conclusions: Although responders exhibited longer survival and PFS than nonresponders, the trial-level and individual-level associations were weak between PFS/ORR and OS. Modifications to PFS did not improve associations. Clin Cancer Res; 24(10); 2268–75. ©2018 AACR. See related commentary by Korn and Freidlin, p. 2239

Purpose The outcome and proportion of patients with bone-only (BO) metastatic breast cancer (MBC) has not been well described. We sought to describe the differential outcomes of patients with BO MBC in clinical trials and explore whether there was a discrepancy in radiographic reads between investigator and blinded independent central review. Methods We pooled and analyzed data on 10,521 patients from 13 prospective trials submitted for MBC treatment in initial or supplemental New Drug or Biologics License Applications from 2005. Three subsets were evaluated: BO, bone with other metastases (BWO), and no bone metastases (NBM). Early discordance rate and late discordance rate were calculated from 3,733 and 2,813 patients subject to a blinded independent central review, respectively. Results Bone metastases were identified in 49% (range: 42% to 73%) of patients across trials. BO disease was present in 12.5% (range: 4% to 26%), dependent on subtype. Investigator-assessed progression-free survival (PFS) and overall survival (OS) for the pooled trials demonstrated improved outcomes for the BO subgroup compared with other subgroups (BO v BWO PFS hazard ratio [HR], 0.64; 95% CI, 0.591 to 0.696; BO v NBM PFS HR, 0.70; 95% CI, 0.65 to 0.76; BO v BWO OS HR, 0.56; 95% CI, 0.50 to 0.61; BO v NBM OS HR, 0.68; 95% CI, 0.61 to 0.76). The BO subgroup has a higher early discordance rate and lower late discordance rate than the BWO and NBM subgroups. Conclusion To our knowledge, this review is the largest analysis to date of the BO subgroup of MBC and suggests this subgroup may have a distinct natural history. There also seems to be a difference in how the local investigators assessed progression events in the BO subgroup when compared with the other two groups.

On December 19, 2016, the FDA granted accelerated approval to rucaparib (RUBRACA; Clovis Oncology, Inc.) for the treatment of patients with deleterious BRCA mutation (germline and/or somatic)–associated advanced ovarian cancer who have been treated with two or more chemotherapies. The FDA also approved the FoundationFocus CDxBRCA test (Foundation Medicine, Inc.), the first next-generation sequencing-based companion diagnostic, for identifying patients with advanced ovarian cancer eligible for treatment with rucaparib based on detection of deleterious BRCA1 and/or BRCA2 mutations in tumor tissue. Rucaparib's approval was based primarily on efficacy data from 106 patients with BRCA mutation–associated ovarian cancer who had prior treatment with two or more chemotherapies and safety data from 377 patients with ovarian cancer treated with rucaparib 600 mg orally twice daily on two open-label, single-arm trials. Investigator-assessed objective response rate was 54% [57/106; 95% confidence interval (CI), 44–64], and median duration of response was 9.2 months (95% CI, 6.6–11.7). The approved companion diagnostic verified tumor BRCA mutation status retrospectively in 96% (64/67) of patients. Common adverse reactions (≥20%) to rucaparib were nausea, fatigue, vomiting, anemia, abdominal pain, dysgeusia, constipation, decreased appetite, diarrhea, thrombocytopenia, and dyspnea. This article summarizes the FDA review and data supporting rucaparib's accelerated approval. Clin Cancer Res; 23(23); 7165–70. ©2017 AACR. See related commentary by Kohn et al., p. 7155

On December 18, 2015, the FDA granted regular approval to pembrolizumab (KEYTRUDA; Merck Sharp & Dohme Corp.) for treatment of patients with unresectable or metastatic melanoma based on results of two randomized, open-label, active-controlled clinical trials. In trial PN006, 834 patients with ipilimumab-naïve metastatic melanoma were randomized (1:1:1) to pembrolizumab 10 mg/kg i.v. every 2 or 3 weeks until disease progression or ipilimumab 3 mg/kg every 3 weeks for up to four doses. In trial PN002, 540 patients with ipilimumab-refractory metastatic melanoma were randomized (1:1:1) to pembrolizumab 2 or 10 mg/kg i.v. every 3 weeks or to investigator's choice of chemotherapy. In trial PN006, patients randomized to pembrolizumab demonstrated a statistically significant improvement in overall survival compared with ipilimumab [every-2-week arm: hazard ratio (HR) = 0.63; 95% confidence interval (CI), 0.47–0.83; P < 0.001; every-3-week arm: HR = 0.69; 95% CI, 0.52–0.90; P = 0.004]. In both trials, patients receiving pembrolizumab demonstrated statistically significant improvements in progression-free survival. The most common (≥2%) immune-mediated adverse reactions in a pooled safety analysis were hypothyroidism, pneumonitis, and hyperthyroidism. Key considerations for approval were determination of pembrolizumab dose and interpretation of tumor response–based endpoints using RECIST or immune-related RECIST. Clin Cancer Res; 23(19); 5661–5. ©2017 AACR.

