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Supplementary Tables and Figures from Efficacy and Safety of Patritumab Deruxtecan (HER3-DXd) in EGFR Inhibitor–Resistant, EGFR-Mutated Non–Small Cell Lung Cancer

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers.Significance:In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism.See related commentary by Lim et al., p. 16.This article is highlighted in the In This Issue feature, p. 1

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Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non–small cell lung cancer (NSCLC).Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m2 ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies.Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia.Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement. Clin Cancer Res; 19(11); 3068–77. ©2013 AACR.

Receptor tyrosine-protein kinase ERBB3 (HER3) is expressed in most EGFR-mutated lung cancers but is not a known mechanism of resistance to EGFR inhibitors. HER3-DXd is an antibody–drug conjugate consisting of a HER3 antibody attached to a topoisomerase I inhibitor payload via a tetrapeptide-based cleavable linker. This phase I, dose escalation/expansion study included patients with locally advanced or metastatic EGFR-mutated non–small cell lung cancer (NSCLC) with prior EGFR tyrosine kinase inhibitor (TKI) therapy. Among 57 patients receiving HER3-DXd 5.6 mg/kg intravenously once every 3 weeks, the confirmed objective response rate by blinded independent central review (Response Evaluation Criteria in Solid Tumors v1.1) was 39% [95% confidence interval (CI), 26.0–52.4], and median progression-free survival was 8.2 (95% CI, 4.4–8.3) months. Responses were observed in patients with known and unknown EGFR TKI resistance mechanisms. Clinical activity was observed across a broad range of HER3 membrane expression. The most common grade ≥3 treatment-emergent adverse events were hematologic toxicities. HER3-DXd has clinical activity in EGFR TKI–resistant cancers independent of resistance mechanisms, providing an approach to treat a broad range of drug-resistant cancers. Significance: In metastatic EGFR-mutated NSCLC, after disease progression on EGFR TKI therapy, treatment approaches include genotype-directed therapy targeting a known resistance mechanism or chemotherapy. HER3-DXd demonstrated clinical activity spanning known and unknown EGFR TKI resistance mechanisms. HER3-DXd could present a future treatment option agnostic to the EGFR TKI resistance mechanism. See related commentary by Lim et al., p. 16. This article is highlighted in the In This Issue feature, p. 1

Background: Poor patients often reside in neighborhoods of lower socioeconomic status (SES) with high levels of airborne pollutants. They also have higher mortality from non–small cell lung cancer (NSCLC) than those living in wealthier communities. We investigated whether living in polluted neighborhoods is associated with somatic mutations linked with lower survival rates, i.e., TP53 mutations. Methods: In a retrospective cohort of 478 patients with NSCLC treated at a comprehensive cancer center between 2015 and 2018, we used logistic regression to assess associations between individual demographic and clinical characteristics, including somatic TP53 mutation status and environmental risk factors of annual average particulate matter (PM2.5) levels, and neighborhood SES. Results: 277 patients (58%) had somatic TP53 mutations. Of those, 45% lived in neighborhoods with “moderate” Environmental Protection Agency–defined PM2.5 exposure, compared with 39% of patients without TP53 mutations. We found significant associations between living in neighborhoods with “moderate” versus “good” PM2.5 concentrations and minority population percentage [OR, 1.06; 95% confidence interval (CI), 1.04–1.08]. There was a significant association between presence of TP53 mutations and PM2.5 exposure (moderate versus good: OR, 1.66; 95% CI, 1.02–2.72) after adjusting for patient characteristics, other environmental factors, and neighborhood-level SES. Conclusions: When controlling for individual- and neighborhood-level confounders, we find that the odds of having a TP53-mutated NSCLC are increased in areas with higher PM2.5 exposure. Impact: The link between pollution and aggressive biology may contribute to the increased burden of adverse NSCLC outcomes in individuals living in lower SES neighborhoods.

Background: Phase 1 clinical trials remain vital for oncology care. Patients on these trials require supportive care for quality-of-life (QOL) concerns. Objective: To test a Palliative Care Intervention (PCI) for patients with solid tumors enrolled in Phase I therapeutic trials with a priori hypothesis that psychological distress, QOL, satisfaction, symptoms, and resource utilization would be improved in the PCI group. Design: This unblinded randomized trial compared the PCI with usual care in patients accrued to Phase I Clinical Trials. Subjects (n = 479) were followed for 24 weeks, with 12 weeks as the primary outcome. Setting: Two Comprehensive Cancer Centers in the United States. Subjects: A consecutive sample, 21 years or older, English fluency, with solid tumors initiating a Phase 1 trial. Measurements: Psychological Distress (Distress Thermometer), QOL total and subscales (FACT-G), satisfaction (FAM-CARE), survival, and resource utilization (chart audit). Results: PCI subjects showed improved Psychological Distress (−0.47, p = 0.015) and Emotional Well-Being (0.81, p = 0.045), with differences on variables of QOL and distress between sites. High rates of symptom-management admissions (41.3%) and low rates of Advance Directive completion (39.0%), and hospice enrollment (30.7%), despite a median survival in both groups of 10.1 months from initiating a Phase 1 study. Conclusions: A nurse-delivered PCI can improve some QOL outcomes and distress for patients participating in Phase 1 trials. Greater integration of PC is needed to provide quality care to these patients and to support transitions from treatment to supportive care, especially at the end of life. ClinicalTrials.gov Identifier: NCT01612598.

