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MET dysregulation promoting tumorigenesis in non-small cell lung cancer (NSCLC) is associated with worse outcomes following chemotherapy as compared to non-driver mutated NSCLC and occurs either through mutations causing MET exon 14 skipping (METex14) or gene amplification and overexpression that result in enhanced receptor signaling. Capmatinib is the first FDA-approved targeted therapy for NSCLC with METex14 skipping mutations, approved in 2020. FoundationOne® CDx, a comprehensive genomic profiling test for solid tumors, was concurrently approved as a companion diagnostic for capmatinib use. The GEOMETRY mono-1 phase II trial of capmatinib monotherapy demonstrated an overall response rate (ORR) of 68% in treatment naïve (n=28) and 41% in pre-treated (n=69) METex14 skipping advanced NSCLC; in MET amplified advanced NSCLC (gene copy number ≥ 10) ORRs of 40% in treatment naïve and 29% in pre-treated disease was seen. This review outlines the clinical data supporting capmatinib approval in the treatment of NSCLC and FoundationOne® CDx approval as a companion diagnostic. We detail the practical clinical administration of capmatinib, including dosing and toxicity management, compare capmatinib to other approved and investigational MET-targeted therapies, discuss limitations of capmatinib, and highlight ongoing trials of capmatinib in combinatorial approaches.

Aims Adjuvant chemotherapy has been shown to improve survival in patients with completely resected early‐stage non‐small cell lung cancer (NSCLC). This study evaluated real‐world relapse rates and healthcare resource utilization in patients with stage II–IIIB NSCLC receiving adjuvant therapy in a community oncology setting after complete resection. Patients and Methods The study included patients with stage II–IIIB NSCLC and complete resection receiving any adjuvant therapy during 06/2008–04/2017 at US Oncology Network clinics, with follow‐up through 04/2019. Primary endpoints were rate of relapse, time to relapse (TTR), disease‐free survival (DFS), overall survival (OS), and monthly emergency department (ED) visits and hospitalizations before and after relapse. Results The study identified 456 patients; median age was 66 years, 50% were male. In patients with relapse (45.2%), median follow‐up was 31.7 months and median TTR was 13.7 months. Median DFS in the overall population was 42.9 months. Median OS was 82.4 months in the overall population and shorter in patients with relapse than without relapse (41.6 months vs. not reached, p, This retrospective study evaluated real‐world relapse rates and healthcare resource utilization in patients with stage II–IIIB non‐small cell lung cancer receiving adjuvant therapy after complete resection in community‐based oncology practices. Patients had high relapse rates, reduced survival, and significantly increased healthcare resource use when relapse occurred.

Expedited reporting of unexpected serious adverse reactions that occur during clinical trials conducted under an IND is a critical component of the clinical trial process designed to protect patients by identifying potential safety issues with new agents. However, in recent years, the US FDA has presented extensive data about the problem of uninformative IND safety reporting. Despite published guidance documents aimed at clarifying requirements for submission of IND safety reports for individual events, there continues to be significant over-reporting of these events by many sponsors. This leads to excessive burden for the sponsors, the investigators who conduct clinical trials, and the FDA reviewers, who must evaluate each individual report submitted by the sponsor. This trend has the potential to endanger patients by obscuring true safety signals. To address this problem, LUNGevity Foundation empaneled a multi-sector working group of its Scientific and Clinical Research Roundtable (SCRT) charged with identifying ways to reduce unnecessary distribution of serious adverse events (SAEs) reports. This paper outlines the working group's activities, including a brief list of serious adverse events "anticipated" to occur within the lung cancer population that are either related to the underlying disease or condition being studied, concomitant or background therapy, or events associated with a demographic parameter such as age. These "anticipated" events, while required to be reported by investigators to sponsors, in general, should not then be individually reported by sponsors to FDA and to individual investigators in an IND safety report because these events require aggregate analysis across the development program to determine if they occur more frequently in treated versus untreated patients. This paper also includes discussion of how the use of background threshold values, generated from real-world data, could serve as one potential tool to guide sponsors in making causality assessments. If sponsors and other key stakeholders within the clinical research ecosystem embrace this type of approach and refrain from reporting "anticipated" events as single IND safety reports to the FDA staff and to each participating investigator, it could significantly reduce the amount of unnecessary reporting and serve as a model for other disease areas.