Multiple myeloma is mostly an incurable disease. The U.S. Food and Drug Administration (FDA) granted daratumumab accelerated approval in November 2015 as monotherapy for patients with multiple myeloma who have received at least three prior lines of therapy, including a proteasome inhibitor and an immunomodulatory agent, or who are double refractory to a proteasome and an immunomodulatory agent. This article describes the FDA review of the strength of evidence for this application and its clinical implications for the multiple myeloma population., On November 21, 2016, the U.S. Food and Drug Administration granted regular approval to daratumumab in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, for the treatment of patients with multiple myeloma who have received at least one prior therapy. Approval was based on two randomized, open‐label trials in which daratumumab was added to these backbone therapies. The MMY3003 trial demonstrated substantial improvement in progression‐free survival (PFS) when daratumumab was added to lenalidomide and dexamethasone compared with lenalidomide and dexamethasone alone. The estimated median PFS had not been reached in the daratumumab arm and was 18.4 months in the control arm (hazard ratio [HR] = 0.37; 95% confidence interval [CI]: 0.27–0.52; p

On December 22, 2014, the FDA granted accelerated approval to nivolumab (OPDIVO; Bristol-Myers Squibb) for the treatment of patients with unresectable or metastatic melanoma and disease progression following ipilimumab and, if BRAF V600 mutation positive, a BRAF inhibitor. Approval was based on a clinically meaningful, durable objective response rate (ORR) in a non-comparative analysis of 120 patients who received 3 mg/kg of nivolumab intravenously every 2 weeks with at least 6-month follow-up in an ongoing, randomized, open-label, active-controlled clinical trial. The ORR as assessed by a blinded independent review committee per RECIST v1.1 was 31.7% (95% confidence interval, 23.5–40.8). Ongoing responses were observed in 87% of responding patients, ranging from 2.6+ to 10+ months. In 13 patients, the response duration was 6 months or longer. The risks of nivolumab, including clinically significant immune-mediated adverse reactions (imARs), were assessed in 268 patients who received at least one dose of nivolumab. The FDA review considered whether the ORR and durations of responses were reasonably likely to predict clinical benefit, the adequacy of the safety database, and systematic approaches to the identification, description, and patient management for imARs in product labeling. Clin Cancer Res; 23(14); 3484–8. ©2017 AACR.

On November 23, 2015, the FDA approved nivolumab (OPDIVO; Bristol-Myers Squibb) as a single agent for the first-line treatment of patients with BRAFV600 wild-type, unresectable or metastatic melanoma. An international, double-blind, randomized (1:1) trial conducted outside of the United States allocated 418 patients to receive nivolumab 3 mg/kg intravenously every 2 weeks (n = 210) or dacarbazine 1,000 mg/m2 intravenously every 3 weeks (n = 208). Patients with disease progression who met protocol-specified criteria (∼25% of each trial arm) were permitted to continue with the assigned treatment in a blinded fashion until further disease progression is documented. Overall survival was statistically significantly improved in the nivolumab arm compared with the dacarbazine arm [hazard ratio (HR), 0.42; 95% confidence interval (CI), 0.30–0.60; P < 0.0001]. Progression-free survival was also statistically significantly improved in the nivolumab arm (HR, 0.43; 95% CI, 0.34–0.56; P < 0.0001). The most common adverse reactions (≥20%) of nivolumab were fatigue, diarrhea, constipation, nausea, musculoskeletal pain, rash, and pruritus. Nivolumab demonstrated a favorable benefit–risk profile compared with dacarbazine, supporting regular approval; however, it remains unclear whether treatment beyond disease progression contributes to the overall clinical benefit of nivolumab. Clin Cancer Res; 23(14); 3479–83. ©2017 AACR.

This article summarizes the evidence for the impact of BRAF mutations on treatment outcome of anti‐EGFR monoclonal antibodies. Based on a review of literature, eight meta‐analyses were included in this study, which consistently show that patients with BRAF mutations have a lack of treatment benefit of anti‐EGFR monoclonal antibodies. Considering the quality and quantity of available evidence, current guidelines may be revised., On August 5, 2016, the U.S. Food and Drug Administration granted accelerated approval to pembrolizumab (KEYTRUDA injection, Merck Sharp & Dohme Corp., Kenilworth, NJ) for treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum‐containing chemotherapy. Approval was based on the objective response rate (ORR) and duration of response (DoR) in a cohort of patients in a nonrandomized multi‐cohort trial (KEYNOTE‐012) that included 174 patients with recurrent or metastatic HNSCC who had disease progression on or after platinum‐containing chemotherapy. Patients received either intravenous pembrolizumab 10 mg/kg every 2 weeks or 200 mg every 3 weeks. ORR was determined by independent review according to Response Evaluation Criteria in Solid Tumors 1.1. ORR was 16% (95% confidence interval 11, 22) with a complete response rate of 5%. DoR ranged from 2.4+ months to 27.7+ months. Twenty‐three of 28 responding patients (82%) had response durations of ≥6 months. Safety was evaluated in 192 patients with HNSCC receiving at least one dose of pembrolizumab. Frequent (≥2%) serious adverse reactions were pneumonia, dyspnea, confusional state, vomiting, pleural effusion, and respiratory failure. Clinically significant immune‐mediated adverse reactions included pneumonitis, colitis, hepatitis, adrenal insufficiency, diabetes mellitus, skin toxicity, myositis, and thyroid disorders. The benefit‐risk profile of pembrolizumab was considered acceptable in this patient population. As a condition of accelerated approval, Merck is required to conduct a confirmatory trial; this trial, KEYNOTE‐040, is ongoing. Implications for Practice. This accelerated approval expands the U.S. Food and Drug Administration‐approved indications for pembrolizumab, providing health care providers with new information regarding pembrolizumab for the treatment of patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum‐containing chemotherapy. Pembrolizumab is the first drug to receive approval for treatment of patients with HNSCC since cetuximab was approved for this indication in 2006.