Background To identify additional at-risk groups for lung cancer screening, which targets persons with a long history of smoking and thereby misses younger or nonsmoking cases, the authors evaluated germline pathogenic variants (PVs) in patients with lung adenocarcinoma for an association with an accelerated onset. Methods The authors assembled a retrospective cohort (1999-2018) of oncogenetic clinic patients with lung adenocarcinoma. Eligibility required a family history of cancer, data on smoking, and a germline biospecimen to screen via a multigene panel. Germline PVs (TP53/EGFR, BRCA2, other Fanconi anemia [FA] pathway genes, and non-FA DNA repair genes) were interrogated for associations with the age at diagnosis via an accelerated failure time model. Results Subjects (n = 187; age, 28-89 years; female, 72.7%; Hispanic, 11.8%) included smokers (minimum of 5 pack-years; n = 65) and nonsmokers (lighter ever smokers [n = 18] and never smokers [n = 104]). Overall, 26.7% of the subjects carried 1 to 2 germline PVs: TP53 (n = 5), EGFR (n = 2), BRCA2 (n = 6), another FA gene (n = 11), or another DNA repair gene (n = 28). After adjustment for smoking, sex, and ethnicity, the diagnosis of lung adenocarcinoma was accelerated 12.2 years (95% confidence interval [CI], 2.5-20.6 years) by BRCA2 PVs, 9.0 years (95% CI, 0.5-16.5 years) by TP53/EGFR PVs, and 6.1 years (95% CI, -1.0 to 12.6 years) by PVs in other FA genes. PVs in other DNA repair genes showed no association. Germline associations did not vary by smoking. Conclusions Among lung adenocarcinoma cases, germline PVs (TP53, EGFR, BRCA2, and possibly other FA genes) may be associated with an earlier onset. With further study, the criteria for lung cancer screening may need to include carriers of high-risk PVs, and findings could influence precision therapy and reduce lung cancer mortality by earlier stage diagnosis.

Background KRAS mutations reported in non-small cell lung cancer (NSCLC) represent a significant percentage of patients diagnosed with NSCLC. However, there still remains no therapeutic option designed to target KRAS. In an era with immunotherapy as a dominant treatment option in metastatic NSCLC, the role of immunotherapy in. Kras mutated patients is not clear. Methods Eligible patients diagnosed with NSCLC and found to have a KRAS mutation were identified in an institutional lung cancer database. Demographic, clinical, and molecular data was collected and analyzed. Results A total of 60 patients were identified for this retrospective analysis. Majority of patients were Caucasian (73%), diagnosed with stage IV (70%) adenocarcinoma (87%), and had a KRAS codon 12 mutation (78%). Twenty percent of patients were treated with immunotherapy. Median overall survival was 28 months in the cohort and patients who received immunotherapy were found to have better survival versus those who did not (33 vs. 22 months, P=0.31). Furthermore, there was an association between high survival and patients who received immunotherapy (P=0.007). Conclusions Patients with KRAS mutations have a unique co-mutation phenotype that requires further investigation. Immunotherapy seems to be an effective choice of treatment for KRAS positive patients in any treatment-line setting and yields better outcomes than conventional chemotherapy. The relationship between immunotherapy and KRAS mutations requires further studies to confirm survival advantage.

Background Papulopustular rash is a common class effect of epidermal growth factor receptor inhibitors (EGFRI) that can affect patients’ health-related quality of life and cause disruptions to treatment. SWOG S1013 (NCT01416688) is a multi-center study designed to validate the Functional Assessment of Cancer Therapy EGFRI 18 (FACT-EGFRI 18) using 7-items from the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 to assess EGFRI-induced skin-related toxicities and their impact on functional status. Methods Patients with a diagnosis of colorectal or lung cancer to receive EGFRI therapies for at least 6 weeks were enrolled. Patient self-assessments using the FACT-EGFRI 18 were completed prior to undergoing CTCAE assessment by trained clinicians at baseline, weekly × 6, and then monthly × 3. The psychometric properties of the FACT-EGFRI 14 (skin toxicity items only) and 18 (plus 2 nail and 2 hair items) were established based on criterion validity, known groups validity, internal consistency reliability, and responsiveness to change. Results Of the 146 registered patients, 124 were evaluable. High Cronbach’s alpha (> 0.70) for both FACT-EGFRI 14 and FACT-EGFRI 18 scores across assessment times were observed. Although agreement (i.e. criterion validity) between individual and summary scales of the FACT-EGFRI 18 for assessing skin toxicity was good, agreement with the clinician-reported CTCAE was only fair. The minimal important difference was determined to be 3 points. The results also demonstrated responsiveness to symptom change. Discussion Based on the results of this multi-center validation study, the FACT-EGFRI 18 patient-reported outcome instrument provided data from the patient’s perspective yielding unique information as well as complementing clinician-rated CTCAE grades, especially for the symptoms of pain, pruritus, and paronychia. Conclusions Good to excellent psychometric properties for the FACT-EGFRI 18 were demonstrated, supporting further use of this patient-reported outcomes measure. Additional validation with a more diverse group of patients should be conducted.

Objectives Patients with cancer who are at a transition to Phase I investigational treatments have been identified as an underserved population with regard to palliative care. This disease transition is often accompanied by spiritual and existential concerns. The study objective was to conduct a secondary analysis of data from a larger study testing a palliative care intervention. This paper reports the findings of this secondary focus on the spiritual needs of this population. Methods Patients (n = 479) were accrued to this study prior to initiating a Phase I clinical trial with data collected at baseline, and 4, 12, and 24 week follow-up. Results Qualitative data revealed that the transition to Phase 1 trial participation is a time of balancing hope for extended life with the reality of advancing disease. Quantitative results demonstrated increased spirituality over time in both religious- and non-religious-affiliated patients. Conclusions Patients entering Phase I trials have important spiritual needs as they face treatment decisions, advancing disease, and often mortality. Spiritual care should be provided to seriously ill patients as a component of quality care.

Palliative care began in academic centers with specialty consultation services, and its value to patients, families, and health systems has been evident. The demand for palliative care to be integrated throughout the cancer trajectory, combined with a limited palliative care workforce, means that new models of care are needed. This review discusses evidence regarding the need for integration of palliative care into routine oncology care and describes best practices recognized for dissemination of palliative care. The available evidence suggests that palliative care be widely adopted by clinicians in all oncology settings to benefit patients with cancer and their families. Efforts are needed to adapt and integrate palliative care into community practice. Limitations of these models are discussed, as are future directions to continue implementation efforts. The benefits of palliative care can only be realized through effective dissemination of these principles of care, with more primary palliative care delivered by oncology clinicians.