BACKGROUND: Sotorasib showed anticancer activity in patients with KRAS p.G12C–mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non–small-cell lung cancer (NSCLC). METHODS: In a single-group, phase 2 trial, we investigated the activity of sotorasib, administered orally at a dose of 960 mg once daily, in patients with KRAS p.G12C–mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: Among the 126 enrolled patients, the majority (81.0%) had previously received both platinum-based chemotherapy and inhibitors of programmed death 1 (PD-1) or programmed death ligand 1 (PD-L1). According to central review, 124 patients had measurable disease at baseline and were evaluated for response. An objective response was observed in 46 patients (37.1%; 95% confidence interval [CI], 28.6 to 46.2), including in 4 (3.2%) who had a complete response and in 42 (33.9%) who had a partial response. The median duration of response was 11.1 months (95% CI, 6.9 to could not be evaluated). Disease control occurred in 100 patients (80.6%; 95% CI, 72.6 to 87.2). The median progression-free survival was 6.8 months (95% CI, 5.1 to 8.2), and the median overall survival was 12.5 months (95% CI, 10.0 to could not be evaluated). Treatment-related adverse events occurred in 88 of 126 patients (69.8%), including grade 3 events in 25 patients (19.8%) and a grade 4 event in 1 (0.8%). Responses were observed in subgroups defined according to PD-L1 expression, tumor mutational burden, and co-occurring mutations in STK11, KEAP1, or TP53. CONCLUSIONS: In this phase 2 trial, sotorasib therapy led to a durable clinical benefit without new safety signals in patients with previously treated KRAS p.G12C–mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.)

Purpose To increase awareness, outline strategies, and offer guidance on the recommended management of immune-related adverse events in patients treated with immune checkpoint inhibitor (ICPi) therapy. Methods A multidisciplinary, multi-organizational panel of experts in medical oncology, dermatology, gastroenterology, rheumatology, pulmonology, endocrinology, urology, neurology, hematology, emergency medicine, nursing, trialist, and advocacy was convened to develop the clinical practice guideline. Guideline development involved a systematic review of the literature and an informal consensus process. The systematic review focused on guidelines, systematic reviews and meta-analyses, randomized controlled trials, and case series published from 2000 through 2017. Results The systematic review identified 204 eligible publications. Much of the evidence consisted of systematic reviews of observational data, consensus guidelines, case series, and case reports. Due to the paucity of high-quality evidence on management of immune-related adverse events, recommendations are based on expert consensus. Recommendations Recommendations for specific organ system–based toxicity diagnosis and management are presented. While management varies according to organ system affected, in general, ICPi therapy should be continued with close monitoring for grade 1 toxicities, with the exception of some neurologic, hematologic, and cardiac toxicities. ICPi therapy may be suspended for most grade 2 toxicities, with consideration of resuming when symptoms revert to grade 1 or less. Corticosteroids may be administered. Grade 3 toxicities generally warrant suspension of ICPis and the initiation of high-dose corticosteroids (prednisone 1 to 2 mg/kg/d or methylprednisolone 1 to 2 mg/kg/d). Corticosteroids should be tapered over the course of at least 4 to 6 weeks. Some refractory cases may require infliximab or other immunosuppressive therapy. In general, permanent discontinuation of ICPis is recommended with grade 4 toxicities, with the exception of endocrinopathies that have been controlled by hormone replacement. Additional information is available at www.asco.org/supportive-care-guidelines and www.asco.org/guidelineswiki .

Background: Necitumumab is a second-generation, recombinant, human immunoglobulin G1 EGFR antibody. In this study, we aimed to compare treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous non-small-cell lung cancer. Methods: We did this open-label, randomised phase 3 study at 184 investigative sites in 26 countries. Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous non-small-cell lung cancer, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion. Enrolled patients were randomly assigned centrally 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomisation scheme (block size of four) by a telephone-based interactive voice response system or interactive web response system. Chemotherapy was gemcitabine 1250 mg/m2 administered intravenously over 30 min on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m2 administered intravenously over 120 min on day 1 of a 3-week cycle. Necitumumab 800 mg, administered intravenously over a minimum of 50 min on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side-effects occurred. Randomisation was stratified by ECOG performance status and geographical region. Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash-a class effect of EGFR antibodies-that would have unmasked most patients and investigators to treatment. The primary endpoint was overall survival, analysed by intention to treat. We report the final clinical analysis. This study is registered with ClinicalTrials.gov, number NCT00981058. Findings: Between Jan 7, 2010, and Feb 22, 2012, we enrolled 1093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n=545) or gemcitabine and cisplatin (n=548). Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median 11·5 months [95% CI 10·4-12·6]) vs 9·9 months [8·9-11·1]; stratified hazard ratio 0·84 [95% CI 0·74-0·96; p=0·01]). In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least one grade 3 or worse adverse event was higher (388 [72%] of 538 patients) than in the gemcitabine and cisplatin group (333 [62%] of 541), as was the incidence of serious adverse events (257 [48%] of 538 patients vs 203 [38%] of 541). More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3-4 hypomagnesaemia (47 [9%] of 538 patients in the necitumumab plus gemcitabine and cisplatin group vs six [1%] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4%] vs one [