Patient-reported outcome (PRO) measures describe how a patient feels or functions and are increasingly being used in benefit-risk assessments in the development of cancer drugs. However, PRO research objectives are often ill-defined in clinical cancer trials, which can lead to misleading conclusions about patient experiences. The estimand framework is a structured approach to aligning a clinical trial objective with the study design, including endpoints and analysis. The estimand framework uses a multidisciplinary approach and can improve design, analysis, and interpretation of PRO results. On the basis of the International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use E9(R1) addendum, we provide an overview of the estimand framework intended for a multistakeholder audience. We apply the estimand framework to a hypothetical trial for breast cancer, using physical function to develop specific PRO research objectives. This Policy Review is not an endorsement of a specific study design or outcome; rather, it is meant to show the application of principles of the estimand framework to research study design and add to ongoing discussion. Use of the estimand framework to review medical products and label PROs in oncology can improve communication between stakeholders and ultimately provide a clearer interpretation of patient experience in the development of oncological drugs.

On May 3, 2019, the FDA granted regular approval to ado-trastuzumab emtansine (KADCYLA), for the adjuvant treatment of patients with HER2-positive early-breast cancer (EBC) who have residual invasive disease after neoadjuvant taxane-based chemotherapy and trastuzumab-based treatment. Approval was based on data from the KATHERINE trial, which randomized patients to receive ado-trastuzumab emtansine or trastuzumab. At 3 years, the event-free rate for invasive disease-free survival in the ado-trastuzumab emtansine arm was 88.3% [95% confidence interval (CI), 85.8–90.7] compared with 77.0% (95% CI, 73.8–80.7) in the trastuzumab arm, (HR, 0.50; 95% CI, 0.39–0.64; P < 0.0001). Results from secondary endpoints, subgroup analyses, and sensitivity analyses generally supported the primary efficacy endpoint results. Common adverse reactions (>25% and higher incidence in ado-trastuzumab emtansine arm) with ado-trastuzumab emtansine were fatigue, nausea, increased transaminases, musculoskeletal pain, hemorrhage, thrombocytopenia, headache, peripheral neuropathy, and arthralgia. Ado-trastuzumab emtansine is the first drug approved for the treatment of patients with residual disease after neoadjuvant treatment and surgery. This article summarizes the FDA review and the data supporting the approval of ado-trastuzumab emtansine as a component of treatment for patients with HER2-positive EBC with residual disease.

The FDA has approved three androgen receptor inhibitors—enzalutamide, apalutamide, and darolutamide—for the treatment of patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). These approvals were all based on randomized, double blind, placebo-controlled trials demonstrating large improvements in metastasis-free survival (MFS) and internally consistent evidence of benefit seen across secondary endpoints. In this article, we summarize the FDA regulatory history of MFS and we describe the design, conduct, and results of the three pivotal trials supporting these important treatment options for patients with nmCRPC.

PURPOSE To assess the relationship among tumor response rate, overall survival, and the development of related adverse events of special interest (AESIs) or related immune-mediated adverse events (imAEs) in patients with urothelial cancer treated with anti–programmed death protein 1 or ligand 1 (anti–PD-1/L1) antibodies. PATIENTS AND METHODS We examined seven trials in 1,747 patients with metastatic or locally advanced urothelial cancer that led to approval of an anti–PD-1/L1 antibody. Five trials enrolled patients who had received prior platinum-based therapy, and two enrolled patients who were cisplatin ineligible. The data sets were searched for AESIs, related AESIs, imAEs, and related imAEs. The relationship to study drug was determined by the investigator. ImAEs were defined as AESIs treated with topical or systemic corticosteroids. RESULTS In these exploratory analyses, a related AESI was reported in 64% of responding patients and in 34% of patients who did not respond to the anti–PD-1/L1 antibody, whereas a related imAE occurred in 28% and 12% of patients who did and did not respond to study drug, respectively. In a responder analysis, an increase in overall survival was seen in patients with related AESIs compared with those with no related AESIs (hazard ratio, 0.45; 95% CI, 0.39 to 0.52). Fifty-seven percent of responding patients with a related AESI reported the AESI before documentation of response. CONCLUSION Patients who responded to treatment with an anti–PD-1/L1 antibody were more likely to report a related AESI or related imAE. This relationship did not seem to be due to the increased duration of exposure in responding patients. Systemic corticosteroid use did not appear to affect the duration of response.