EGFR-mutated lung adenocarcinoma patients who received tyrosine kinase inhibitors (TKIs) may initially respond to therapy, but over time, resistance eventually occurs. In a small population (5–10%), these patients can have a histological transformation to SCLC. Nine patients with EGFR-mutated lung adenocarcinoma who transformed to SCLC were evaluated at City of Hope. Patient clinical and pathology data, including multiple next-generation sequencing (NGS) results, clinical therapies, histology, and outcomes, were collected across multiple time points. Descriptive statistics were utilized to visualize and interpret the clinical therapeutic timeline and molecular transformation profiles for these patients. All patients received at least one line of EGFR TKI therapies prior to small cell lung cancer transformation, including erlotinib, afatinib, and osimertinib. Two patients also received chemotherapy prior to transformation (one with immunotherapy). The median months to small cell lung cancer transformation was 16 months, ranging from 4–49 months. The median overall survival (OS) was 29 months from diagnosis, with the minimum of 16 months and maximum of 62 months. The majority of patients had EGFR exon 19 deletion (n = 7, 77.8%), and no patients had a change of original oncogenic EGFR mutation over the different time points. Though a TP53 mutation was detected in eight patients (88.9%) either at the first biopsy or the subsequent biopsies, an RB1 alteration was only detected in one patient at presentation, and three patients upon subsequent biopsies (n = 4, 44.4%). Each patient had a unique molecular profile in the subsequent molecular testing post-transformation, but BRAF alterations occurred frequently, including BRAF rearrangement (n = 1), fusion (n = 1), and amplification (n = 1). Our results showed that EGFR-mutated lung adenocarcinoma to SCLC transformation patients have a unique histological, molecular, and clinical profile over multiple time points, with further heterogeneity that is not currently reported in the literature, and we suggest more work is required to better understand the molecular heterogeneity and clinical outcomes over time for this EGFR TKI resistance subtype.

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Small Cell Lung Cancer (SCLC) provide recommended management for patients with SCLC, including diagnosis, primary treatment, surveillance for relapse, and subsequent treatment. This selection for the journal focuses on metastatic (known as extensive-stage) SCLC, which is more common than limited-stage SCLC. Systemic therapy alone can palliate symptoms and prolong survival in most patients with extensive-stage disease. Smoking cessation counseling and intervention should be strongly promoted in patients with SCLC and other high-grade neuroendocrine carcinomas. The “Summary of the Guidelines Updates” section in the SCLC algorithm outlines the most recent revisions for the 2022 update, which are described in greater detail in this revised Discussion text.

IMPORTANCE: Although geriatric assessment–driven intervention improves patient-centered outcomes, its influence on chemotherapy-related toxic effects remains unknown. OBJECTIVE: To assess whether specific geriatric assessment–driven intervention (GAIN) can reduce chemotherapy-related toxic effects in older adults with cancer. DESIGN, SETTING, AND PARTICIPANTS: A randomized clinical trial enrolled 613 participants from a National Cancer Institute–designated cancer center between 2015 and 2019. Patients were 65 years and older with a solid malignant neoplasm, were starting a new chemotherapy regimen, and completed a geriatric assessment. Patients were followed up until chemotherapy completion or 6 months after initiation, whichever occurred first. Data analysis was done by intention-to-treat principle. INTERVENTIONS: Patients were randomized (2:1) to either the GAIN (intervention) or standard of care (SOC) arm. In the GAIN arm, a geriatrics-trained multidisciplinary team composed of an oncologist, nurse practitioner, social worker, physical/occupation therapist, nutritionist, and pharmacist reviewed geriatric assessment results and implemented interventions based on prespecified thresholds built into the geriatric assessment’s domains. In the SOC arm, geriatric assessment results were sent to treating oncologists for consideration. MAIN OUTCOMES AND MEASURES: The primary outcome was incidence of grade 3 or higher chemotherapy-related toxic effects (graded using National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0). Secondary outcomes included advance directive completion, emergency department visits, unplanned hospitalizations, average length of stay, unplanned hospital readmissions, chemotherapy dose modifications, and early discontinuation. Overall survival analysis was performed up to 12 months after chemotherapy initiation. RESULTS: Among the 605 eligible participants for analysis, median (range) age was 71 (65-91) years, 357 (59.0%) were women, and 432 (71.4%) had stage IV disease. Cancer types included gastrointestinal (202 [33.4%]), breast (136 [22.5%]), lung (97 [16.0%]), genitourinary (91 [15.0%]), gynecologic (54 [8.9%]), and other (25 [4.1%]). Incidence of grade 3 or higher chemotherapy-related toxic effects was 50.5% (95% CI, 45.6% to 55.4%) in the GAIN arm and 60.6% (95% CI, 53.9% to 67.3%) in the SOC arm, resulting in a significant 10.1% reduction (95% CI, −1.5 to −18.2%; P = .02). A significant absolute increase in advance directive completion of 28.4% with GAIN vs 13.3% with SOC (P

BackgroundWe conducted a2-part study to evaluate the incorporation of veliparib, a PARP inhibitor, into chemoradiotherapy (CRT) for stage III non-small-cell lung cancer.Patients and methodsIn the phase I part, patients were treated successivelyat3dose levels of veliparib(40,80, and120mg) twice daily during CRT. In the phase II part, patients were randomized to receive veliparib or placebo during thoracic radiotherapy with concurrent weekly carboplatin andpaclitaxel, followed by 2 cycles of consolidation carboplatin and paclitaxel with veliparib or placebo. The study was prematurely discontinued owing to the emergence of adjuvant immunotherapy as standard of care.ResultsOf 21 patients enrolled in phase I, 2 patients developed dose-limiting toxicities (DLTs): 1 grade 3 esophagitis with dysphagia (at 40 mg) and 1 grade 3 esophagitis with dehydration (at 80 mg). No DLTs were seen at veliparib dose of 120 mg twice daily, which was selected for the phase II part that enrolled 31 eligible patients. Progression-free survival (PFS) was not different between the 2 arms (P=.20). For the veliparib and placebo arms, response rates were 56% and 69%, PFS at 1 year 47% and 46%, and overall survival at 1 year 89% and 54%, respectively.ConclusionVeliparib with CRT was feasible and well tolerated. Efficacy could not accurately be determined because of early study closure. Nonetheless, there is enthusiasm for the evaluation of PARP inhibitors in lung cancer as predictive biomarkers are being developed and combinations with immunotherapy are attractive.