Historically, cancer has been studied, and therapeutic agents have been evaluated based on organ site, clinical staging, and histology. The science of molecular profiling has expanded our knowledge of cancer at the cellular and molecular level such that numerous subtypes are being described based on biomarker expression and genetic mutations rather than traditional classifications of the disease. Drug development has experienced a concomitant revolution in response to this knowledge with many new targeted therapeutic agents becoming available, and this has necessitated an evolution in clinical trial design. The traditional, large phase II and phase III adjuvant trial models need to be replaced with smaller, shorter, and more focused trials. These trials need to be more efficient and adaptive in order to quickly assess the efficacy of new agents and develop new companion diagnostics. We are now seeing a substantial shift from the traditional multiphase trial model to an increase in phase II adjuvant and neoadjuvant trials in earlier-stage disease incorporating surrogate endpoints for long-term survival to assess efficacy of therapeutic agents in shorter time frames. New trial designs have emerged with capabilities to assess more efficiently multiple disease types, multiple molecular subtypes, and multiple agents simultaneously, and regulatory agencies have responded by outlining new pathways for accelerated drug approval that can help bring effective targeted therapeutic agents to the clinic more quickly for patients in need.

Background: BION-1301 is a first-in-class humanized antibody targeting a proliferation-inducing ligand (APRIL) that is currently being evaluated for the treatment of relapsed multiple myeloma (MM). APRIL binds to BCMA, thereby driving proliferation and survival of human MM cells. APRIL can also bind to TACI to promote MM cell survival (Tai et al., 2018). APRIL induces resistance to lenalidomide, bortezomib, and other standard-of-care drugs (Tai et al., 2016). BION-1301 blocks APRIL from binding to BCMA and TACI, leading to inhibition of MM cell proliferation and survival, and enhancement of MM sensitivity to other treatments (Tai et al., 2016). The objective of this Phase I/II first-in-human study is to determine the recommended phase 2 dose (RP2D) of BION-1301 by evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and clinical activity of BION-1301 administered as an intravenous (IV) infusion alone or with low dose dexamethasone (DEX). Trial Design: This is an open-label, multicenter, first-in-human, 3+3 Phase I/II clinical study for subjects with relapsed or refractory MM whose disease has progressed after at least 3 prior systemic therapies. Phase I (Dose Escalation) dosing started as a 50 mg BION-1301 IV infusion. Dose escalation is to proceed in successive cohorts of subjects until the RP2D is identified. The maximum administered dose will not exceed 2700 mg. During initial dose escalation, the dosing interval is once every two weeks (Q2W) as a 2-hour infusion (3 hours for doses ≥2000 mg). Additional cohorts will be enrolled to evaluate weekly dosing for up to 8 weeks, followed by Q2W dosing with the same or a lower dose. Once an RP2D and schedule are identified, subjects will be randomized in the Phase II (Dose Confirmation) portion of the study to receive open-label BION-1301 alone or BION-1301 with low dose DEX at the assigned dose and schedule until disease progression or unacceptable toxicity. Phase I endpoints include incidence of dose-limiting toxicities, number and grade of treatment-emergent adverse events, PK/PD parameters, and relative reduction in serum and 24-hour urine M-protein levels defined as the maximum reduction from baseline; Phase II endpoints include objective response rate, progression-free survival, and overall survival. This study is designed to provide the RP2D of BION-1301 based on the totality of safety, tolerability, PK/PD, and clinical response data, and will inform future development of clinical studies for patients with MM. Citation Format: Parameswaran Hari, Anastasios Raptis, James Berenson, Alexander Spira, Ajay Nooka, Maria Chaudhry, Nitya Nair, Hamid Namini, Jackie Walling, Deb Chapman, William Bensinger. Phase I/II safety and pharmacokinetics of BION-1301 targeting APRIL, a proliferation-inducing ligand, in adults with relapsed or refractory multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT107.