1055 JJG, JC, TMP contributed equally. JAB, LAK contributed equally. Background: Cyclin dependent kinase 4/6 inhibitors (CDKIs) are oral targeted agents approved for use in combination with endocrine therapy as first or secondline treatment of hormone-receptor positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative advanced or metastatic breast cancer. We previously reported the pooled analyses of progression-free survival of patients in certain clinicopathologic subgroups, and results showed a consistent benefit from the addition of a CDKI to endocrine therapy. Here, we report the pooled overall survival (OS) results in patients treated with a CDKI plus fulvestrant. Methods: We pooled individual patient data (n=1948) from three phase III randomized breast cancer trials of a CDKI plus fulvestrant submitted to the FDA in support of marketing applications. All analyzed patients received at least one dose of a CDKI or placebo, plus fulvestrant. The median OS was estimated using Kaplan-Meier (KM) methods, and hazard ratios (HR) with corresponding 95% confidence intervals (CIs) were estimated using Cox regression models. Results: Results of OS analyses, including all pooled patients, patients treated in the first-line setting, and patients treated in the second line and later settings, are summarized in the table below. Additional subgroup analyses of OS by progesterone receptor status, site of metastases, breast cancer histology, ECOG performance status, race, and de novo metastatic presentation all favored adding a CDKI to fulvestrant. In patients age < 40, the estimated OS HR favored fulvestrant alone, but this subgroup had a small sample size (n=89), so this result must be interpreted with caution. All results are considered exploratory and hypothesis-generating. Conclusions: Addition of CDKIs to fulvestrant appears to confer a consistent survival benefit across all pooled patients and within most clinicopathological subgroups of interest.[Table: see text]

On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab for patients with advanced renal cell carcinoma who have received prior anti‐angiogenic therapy. The overall benefit/risk profile demonstrated in trial CA209025 supported this approval, and the trial design and results are presented here. Patients' prognostic risk category may serve as a putative predictive biomarker for treatment selection., On November 23, 2015, the U.S. Food and Drug Administration approved nivolumab (OPDIVO, Bristol‐Myers Squibb Company) for patients with advanced renal cell carcinoma (RCC) who have received prior anti‐angiogenic therapy. The approval was based on efficacy and safety data demonstrated in an open‐label, randomized study of 821 patients with advanced RCC who progressed after at least one anti‐angiogenic therapy. Patients were randomized to nivolumab or everolimus and followed for disease progression. The primary end point was overall survival. Subsequent therapies, including everolimus for patients who developed progressive disease on the nivolumab arm, were allowed, but no cross‐over was permitted. The median overall survival was 25.0 months on the nivolumab arm and 19.6 months on everolimus arm (hazard ratio: 0.73; 95% confidence interval: 0.60–0.89). The confirmed response rates were 21.5% versus 3.9%; median durations of response were 23.0 versus 13.7 months, and median times to response were 3.0 versus 3.7 months in the nivolumab and everolimus arms, respectively. A statistically significant improvement in progression‐free survival was not observed in this trial. The safety profile of nivolumab in renal cell cancer was similar to that in other disease settings. However, the incidence of immune‐mediated nephritis appeared to be higher in patients with RCC. Implications for Practice. The overall benefit/risk profile demonstrated in trial CA209025 supported the approval of nivolumab as an additional treatment option for patients with advanced renal cell carcinoma after anti‐angiogenic therapy. The use of nivolumab in patients who had received vascular endothelial growth factor‐targeted therapy resulted in a 5.4 month improvement in median overall survival compared with the everolimus arm. This difference is statistically significant and clinically meaningful.

On February 19, 2016, the FDA approved palbociclib (Ibrance, Pfizer) for use in combination with fulvestrant (Faslodex, AstraZeneca) for the treatment of women with hormone receptor (HR)-positive, HER2-negative advanced or metastatic breast cancer (MBC) with disease progression following endocrine therapy. The approval was based on the results of a randomized, double-blind, placebo-controlled trial conducted in 521 pre- and postmenopausal women with HR-positive, HER2-negative advanced or MBC. Patients were randomized (2:1) to receive palbociclib plus fulvestrant (n = 347) or placebo plus fulvestrant (n = 174). The primary endpoint was investigator-assessed progression-free survival (PFS). A statistically significant and clinically meaningful improvement in PFS (9.5 months vs. 4.6 months) was observed in patients receiving palbociclib plus fulvestrant [HR 0.46; 95% confidence interval (CI), 0.36–0.59; P < 0.0001]. Safety data confirmed the known adverse reaction profile of palbociclib. The most common adverse reactions (>20%) in patients treated with palbociclib were neutropenia, leukopenia, infections, fatigue, nausea, anemia, stomatitis, headache, diarrhea, and thrombocytopenia. This approval was granted in the context of a prior accelerated approval for palbociclib in combination with letrozole in patients with HR-positive, HER2-negative advanced breast cancer as initial endocrine-based therapy. Clin Cancer Res; 22(20); 4968–72. ©2016 AACR.