Tyrosine kinase inhibitor (TKI) therapy is the recommended first-line treatment for metastatic non-small-cell lung cancer (NSCLC) positive for epidermal growth factor receptor (EGFR) gene mutation. However, most individuals treated with TKI therapy for EGFR-mutant NSCLC will develop tumor resistance to TKI therapy. Therapeutic strategies to overcome TKI resistance are the topic of several ongoing clinical trials. One potential strategy, which has been explored in numerous trials, is the treatment of progressive sites of disease with stereotactic body radiation treatment (SBRT) or stereotactic radiosurgery (SRS). We sought to review the literature pertaining to the use of local ablative radiation therapy in the setting of acquired resistance to TKI therapy and to discuss stereotactic radiation therapy as a strategy to overcome TKI resistance.

Introduction Preclinical evidence suggests the feedforward cytokine loop of interleukin-6/Janus kinases (JAK)/STAT3 plays a role in epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) resistance in EGFR-mutated non-small cell lung cancer (NSCLC). Methods In this phase 1b study, the JAK1/2 and TANK-binding kinase 1 (TBK1) inhibitor momelotinib was evaluated in combination with erlotinib in patients with EGFR TKI-naive, EGFR-mutated NSCLC. After erlotinib lead-in (50, 75, 100, or 150 mg oral daily [QD]), momelotinib was combined and dose escalated in a 3 + 3 study design. The primary endpoint of maximum tolerated dose (MTD) of momelotinib was determined based on the incidence of dose-limiting toxicities (DLTs) during the first 28-day cycle. Secondary endpoints included efficacy and pharmacokinetics (PK). Results Eleven patients were enrolled across 3 dose levels of momelotinib (100 mg QD, 200 mg QD, and 100 mg twice daily [BID]). The MTD was momelotinib 200 mg QD in combination with erlotinib. Two DLTs of grade 4 neutropenia without fever and grade 3 diarrhea occurred at momelotinib 100 mg BID. Most common treatment-emergent adverse events included diarrhea, dry skin, fatigue, and decreased appetite; the vast majority being grades 1–2. The overall response rate was 54.5% (90% CI 27.1–80.0; all partial) and median progression-free survival was 9.2 months (90% CI 6.2–12.4). Momelotinib did not affect the PK of erlotinib. Conclusions The JAK1/2 and TBK1 inhibitor momelotinib in combination with erlotinib did not appear to enhance benefit over the historical data of erlotinib monotherapy in patients with EGFR-mutated NSCLC. ClinicalTrials.gov identifier NCT02206763.

Lung cancer patients undergoing systemic treatment with immune checkpoint inhibitors (ICIs) can lead to severe immune-related adverse events (irAEs) that may warrant immediate hospitalization. Patients with thoracic malignancies hospitalized at City of Hope while undergoing treatment with ICIs were identified. Pathology and available next-generation sequencing (NGS) data, including the programmed death-ligand 1 (PD-L1) status and clinical information, including hospitalizations, invasive procedures, and the occurrence of irAEs, were collected. Unpaired T-tests, Chi-square/Fisher’s exact test, and logistic regression were used to analyze our cohort. The overall survival (OS) was calculated and compared using univariate and multivariate COX models. Ninety patients with stage IV lung cancer were admitted after ICI treatment. Of those patients, 28 (31.1%) had documented irAEs. Genomic analyses showed an enrichment of LRP1B mutations (n = 5/6 vs. n = 7/26, 83.3% vs. 26.9%, odds ratio (OR) (95% confidence interval (CI): 13.5 (1.7–166.1), p &lt, 0.05) and MLL3 mutations (n = 4/6, 66.7% vs. n = 5/26, 19.2%, OR (95% CI): 8.4 (1.3–49.3), p &lt, 0.05) in patients with irAE occurrences. Patients with somatic genomic alterations (GAs) in MET (median OS of 2.7 vs. 7.2 months, HR (95% CI): 3.1 (0.57–17.1), 0.05) or FANCA (median OS of 3.0 vs. 12.4 months, HR (95% CI): 3.1 (0.70–13.8), 0.05) demonstrated a significantly shorter OS. Patients with irAEs showed a trend toward improved OS (median OS 16.4 vs. 6.8 months, p = 0.19) compared to hospitalized patients without documented irAEs. Lung cancer patients who required treatment discontinuance or interruption due to irAEs (n = 19) had significantly longer OS (median OS 18.5 vs. 6.2 months, HR (95% CI): 0.47 (0.28–0.79), 0.05). Our results showed a significant survival benefit in lung cancer patients hospitalized due to irAEs that necessitated a treatment interruption. Patients with positive somatic GAs in MET and FANCA were associated with significantly worse OS compared to patients with negative GAs.

The implication of MET alterations in solid tumors and the immune microenvironment remains elusive. Formalin-fixed, paraffin-embedded samples of 21 patients with solid tumors harboring MET alterations were used for immunohistochemical staining. Extracted RNA was analyzed with the NanoString nCounter human PanCancer immune profiling panel (NanoString Technologies, Inc., WA, USA). Patients were diagnosed with lung (n = 10), breast (n = 5), genitourinary (n = 3) or colorectal cancer (n = 3). Eleven had a MET missense mutation, four had an exon 14 splice site mutation and six had MET amplification. CD6, CCL19, CD40LG, XCR1, MAGEA1, ATM and CCL19 genes were significantly differentially expressed in MET-altered cancers. MET alterations may have a role in various solid tumors as potential therapeutic targets and combination therapy candidates with immune checkpoint inhibitors., Lay abstract MET is a receptor for growth signals that keeps cells alive and healthy. However, some tumors have changes in MET that allow for uncontrollable cell growth. Patients with MET-altered tumors may benefit from treatments targeting this gene, but eventually they become resistant to the treatments. Thus, there is a need to identify additional therapies for this patient population. The authors tested immune gene expression in tumors with MET alterations to determine if these patients would benefit from a new class of treatments called immunotherapies and found that patients with and without MET changes had differences in immune gene expression.