Background: There is currently no standard treatment for patients (pts) with platinum refractory, recurrent metastatic (R/M) NPC. Spartalizumab, a humanized anti-PD-1 IgG4 mAb, blocks interaction with PD-L1 and PD-L2. This is the first randomized phase II study to evaluate efficacy and safety of spartalizumab vs CT in NPC. Methods: This phase II open-label study recruited pts with non-keratinizing locally advanced R/M NPC who progressed on/after platinum-based CT and received up to 2 systemic therapies. Pts were randomized (2:1) to receive spartalizumab or CT, per investigator’s choice. Spartalizumab was dosed 400 mg every 4 weeks intravenously. Pts in CT arm could cross over to receive spartalizumab if progression confirmed by RECIST v1.1, based on independent central review. Primary endpoint was progression free survival (PFS); secondary endpoints were overall response rate (ORR), based on central review by RECIST v1.1, duration of response (DOR), overall survival, safety and pharmacokinetics. Correlation between efficacy and expression of immunologic biomarkers and immune-related genes was also studied. Results: In total, 76 pts in spartalizumab arm and 37 pts in CT arm were randomized (median age 51 years, ECOG performance status 0-2). As of Jan 31, 2018, 18/76 (23.7%) spartalizumab-treated pts, 8/37 (21.6%) CT-treated pts and 4/20 (20.0%) pts in crossover group were ongoing. Discontinuation rates were similar between arms, mainly due to progressive disease in spartalizumab arm (67.0%) and CT arm (68.0%). Median PFS (95% CI) was 1.9 mo (1.8;3.5) in spartalizumab arm vs 6.6 mo (3.7;9.2) in CT arm; primary endpoint was not met, with hazard ratio of 1.53 (95% CI 1.02;2.27). ORR (95% CI) was 18.4% (10.5;29.0) vs 32.4% (18.0;49.8) in spartalizumab vs CT arm, respectively, and 5.0% (0.1;24.9) in crossover group. ORR for pts treated with monotherapy CT was 19.2% (5/26) and for pts treated with CT doublet/triplet was 63.3% (7/11). The Kaplan-Meier estimate of DOR rate at 12 mo in responding spartalizumab-treated pts was 61.0% (95% CI 20.2;85.8). In CT arm, 11/12 pts either progressed or discontinued at 12 mo; at data cut-off, 1 pt remained responding for 3.61 mo. Safety profile of spartalizumab was largely consistent with results obtained from other spartalizumab single-agent studies. Overall, treatment-related grade 3/4 adverse events were reported in 18.4% of spartalizumab-treated pts and 40.5% of CT-treated pts. No treatment-related deaths occurred. RNA sequencing analyses of tumors revealed a correlation between response to spartalizumab and IFN-γ signature, TIM3 and LAG3 gene expression; this correlation was not observed in pts treated with CT. Conclusions: Spartalizumab was well tolerated and despite the study not reaching its primary endpoint, long-lasting tumor responses were observed in a subset of spartalizumab-treated pts with NPC. Biomarker analysis is ongoing. Citation Format: Darren Wan-Teck Lim, Hung-Ming Wang, Shau-Hsuan Li, Roger Ngan, Arunee Dechaphunkul, Li Zhang, Chia Jui Yen, Po Chung Chan, Somvilai Chakrabandhu, Brigette Ma, Suebpong Tanasanvimon, Victor Lee, Pei-Jen Lou, Zujun Li, Alexander Spira, Ammar Sukari, Joël Guigay, Steven McCune, Yongjian Sun, Sebastian Szpakowski, Yao Yao, Xueqiang Fan, Luigi Manenti, Caroline Even. Phase II study of spartalizumab (PDR001) vs chemotherapy (CT) in patients with recurrent/metastatic nasopharyngeal cancer (NPC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT150.