Purpose: Cancer trials are often open-label and include patient-reported outcomes (PROs). Previous work has demonstrated that patients may complete PRO assessments less frequently in the control arm compared with the experimental arm in open-label trials. Such differential completion may affect PRO results. This paper sought to explore principal stratification methodology to address potential bias caused by the posttreatment intermediate variable of questionnaire completion. Methods: We evaluated six randomized trials (five open-label and one double-blind) of anticancer therapies with varying levels of PRO completion submitted to the Food and Drug Administration (FDA). We applied complete case analysis (CCA), multiple imputation (MI), and principal stratification to evaluate PRO results for quality of life (QOL) and the domains of physical, role, and emotional function (PF, RF, and EF). Assignment to potential principal strata was by the expectation maximization algorithm using patient baseline characteristics. Results: Completion rates in the experimental arm ranged from 66% to 94% and 51% to 95% in the control arm. Four trials had negligible completion differences between arms (1%-2%), and two had large differences favoring the experimental arm (15%-17%). For trials with negligible completion differences, principal stratification results were similar to CCA and MI results for all domains. Notable differences in point estimates may be observed in trials with large differences in completion rates. However, in the examined trials, the confidence intervals for the principal stratification estimates overlapped with the ones obtained using CCA. Conclusions: The principal stratification estimand may be a useful additional analysis, especially if PRO completion differs between arms.

This study evaluated the circumstances under which the observed progression-free survival (PFS) benefit may translate into an overall survival (OS) benefit.A simulation study, based on PFS and OS joint model decomposition, was conducted to evaluate the impact of crossover rates, survival post progression (SPP) lengths, and magnitudes of difference in median PFS on OS. Under different simulation scenarios, the degree of impact was investigated based on the probability of observing a significant OS benefit given an observed PFS benefit.Using simulation parameters defined based on historical NDA datasets, the probability of detecting an OS benefit given the observed PFS benefit depends largely on crossover rate and SPP length (ie, SPP median times). Compared to no crossover, a crossover rate of ≤ 50% decreases the probability of detecting an OS benefit by at most 15% regardless of the SPP length. A crossover rate of50% decreases the probability of detecting an OS benefit much further, and the extent of decrease is proportional to the length of SPP.Crossover rate and SPP length are important factors affecting the benefit translating from PFS to OS. This simulation study identified a threshold, of 50%, for crossover rate that is likely to confound OS effect. With a greater than 50% crossover rate, longer SPP further decreases the probability of translating a PFS benefit to OS.

Use of blinded independent central review (BICR) has become more common in oncology phase 3 trials as progression-free survival (PFS) has been increasingly used as an endpoint for regulatory approval. Since PFS is primarily a radiographic endpoint, BICR has been implemented to assess and reduce potential bias in the local evaluation (LE) of PFS. Recent publications note an agreement between LE and BICR of the ultimate reported PFS treatment effect, which questions the need for costly and time-consuming complete-case BICR of PFS. A meta-analysis was conducted to systematically evaluate the relationship between BICR- and LE-assessed PFS based on FDA’s regulatory experience from 2005 to present. Our results support the claim that a complete review of all radiographs by BICR may not be necessary for oncology trials, and alternative methods should be explored to evaluate bias. One potential alternative is to use BICR as an audit tool to detect evaluation bias in LE assessments.

On March 28- 29, 2017, the National Cancer Institute (NCI) Thoracic Malignacy Steering Committee, International Association for the Study of Lung Cancer, and Mesothelioma Applied Research Foundation convened the NCI-International Association for the Study of Lung Cancer- Mesothelioma Applied Research Foundation Mesothelioma Clinical Trials Planning Meeting in Bethesda, Maryland. The goal of the meeting was to bring together lead academicians, clinicians, scientists, and the U.S. Food and Drug Administration to focus on the development of clinical trials for patients in whom malignant pleural mesothelioma has been diagnosed. In light of the discovery of new cancer targets affecting the clinical development of novel agents and immunotherapies in malignant mesothelioma, the objective of this meeting was to assemble a consensus on at least two or three practice-changing multimodality clinical trials to be conducted through NCI's National Clinical Trials Network.