Background The usefulness of circulating tumor DNA (ctDNA) in detecting mutations and monitoring treatment response has not been well studied beyond a few actionable biomarkers in non-small cell lung cancer (NSCLC). Research Question How does the usefulness of ctDNA analysis compare with that of solid tumor biopsy analysis in patients with NSCLC? Methods We retrospectively evaluated 370 adult patients with NSCLC treated at the City of Hope between November 2015 and August 2019 to assess the usefulness of ctDNA in mutation identification, survival, concordance with matched tissue samples in 32 genes, and tumor evolution. Results A total of 1,688 somatic mutations were detected in 473 ctDNA samples from 370 patients with NSCLC. Of the 473 samples, 177 showed at least one actionable mutation with currently available Food and Drug Administration-approved NSCLC therapies. MET and CDK6 amplifications co-occurred with BRAF amplifications (false discovery rate [FDR], < 0.01), and gene-level mutations were mutually exclusive in KRAS and EGFR (FDR, 0.0009). Low cumulative percent ctDNA levels were associated with longer progression-free survival (hazard ratio [HR], 0.56; 95% CI, 0.37-0.85; P = .006). Overall survival was shorter in patients harboring BRAF mutations (HR, 2.35; 95% CI, 1.24-4.6; P = .009), PIK3CA mutations (HR, 2.77; 95% CI, 1.56-4.9; P < .001) and KRAS mutations (HR, 2.32; 95% CI, 1.30-4.1; P = .004). Gene-level concordance was 93.8%, whereas the positive concordance rate was 41.6%. More mutations in targetable genes were found in ctDNA than in tissue biopsy samples. Treatment response and tumor evolution over time were detected in repeated ctDNA samples. Interpretation Although ctDNA analysis exhibited similar usefulness to tissue biopsy analysis, more mutations in targetable genes were missed in tissue biopsy analyses. Therefore, the evaluation of ctDNA in conjunction with tissue biopsy samples may help to detect additional targetable mutations to improve clinical outcomes in advanced NSCLC.

Background Symptoms are common among patients enrolled in phase I trials. We assessed the validity of Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events (PRO-CTCAE) items in relation to previously validated assessments of quality of life and psychological distress. We used data from a randomized trial testing a palliative care support intervention for patients enrolled on phase I trials. Methods Patients (n = 479) were accrued to the parent study prior to initiating a phase I clinical trial with data collected at baseline, 4, and 12 weeks. We determined the correlation of PRO-CTCAE with distress level, Functional Assessment of Cancer Therapy - General (FACT-G) total, and subscale domain scores. Results Patients were predominantly female (56.8%) and older than age 60 years, and 30.7% were from minority populations. The correlation coefficient for distress level for all PRO-CTCAE items was small to moderate (Pearson r = 0.33-0.46). Pearson correlation coefficient for FACT-G total was moderate (r = -0.45 to -0.69). Stronger associations were noted for mood items of the PRO-CTCAE only (with distress level, r = 0.55-0.6; with FACT-G, r = -0.54 to -0.6). PRO-CTCAE symptom interference scores had the strongest correlation with distress level (Pearson r = 0.46) and FACT-G total (Pearson r = -0.69). Correlations between PRO-CTCAE items and corresponding FACT-G (total and subscales) and distress levels reached statistical significance for all items (P Conclusion Evidence demonstrates validity of PRO-CTCAE in a heterogeneous US sample of patients undergoing cancer treatment on phase I trials, with small to moderate correlations with distress level for all PRO-CTCAE items and moderate correlations with quality of life as measured by FACT-G total.

PURPOSE: Omic-informed therapy is being used more frequently for patients with non–small-cell lung cancer (NSCLC) being treated on the basis of evidence-based decision-making. However, there is a lack of a standardized framework to evaluate those decisions and understand the association between omics-based management strategies and survival among patients. Therefore, we compared outcomes between patients with lung adenocarcinoma who received omics-driven targeted therapy versus patients who received standard therapeutic options. PATIENTS AND METHODS: This was a retrospective study of patients with advanced NSCLC adenocarcinoma (N = 798) at City of Hope who received genomic sequencing at the behest of their treating oncologists. A thoracic oncology registry was used as a clinicogenomic database to track patient outcomes. RESULTS: Of 798 individuals with advanced NSCLC (median age, 65 years [range, 22-99 years]; 60% white; 50% with a history of smoking), 662 patients (83%) had molecular testing and 439 (55%) received targeted therapy on the basis of the omic-data. A fast-and-frugal decision tree (FFT) model was developed to evaluate the impact of omics-based strategy on decision-making, progression-free survival (PFS), and overall survival (OS). We calculated that the overall positive predictive value of the entire FFT strategy for predicting decisions regarding the use of tyrosine kinase inhibitor–based targeted therapy was 88% and the negative predictive value was 96%. In an adjusted Cox regression analysis, there was a significant correlation with survival benefit with the FFT omics-driven therapeutic strategy for both PFS (hazard ratio [HR], 0.56; 95% CI, 0.42 to 0.74; P < .001) and OS (HR, 0.51; 95% CI, 0.36 to 0.71; P < .001) as compared with standard therapeutic options. CONCLUSION: Among patients with advanced NSCLC who received care in the academic oncology setting, omics-driven therapy decisions directly informed treatment in patients and was correlated with better OS and PFS.