Outcomes are poor for patients with previously treated, advanced or metastatic non-small-cell lung cancer (NSCLC). The anti-programmed death ligand 1 (PD-L1) antibody atezolizumab is clinically active against cancer, including NSCLC, especially cancers expressing PD-L1 on tumour cells, tumour-infiltrating immune cells, or both. We assessed efficacy and safety of atezolizumab versus docetaxel in previously treated NSCLC, analysed by PD-L1 expression levels on tumour cells and tumour-infiltrating immune cells and in the intention-to-treat population.In this open-label, phase 2 randomised controlled trial, patients with NSCLC who progressed on post-platinum chemotherapy were recruited in 61 academic medical centres and community oncology practices across 13 countries in Europe and North America. Key inclusion criteria were Eastern Cooperative Oncology Group performance status 0 or 1, measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST v1.1), and adequate haematological and end-organ function. Patients were stratified by PD-L1 tumour-infiltrating immune cell status, histology, and previous lines of therapy, and randomly assigned (1:1) by permuted block randomisation (with a block size of four) using an interactive voice or web system to receive intravenous atezolizumab 1200 mg or docetaxel 75 mg/m(2) once every 3 weeks. Baseline PD-L1 expression was scored by immunohistochemistry in tumour cells (as percentage of PD-L1-expressing tumour cells TC3≥50%, TC2≥5% and50%, TC1≥1% and5%, and TC01%) and tumour-infiltrating immune cells (as percentage of tumour area: IC3≥10%, IC2≥5% and10%, IC1≥1% and5%, and IC01%). The primary endpoint was overall survival in the intention-to-treat population and PD-L1 subgroups at 173 deaths. Biomarkers were assessed in an exploratory analysis. We assessed safety in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT01903993.Patients were enrolled between Aug 5, 2013, and March 31, 2014. 144 patients were randomly allocated to the atezolizumab group, and 143 to the docetaxel group. 142 patients received at least one dose of atezolizumab and 135 received docetaxel. Overall survival in the intention-to-treat population was 12·6 months (95% CI 9·7-16·4) for atezolizumab versus 9·7 months (8·6-12·0) for docetaxel (hazard ratio [HR] 0·73 [95% CI 0·53-0·99]; p=0·04). Increasing improvement in overall survival was associated with increasing PD-L1 expression (TC3 or IC3 HR 0·49 [0·22-1·07; p=0·068], TC2/3 or IC2/3 HR 0·54 [0·33-0·89; p=0·014], TC1/2/3 or IC1/2/3 HR 0·59 [0·40-0·85; p=0·005], TC0 and IC0 HR 1·04 [0·62-1·75; p=0·871]). In our exploratory analysis, patients with pre-existing immunity, defined by high T-effector-interferon-γ-associated gene expression, had improved overall survival with atezolizumab. 11 (8%) patients in the atezolizumab group discontinued because of adverse events versus 30 (22%) patients in the docetaxel group. 16 (11%) patients in the atezolizumab group versus 52 (39%) patients in the docetaxel group had treatment-related grade 3-4 adverse events, and one (1%) patient in the atezolizumab group versus three (2%) patients in the docetaxel group died from a treatment-related adverse event.Atezolizumab significantly improved survival compared with docetaxel in patients with previously treated NSCLC. Improvement correlated with PD-L1 immunohistochemistry expression on tumour cells and tumour-infiltrating immune cells, suggesting that PD-L1 expression is predictive for atezolizumab benefit. Atezolizumab was well tolerated, with a safety profile distinct from chemotherapy.F Hoffmann-La Roche/Genentech Inc.

The accelerating science of molecular profiling has necessitated a rapid evolution in clinical trial design. Traditional clinical research begins with Phase I studies to characterize dose-limiting toxicities and defines maximally tolerated doses of drugs in small numbers of patients. Traditional Phase II studies test these drugs at the doses discovered during Phase I drug development in small numbers of patients evaluating efficacy and safety. Phase III studies test new therapies to demonstrate improved activity or improved tolerability compared with a standard of care regimen or a placebo. The rapid advances in the understanding of signal transduction, and the identification of new potential diagnostic and therapeutic targets, now require the design and implementation of molecular clinical trials that are very different than traditional Phase I, II, or III trials. The main differentiating factor is the use of a molecular end point to stratify a subset of patients to receive a specific treatment regimen. This chapter focuses on the issues surrounding (a) the definition of clinical end points and the assessment of tumor response; (b) clinical trial design models to define the targeted pathway; and (c) the need for appropriate biomarkers to monitor the response.