Advanced and metastatic melanoma has historically been one of the most difficult cancers to treat, with few treatment options. For over 20 years, dacarbazine chemotherapy was the only treatment approved by the US Food and Drug Administration for melanoma. In recent years, breakthroughs have been made in the areas of monoclonal antibody immunotherapies and genetically targeted therapies, leading to FDA approval of several new drugs for metastatic melanoma that have demonstrated improved patient response and survival. In an effort to understand the changing landscape of therapies for advanced and metastatic melanoma, we have reviewed 38 publicly available randomized clinical trials from http://ClinicalTrials.gov in metastatic and unresectable melanoma since the year 2000, to assess developments in the design and conduct of clinical trials over time and to compare the clinical efficacy of old and new therapies. We first present a brief history of FDA approvals of therapies for melanoma, followed by an exploration of trends in the patient population and demographics, eligibility criteria, and statistical methods of clinical trials over time. Next, we compare the efficacy results of old and new study treatments, examining the endpoints of progression-free survival, overall survival, and response rate. Overall, we find that the clinical trial population largely reflected the general population of patients with melanoma in demographic factors, with the exception of patient age. Our findings suggest that the developments of immunotherapies and targeted therapies have improved patient trial results on the discussed endpoints.

The U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). At the prespecified interim analysis, a statistically significant improvement in overall survival was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm. The overall benefit-risk profile supports the expanded indication for enzalutamide. On September 10, 2014, the U.S. Food and Drug Administration approved enzalutamide for the treatment of patients with chemotherapy-naïve metastatic castration-resistant prostate cancer (mCRPC). Enzalutamide was initially approved in 2012 for use in patients with mCRPC who had previously received docetaxel. The current approval was based on the results of a randomized, placebo-controlled, double-blind trial conducted in 1,717 asymptomatic or minimally symptomatic patients with chemotherapy-naïve mCRPC. Patients were assigned to receive either enzalutamide 160 mg or placebo orally once daily. The coprimary endpoints were overall survival (OS) and radiographic progression-free survival (rPFS), which was assessed by independent central radiology review. At the prespecified interim analysis, a statistically significant improvement in OS was demonstrated for patients in the enzalutamide arm compared with patients in the placebo arm (hazard ratio [HR], 0.71; 95% confidence interval [CI], 0.60–0.84). The median OS was 32.4 and 30.2 months in the enzalutamide and placebo arms, respectively. A statistically significant prolongation of rPFS was observed in patients in the enzalutamide arm (HR, 0.17; 95% CI, 0.14–0.21). In addition, the time to initiation of cytotoxic chemotherapy was prolonged in the enzalutamide arm (HR, 0.35; 95% CI, 0.30–0.40), with median times of 28.0 and 10.8 months in the enzalutamide and placebo arms, respectively. The safety profile was similar to that previously reported for enzalutamide. Adverse reactions of interest included seizure, hypertension, and falls. Enzalutamide should be discontinued if a seizure occurs during treatment. The overall benefit-risk profile supports the expanded indication for enzalutamide. Implications for Practice: This new approval expands the enzalutamide indication, allowing health care providers and patients to use enzalutamide for the treatment of metastatic castration-resistant prostate cancer either before or after cytotoxic chemotherapy.

This article summarizes the data supporting FDA approval of atezolizumab and pembrolizumab for the treatment of patients with advanced urothelial carcinoma ineligible for cisplatin‐based chemotherapy and the subsequent revision of the indications for both agents., The U.S. Food and Drug Administration (FDA) granted accelerated approval to atezolizumab and pembrolizumab in April and May 2017, respectively, for the treatment of patients with locally advanced or metastatic urothelial carcinoma who are not eligible for cisplatin‐containing chemotherapy. These approvals were based on efficacy and safety data demonstrated in the two single‐arm trials, IMvigor210 (atezolizumab) and KEYNOTE‐052 (pembrolizumab). The primary endpoint, confirmed objective response rate, was 23.5% (95% confidence interval [CI]: 16.2%–32.2%) in patients receiving atezolizumab and 28.6% (95% CI: 24.1%–33.5%) in patients receiving pembrolizumab. The median duration of response was not reached in either study and responses were seen regardless of PD‐L1 status. The safety profiles of both drugs were generally consistent with approved agents targeting PD‐1/PD‐L1. Two ongoing trials (IMvigor130 and KEYNOTE‐361) are verifying benefit of these drugs. Based on concerning preliminary reports from these trials, FDA revised the indications for both agents in cisplatin‐ineligible patients. Both drugs are now indicated for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors/infiltrating immune cells express a high level of PD‐L1. The indications for atezolizumab and pembrolizumab in patients who have received prior platinum‐based therapy have not been changed. This article summarizes the FDA thought process and data supporting the accelerated approval of both agents and the subsequent revision of the indications. Implications for Practice. The accelerated approvals of atezolizumab and pembrolizumab for cisplatin‐ineligible patients with advanced urothelial carcinoma represent the first approved therapies for this patient population. These approvals were based on single‐arm trials demonstrating reasonable objective response rates and favorable durations of response with an acceptable toxicity profile compared with available non‐cisplatin‐containing chemotherapy regimens. However, based on concerning preliminary reports from two ongoing phase III trials, the FDA revised the indication for both agents in cisplatin‐ineligible patients. Both are now indicated either for patients not eligible for any platinum‐containing chemotherapy or not eligible for cisplatin‐containing chemotherapy and whose tumors have high expression of PD‐L1.