OBJECTIVES: Immune checkpoint inhibitors (ICIs) have changed the landscape of lung cancer therapy. However significant proportions of patients have primary or acquired resistance to ICIs. Molecular characterization is critical for patient selection and overcoming resistance to checkpoint inhibitors. The purpose of this study is to investigate the molecular characteristics associated with ICIs outcomes in advanced non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: All advanced stage NSCLC patients at City of Hope who received ICIs (pembrolizumab, nivolumab, atezolizumab, and durvalumab) were identified retrospectively. Overall survival (OS, from the start of the ICIs), Pathology and information on genomic alterations (GAs) including next-generation sequencing (NGS) data, tumor mutation burden (TMB), and Programmed death-ligand 1 (PD-L1) levels were collected. Chi-square and Fisher’s exact test, Log-rank test were used for comparison of demographics, and survival curves respectively. Univariate and multivariate COX proportional hazards model was used for survival analysis. RESULTS: 346 NSCLC patients were identified. Univariate and multivariate analysis found the association of OS with PD-L1 level ≥50% (Hazard ratio [HR], 0.19; 95% confidence interval [CI], 0.06–0.59; P

Introduction JUNIPER compared the efficacy and safety of abemaciclib, a selective cyclin-dependent kinase 4 and 6 inhibitor, with erlotinib in patients with non-small cell lung cancer (NSCLC) harboring a Kirsten rat sarcoma (KRAS) mutation. Methods JUNIPER was a Phase III, multicenter, randomized, open-label trial of abemaciclib versus erlotinib in patients with stage IV NSCLC and a detectable mutation in codons 12 or 13 of the KRAS oncogene, who progressed after platinum-based chemotherapy and 1 additional therapy (could include immune checkpoint inhibitor therapy). Randomized patients (3:2) received either 200 mg abemaciclib twice daily or 150 mg erlotinib once daily with best supportive care until disease progression or unacceptable toxicity. the primary endpoint was overall survival (OS); secondary endpoints included overall response rate (ORR), progression-free survival (PFS), and safety. Results Between December 2014 and April 2017, 453 patients were randomly assigned to receive abemaciclib (N = 270) or erlotinib (N = 183). Median OS was 7.4 months (95% confidence interval [CI]: 6.5, 8.8) with abemaciclib and 7.8 months (95% CI: 6.4, 9.5) with erlotinib (hazard ratio [HR] = 0.968 [95% CI: 0.768, 1.219]; p = .77). Median PFS was 3.6 months (95% CI: 2.8, 3.8) with abemaciclib and 1.9 months (95% CI: 1.9, 2.0) with erlotinib (HR = 0.583 [95% CI: 0.470, 0.723]; p, Eli Lilly and CompanyEli Lilly, This study was funded by Eli Lilly and Company.

© 2018 Elsevier Inc. We evaluated the multitargeted Janus kinase/TRAF family member associated NF-κβ activator (TANK)-binding kinase 1 (TBK1) inhibitor momelotinib combined with trametinib in 21 patients with Kirsten rat sarcoma viral oncogene homolog-mutated non–small-cell lung cancer. The maximum tolerated dose of momelotinib was 150 mg twice daily (insufficient to achieve significant TBK1 inhibition). No patients achieved objective response and the combination did not improve on the activity of single-agent trametinib on the basis of historic data. Introduction: Specific treatment options are lacking for Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutated non–small-cell lung cancer (NSCLC) despite treatment advances in other mutation-driven subgroups. Patients and Methods: In this study we evaluated the multitargeted Janus kinase/TANK-binding kinase 1 (TBK1) inhibitor momelotinib combined with the mitogen/extracellular signal-related kinase (MEK)1/MEK2 inhibitor trametinib in patients with platinum-treated, refractory, metastatic, KRAS-mutated NSCLC. Dose escalations (3 + 3 design) were conducted with momelotinib in combination with trametinib 1.0 mg once daily, then with trametinib in combination with the maximum tolerated dose (MTD) of momelotinib. MTD was determined from dose-limiting toxicity (DLT) during patients' first 28-day cycle. Safety was the primary end point, and efficacy parameters, including disease control rate (DCR) at 8 weeks, were secondary end points. Results: Twenty-one patients were enrolled (median age: 68 years; 14 [66.7%] female). The MTD was momelotinib 150 mg twice daily in combination with trametinib 1.0 mg once daily. DLTs that determined the MTD were increased alanine aminotransferase and fatigue. The most common adverse events of any grade were nausea (n = 14 [66.7%]), diarrhea (n = 11 [52.4%]), and fatigue (n = 11 [52.4%]). The most common Grade ≥3 event was hypoxia (n = 3 [14.3%]). No patients achieved objective response. DCR at 8 weeks was 12 patients (57.1%) (90% confidence interval [CI], 37.2%-75.5%). Median progression-free and overall survival were 3.6 months (90% CI, 2.2-5.6 months) and 7.4 months (90% CI, 4.0-15.3 months), respectively. Maximum momelotinib plasma concentrations were reached 1 to 2 hours after dosing, but were insufficient to achieve significant TBK1 inhibition. Conclusion: The additional use of momelotinib with trametinib does not improve on the activity of single-agent trametinib in KRAS-mutated NSCLC on the basis of historic data.

The NCCN Guidelines for Small Cell Lung Cancer (SCLC) address all aspects of disease management. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for SCLC regarding immunotherapy, systemic therapy, and radiation therapy. For the 2018 update, new sections were added on "Signs and Symptoms of SCLC" and "Principles of Pathologic Review."

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. Preclinical data have demonstrated that RMC-4630 can shrink tumors carrying certain mutations in the RAS pathway such as KRASG12C, NF1LOF, and BRAFClass3. Longitudinal circulating tumor DNA (ctDNA) was isolated from blood using GuardantOMNI in 80 patients with relapsed/refractory solid tumors in the phase 1 dose-escalation trial of RMC-4630 (NCT03634982) to characterize and confirm RAS pathway mutations and to evaluate molecular responses in patients receiving RMC-4630 monotherapy. Safety, PK and efficacy findings from this study are reported in a separate abstract. 78 of 80 patients had baseline somatic mutations detected in plasma, of which 60 were either KRASG12X, NF1LOF, or BRAFClass3; 48 of these 60 patients also had on-treatment ctDNA assessments and these patients constitute the population reported here. 9 of 48 patients (19%) had KRASG12C detected at baseline, available scan results and a ctDNA sample after 4 weeks of receiving RMC-4630. A decrease in KRASG12C variant allele frequency (VAF) was detected in 5/9 patients (56%) with clearance in 1 patient with a partial response. Decrease in KRASG12C VAF was associated with change in tumor volume (PCC=0.85, p=0.008), preceding scan results by approximately 1 month, suggesting that change in KRASG12C VAF may be an early measure of drug activity or possibly response. 5 of 48 patients (10%) had NF1LOF detected at baseline. A decrease, or stability in NF1LOF VAF on treatment compared to baseline was detected in 4 (80% of all NF1LOF patients). The decrease in NF1LOF VAF was not associated with change in tumor volume and may represent effects of RMC-4630 on a subclone harboring NF1LOF. One patient had a detectable BRAFClass3 mutation at baseline, which decreased in VAF on treatment compared to baseline. Of the remaining patients there were 12 KRASG12D, 9 KRASG12V and other KRASG12X. The majority progressed with an increase in VAF of all mutations including KRASG12X, suggesting that the KRASG12X-containing clone is responsible for escape from single agent RMC-4630. In most instances the increase in KRASG12X VAF in blood preceded determination of clinical progression. Longitudinal assessment of ctDNA indicates that some patients with RAS-addicted tumors undergo a molecular response on treatment with the SHP2 inhibitor RMC-4630. Citation Format: Josie L. Hayes, Marianna Koczywas, Sai-Hong Ignatius Ou, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Ariel Chen, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Eric Haura. Confirmation of target inhibition and anti-tumor activity of the SHP2 inhibitor RMC-4630 via longitudinal analysis of ctDNA in a phase 1 clinical study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB054.

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node in the RAS signaling pathway. In preclinical models, SHP2 inhibition not only directly inhibited tumor growth through suppression of tumor-intrinsic RAS signaling, but also resulted in transformation of the tumor immune microenvironment, characterized by an increase in CD8+T cell infiltrates and selective depletion of pro-tumorigenic M2 macrophages. In this study, we evaluated pharmacodynamic biomarkers in blood and tumors from patients in the RMC-4630 phase I monotherapy clinical trial (NCT 03634982) by using flow cytometry and immunohistochemistry (IHC). Safety, PK and efficacy data are reported in a separate abstract. Longitudinal analysis of immune cell phenotyping in blood was conducted in 35 patients. There was a trend for lower pre-study monocytic myeloid-derived suppressor cell (mMDSC) to be associated with a better clinical outcome on RMC-4630 therapy. While the proportion of circulating T cell and B cell populations did not change, both blood mMDSC and total monocytes were significantly reduced during RMC-4630 administration. Furthermore, tumor volumes changes, and the proportion of patients with SD versus PD, positively correlated with the ratio of mMDSCs to total monocytes on RMC-4630 treatment. Inhibition of pERK was observed in a subset of patients. Three paired tumor biopsies from efficacy-evaluable patients, including 1 PR, 1 SD and 1 PD, were available for tumor microenvironment analysis by multiplexed-IHC assays. Increase in tumor infiltrating T cells in the tumors of one patient with a PR and another with SD was observed on RMC-4630 therapy. Inhibition of tumor PD-L1 expression and a decrease in M2 macrophages was also observed on treatment in the tumor biopsy of the PR patient. Collectively, the preliminary clinical biomarker data supports the preclinical observations that SHP2 inhibition with RMC-4630 modulates both innate and adaptive anti-tumor immunity. Citation Format: Ariel Yung-Chia Chen, Eric Haura, Jose Pacheco, Marianna Koczywas, Michael Gordon, Susanna Ulahannan, Howard A. Burris, Sai-Hong Ignatius Ou, Judy S. Wang, Jonathan W. Riess, Caroline McCoach, Anna Capasso, Elsa Quintana, Josie Hayes, Richa Dua, Bojena Bitman, Martha Guerra, Hongfang Wang, Xiaolin Wang, Pasi A. Janne. Modulation of innate and adaptive immunity in blood and tumor of patients receiving the SHP2 inhibitor RMC-4630 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB050.

RMC-4630 is a potent, selective, orally bioavailable allosteric inhibitor of SHP2, a central node regulating RAS signaling. Consistent with preclinical observations, initial data from a phase 1 trial of RMC-4630 showed anti-tumor activity in tumors harboring diverse mutations in the RAS pathway including KRASG12C, KRASG12D, NF1LOF, and BRAF Class 3. Here we report data from the dose-escalation phase of this study. A total of 104 patients were dosed across three schedules: daily dosing (n = 49) and two intermittent dosing schedules, twice weekly on D1D4 (n = 31) or D1D2 (n = 24). Based on PK and tolerability, the recommended phase 2 dose and schedule (RP2DS) was determined to be 200 mg D1D2, delivering a 400 mg weekly dose intensity. Of the 80 efficacy evaluable patients, there was 1 CR (NF1LOF uterine carcinosarcoma), 1 PR (KRASG12C NSCLC), and 1 unconfirmed PR (KRASG12D NSCLC). Tumor regressions were observed in another 11 patients (-2.4% to -27.1%). Disease control rate was 61% (23/38) in patients with KRASMUT NSCLC and 80% (12/15) in KRASG12C NSCLC specifically. The safety and tolerability profile of RMC-4630 were consistent with the mechanism of action and RAS pathway inhibition. The most frequent adverse events (AEs) were edema (48%), diarrhea (47%), fatigue (36%), anemia (34%), and thrombocytopenia (33%). Most AEs were grade 1 or 2 and were manageable. Intermittent dosing with either D1D2 or D1D4 weekly was generally better tolerated than daily dosing at an equivalent weekly dose intensity. Plasma concentrations of RMC-4630 after dosing with 200 mg D1D2 were above those predicted to be clinically active based on preclinical models. Cmax reached and often exceeded the ‘apoptotic threshold' defined as plasma exposures that were associated with induction of tumor regressions in preclinical models. Trough concentrations at the end of each week were at or around the EC50 for RAS pathway inhibition in tumor which is predicted to be sufficient to allow normal tissue recovery and therefore maintain tolerability with sustained dosing up to 6 months. Sequential analysis of pERK levels in peripheral blood cells and paired pre- and on-treatment tumor biopsies showed evidence of RAS pathway inhibition. Tumor and blood-based immune-oncology biomarkers showed preliminary evidence of anti-tumor immune activation. Longitudinal analysis of circulating tumor DNA indicated molecular responses consistent with anti-tumor activity in tumors carrying specific driver mutations in the RAS signaling pathway. An expansion cohort of patients with gynecologic cancers with NF1LOF is underway with monotherapy at the RP2DS. RMC-4630 continues to be evaluated in combination with the MEK inhibitor cobimetinib (Cotellic), the KRASG12C(OFF) inhibitor sotorasib, the PD1 inhibitor pembrolizumab (Keytruda) and the EGFR inhibitor osimertinib (Tagrisso). Additional combination studies are also planned. Citation Format: Marianna Koczywas, Eric Haura, Pasi A. Janne, Jose M. Pacheco, Susanna Ulahannan, Judy S. Wang, Howard A. Burris, Jonathan W. Riess, Caroline McCoach, Michael S. Gordon, Anna Capasso, Richa Dua, Zhengping Wang, Ariel Chen, Josie Hayes, Luxi Yang, Serena Masciari, Xiaolin Wang, S Ignatius Ou. Anti-tumor activity and tolerability of the SHP2 inhibitor RMC-4630 as a single agent in patients with RAS-addicted solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB001.