The FDA approved niraparib, a poly(ADP-ribose) polymerase (PARP) inhibitor, on March 27, 2017, for maintenance treatment of patients with recurrent epithelial ovarian, fallopian tube, or primary peritoneal cancer who are in response to platinum-based chemotherapy. Approval was based on data from the NOVA trial comparing niraparib with placebo in two independent cohorts, based on germline BRCA mutation status (gBRCAm vs. non-gBRCAm). Progression-free survival (PFS) in each cohort was the primary endpoint. In the gBRCAm cohort, estimated median PFS on niraparib was 21 months versus 5.5 months on placebo [HR, 0.26; 95% confidence interval (CI), 0.17–0.41; P < 0.0001]. In the non-gBRCAm cohort, estimated median PFS for niraparib and placebo was 9.3 and 3.9 months, respectively (HR, 0.45; 95% CI, 0.34–0.61; P < 0.0001). Common adverse reactions (>20% and higher incidence in the niraparib arm) with niraparib included thrombocytopenia, anemia, neutropenia, nausea, constipation, vomiting, mucositis, fatigue, decreased appetite, headache, insomnia, nasopharyngitis, dyspnea, rash, and hypertension. There were five cases of myelodysplastic syndrome and acute myeloid leukemia (1.4%) in patients treated with niraparib compared with two cases (1.1%) on placebo. Niraparib is the first PARP inhibitor approved as maintenance therapy for patients with ovarian, fallopian tube, or primary peritoneal cancer, with improvement in PFS, regardless of gBRCAm status. Clin Cancer Res; 24(17); 4066–71. ©2018 AACR. See related commentary by Konstantinopoulos and Matulonis, p. 4062

Background We previously conducted an overview of oncology products reviewed by the Office of Oncology Drug Products in the Center for Drug Evaluation and Research at the US Food and Drug Administration for marketing approval and the regulatory actions taken during July 2005 to December 2007. There is a need to understand if the changes in the laws, regulations, and the organization that occurred after 2007 had any impact on the regulatory drug approvals. We present a detailed overview of hematology and oncology products reviewed by Office of Oncology Drug Products and Office of Hematology and Oncology Drug Products. Methods We identified all oncology-hematology applications that were submitted to the US Food and Drug Administration from January 1, 2008 through December 31, 2016, and reviewed the approval actions taken. Results During the study period, the Office of Hematology and Oncology Products approved 239 applications that supported 260 new indications. Of the 239 applications approved, 141 were approved via priority review and 98 were approved via standard review. Fifty-three of these applications were granted accelerated approval, 29 were converted from accelerated approval to regular approval, and 157 received regular approval. Since its promulgation in 2013, breakthrough designation status has been granted to 25.7% of applications. A variety of endpoints were used to support these approvals. Conclusion During the study period, despite changes in the regulations and organization, the Office of Hematology and Oncology Products consistently utilized regulatory mechanisms that expedite the development and approval of promising oncology and hematology drug products resulting in the approval of 260 new indications.

Clinical trial eligibility criteria are necessary to define the patient population under study and improve trial safety. However, there are concerns that eligibility criteria for cancer clinical trials are too restrictive and limit patient enrollment in clinical trials. Recently, there have been initiatives to re-examine and modernize eligibility criteria for oncology clinical trials. To assess current eligibility requirements for cancer clinical trials, we have conducted a comprehensive review of eligibility criteria for commercial investigational new drug clinical trial applications submitted to the US Food and Drug Administration Office of Hematology and Oncology Products in 2015. Our findings suggest that eligibility criteria for current cancer clinical trials tend to narrowly define the study population and limit the study to lower-risk patients, which may not be reflective of the greater patient population outside of the study. We discuss potential areas for expanding eligibility criteria to include more patients in clinical trials and design options for clinical trials incorporating expanded eligibility criteria. The broadening of clinical trial eligibility criteria can be considered to better reflect the real-world patient population, improve clinical trial participation, and increase patient access to new investigational treatments.

On March 13, 2017, the FDA approved ribociclib (KISQALI; Novartis Pharmaceuticals Corp.), a cyclin-dependent kinase 4/6 inhibitor, in combination with an aromatase inhibitor as initial endocrine-based therapy for the treatment of postmenopausal women with hormone receptor (HR)–positive, HER2-negative advanced or metastatic breast cancer. The approval was based on a randomized, double-blind, placebo-controlled, international clinical trial (MONALEESA-2). A total of 668 patients were randomized to receive either ribociclib plus letrozole (n = 334) or placebo plus letrozole (n = 334). An improvement in progression-free survival (PFS) was observed in patients receiving ribociclib plus letrozole compared with patients receiving placebo plus letrozole [HR = 0.556; 95% confidence interval (CI), 0.429–0.720]. Overall response rate (ORR) in patients with measurable disease was 52.7% (95% CI, 46.6–58.9) in the ribociclib plus letrozole arm and 37.1% (95% CI, 31.1–43.2) in the placebo plus letrozole arm. Overall survival data were immature. The most common adverse reactions observed in 20% or more of patients taking ribociclib were neutropenia, nausea, fatigue, diarrhea, leukopenia, alopecia, vomiting, constipation, headache, and back pain. This article summarizes FDA decision-making and data supporting the approval of ribociclib. Clin Cancer Res; 24(13); 2999–3004. ©2018 AACR. See related commentary by Spring and Bardia, p. 2981