SummaryTumor heterogeneity and cisplatin resistance are a major cause of tumor relapse and poor survival. Here we show that in lung adenocarcinoma (LUAD), paxillin (PXN) and integrin beta 4 (ITGB4) are associated with tumor progression, and cisplatin resistance. Silencing PXN and ITGB4 render cisplatin tolerant cells sensitive, and immunologically neutralizing ITGB4 improves sensitivity. The N-terminal half of PXN is intrinsically disordered and interacts with ITGB4 to regulate expression of USP1 and VDAC1 which are required for maintaining genomic stability and mitochondrial function in LUAD. By virtual screening an FDA-approved compound library, we identified compounds that interact with PXNin silicoand attenuate cisplatin resistance in LUAD cells. RNAseq analysis identified a double negative feedback loop between ITGB4 and microRNA miR-1-3p, suggesting that bistability could lead to stochastic switching between cisplatin-sensitive and resistant states in these cells. The data highlight an alternate, non-genetic, mechanism underlying chemoresistance in lung cancer.

Background Oral metronomic chemotherapy, which has low toxicity, has demonstrated promising anti-tumor and anti-angiogenic properties that may lead to prolonged progression-free survival and improved response rates in patients with recurrent epithelial ovarian cancer (EOC). These effects may be enhanced by the co-administration of anti-angiogenic agents. Methods We conducted a randomized phase II clinical trial to evaluate the therapeutic benefit of oral metronomic cyclophosphamide (CTX) alone and with the anti-angiogenic drug celecoxib in patients with gynecological malignancies. 52 patients were randomly assigned to two treatments arms: 50 mg oral CTX daily alone (Arm A) or with 400 mg celecoxib twice daily (Arm B). The primary endpoint was response rate. Secondary endpoints included toxicity, time to treatment failure, and overall survival. Results In Arm A (n = 26), 3 patients (12%) had stable disease >6 months and 1 (4%) had a partial response. In Arm B, 5 (19%) had stable disease >6 months and 1 patient (4%) had a partial response. There were no significant between-group differences in overall survival (9.69 months [95% CI 3.84–13.18] vs. 12.55 months [6.67–17.61]) or in median time to treatment failure (1.84 months [1.68–2.76] vs. 1.92 months [1.64–5.22]). The most common adverse events were nausea, vomiting, and abdominal pain. Conclusions Oral metronomic CTX has activity with no major toxicities in heavily pretreated recurrent gynecological cancers and may be considered in patients with indolent disease. We did not observe any additional benefit of celecoxib treatment, though this may be due to small sample sizes.

Introduction: Mesenchymal epidermal transition and vascular endothelial growth factor pathways are important in mediating non-small cell lung cancer (NSCLC) tumorigenesis and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance. We hypothesized that treatment with cabozantinib plus erlotinib in EGFR mutation-positive NSCLC following progression on EGFR TKI therapy may allow tumors to overcome this resistance or restore sensitivity to therapy regardless of T790M status. Methods: Patients with advanced NSCLC, known EGFR mutation and progressive disease on an EGFR TKI immediately prior to enrollment without intervening therapy were enrolled. Patients received erlotinib 150 mg and cabozantinib 40 mg daily. The primary endpoint was evaluation of efficacy by objective response rate. Secondary endpoints included assessment of progression free survival (PFS), overall survival, change in tumor growth rate, safety and toxicity, and the evaluation of specific EGFR mutations and MET amplification in pre-treatment tissue and plasma. Results: Thirty-seven patients were enrolled at 4 centers. Four patients had partial response (10.8%) and 21 had stable disease (59.5%). A greater than 30% increase in tumor doubling time was observed in 79% of assessable patients (27/34). Median PFS was 3.6 months for all patients. Diarrhea (32%) was the most common grade 3 adverse event; 3 patients had asymptomatic grade 4 elevation of amylase and lipase. Conclusions: Combination erlotinib and cabozantinib demonstrates activity in a highly pretreated population of patients with EGFR mutation and progression on EGFR TKI. Further elucidation of beneficial patient subsets is warranted. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT01866410.

In lung cancer, outcome measurement has been mostly limited to survival. Proper assessment of the value of lung cancer treatments, and the performance of institutions delivering care, requires more comprehensive measurement of standardised outcomes. The International Consortium for Health Outcomes Measurement convened an international, multidisciplinary working group of patient representatives, medical oncologists, surgeons, radiation oncologists, pulmonologists, palliative care specialists, registry experts and specialist nurses to review existing data and practices. Using a modified Delphi method, the group developed a consensus recommendation (“the set”) on the outcomes most essential to track for patients with lung cancer, along with baseline demographic, clinical and tumour characteristics (case-mix variables) for risk adjustment. The set applies to patients diagnosed with nonsmall cell lung cancer and small cell lung cancer. Our working group recommends the collection of the following outcomes: survival, complications during or within 6 months of treatment and patient-reported domains of health-related quality of life including pain, fatigue, cough and dyspnoea. Case-mix variables were defined to improve interpretation of comparisons. We defined an international consensus recommendation of the most important outcomes for lung cancer patients, along with relevant case-mix variables, and are working to support adoption and reporting of these measures globally., ICHOM Lung Cancer Standard Set of patient-centred outcomes: aligning global efforts to improve lung cancer care http://ow.ly/bFDR300EhY7