Importance Novel intermediate end points may be useful to detect signals of early activity and prioritize new therapies to treat patients with advanced malignant neoplasms, including metastatic non–small cell lung cancer (mNSCLC). Objective To explore milestone rate, a proposed intermediate end point for immunotherapy trials. Data Sources Trials submitted to the US Food and Drug Administration with more than 150 patients and in which the intention-to-treat population was assessed were identified. Study Selection An initial meta-analysis identified 14 randomized clinical trials for treatment of mNSCLC with active controls submitted to the US Food and Drug Administration from January 1, 2003, through December 31, 2013. An additional 11 randomized clinical trials submitted from January 1, 2014, through December 31, 2016 were included. Data Extraction and Synthesis Two investigators abstracted data and pooled data to compare trial-level milestone ratios with conventional end points. Main Outcomes and Measures Trial-level milestone ratios for milestone rates were calculated for overall response rate (ORR) within 6 months, 9-month progression-free survival (PFS), 9-month overall survival (OS), and 12-month OS. A weighted linear regression model evaluated associations between milestone ratios and hazard ratios (HRs). Experimental and control arms of trials testing immunotherapy, targeted therapy, and other trials were pooled to compare Kaplan-Meier survival estimates in the 3 therapeutic classes. Results A total of 20 013 unique patients (65.4% male and 34.6% female; mean age, 60 [range, 18-92] years) with advanced lung cancer were identified in 25 unique trials. A moderate association was observed between 12-month OS milestone ratio and OS HR ( R 2 = 0.80; 95% CI, 0.63-0.91) and 9-month OS milestone ratio and OS HR ( R 2 = 0.67; 95% CI, 0.49-0.82). No associations were observed between 9-month PFS milestone ratio and OS HR ( R 2 = 0.19; 95% CI, 0.03-0.49) or 6-month ORR and OS HR ( R 2 = 0.05; 95% CI, 0.0001-0.31). The aggregated Kaplan-Meier analysis of immunotherapy trials vs chemotherapy revealed an OS HR of 0.69 (95% CI, 0.63-0.75) and PFS HR of 0.82 (95% CI, 0.76-0.89). Targeted therapy trials vs chemotherapy had an OS HR of 0.98 (95% CI, 0.80-1.19) and PFS HR of 0.48 (95% CI, 0.42-0.56). Conclusions and Relevance This analysis of milestone rates suggests a moderate association between OS milestones at 12 or 9 months and OS HR but not 9-month PFS or 6-month ORR milestones and OS HR. Although OS at 12 months had the strongest association with OS HR, it may not be the optimal time for future trials, which will increasingly have immunotherapy as the control, deploy new biomarker-enrichment strategies, and likely enroll patients with longer survival. Milestone rates may be useful as a complementary tool to summarize or interpret trial results or as a secondary end point in exploratory studies.

BackgroundResponse criteria developed when cytotoxic chemotherapy was the predominant therapeutic modality to treat patients with cancer, do not capture the full spectrum of tumor response patterns observed with anti-PD-1/PD-L1 antibody treatment. iRECIST was developed to capture both typical and atypical response patterns.MethodsTarget, non-target, and new lesion measurements for 7920 patients receiving anti-PD-1/PD-L1 antibody (n=4751) or anti-CTLA-4 antibody (n=613) or undergoing chemotherapy (n=2556) from 14 randomized controlled trials submitted to the U.S. Food and Drug Administration were used to calculate the best overall response, objective response rate and progression-free survival (PFS) per iRECIST (iPFS) and Response Evaluation Criteria in Solid Tumours (RECIST). Associations between either PFS or iPFS and overall survival (OS) were evaluated using the method adopted by Obaet al.1ResultsAmong 4751 anti-PD-1/PD-L1-antibody treated patients, 31.5% (95% CI 30.2% to 32.9%) and 30.5% (95% CI 29.2% to 31.8%) achieved an objective response per iRECIST or RECIST V.1.1, respectively. OS among the 48 patients with objective response by iRECIST only resembled that in patients with responses per RECIST V.1.1. The association between iPFS and OS was R2=0.277 and that between PFS and OS was R2=0.260.ConclusionsPatients treated with anti-PD-1/PD-L1 antibodies with initial progressive disease per RECIST V.1.1 can experience prolonged stability or substantial reductions in tumor burden per iRECIST, atypical response patterns associated with prolonged OS. In the subgroup of patients with atypical responses, the application of iRECIST retrospectively in the evaluation of the objective response durations and the magnitude of PFS results in large differences compared with RECIST V.1.1. For the overall pooled population, the magnitude of these differences was modest, although a large proportion of patients had no further tumor assessments following RECIST V.1.1-defined progressive disease. Prospective studies employing iRECIST will be required to assess whether this response criteria more fully captures the benefit of immune checkpoint inhibitors.