Aaron Lisberg

Previous radiotherapy and the clinical activity and toxicity of pembrolizumab in the treatment of non-small-cell lung cancer: a secondary analysis of the KEYNOTE-001 phase 1 trial

BACKGROUNDnPreclinical studies have found radiotherapy enhances antitumour immune responses. We aimed to assess disease control and pulmonary toxicity in patients who previously received radiotherapy for non-small-cell lung cancer (NSCLC) before receiving pembrolizumab.nnnMETHODSnWe assessed patients with advanced NSCLC treated on the phase 1 KEYNOTE-001 trial at a single institution (University of California, Los Angeles, CA, USA). Patients were aged 18 years or older, had an Eastern Cooperative Oncology Group performance status of 1 or less, had adequate organ function, and no history of pneumonitis. Patients received pembrolizumab at a dose of either 2 mg/kg of bodyweight or 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks, until disease progression, unacceptable toxicity, or other protocol-defined reasons for discontinuation. Disease response and pulmonary toxicity were prospectively assessed by Immune-related Response Criteria and Common Terminology Criteria for Adverse Events version 4.0. The primary objective of the KEYNOTE-001 trial was to assess the safety, side-effect profile, and antitumour activity of pembrolizumab. For our secondary analysis, patients were divided into subgroups to compare patients who previously received radiotherapy with patients who had not. Our primary objective was to determine whether previous radiotherapy affected progression-free survival, overall survival, and pulmonary toxicity in the intention-to-treat population. The KEYNOTE-001 trial was registered with ClinicalTrials.gov, number NCT01295827.nnnFINDINGSnBetween May 22, 2012, and July 11, 2014, 98 patients were enrolled and received their first cycle of pembrolizumab. One patient was lost to follow-up. 42 (43%) of 97 patients had previously received any radiotherapy for the treatment of NSCLC before the first cycle of pembrolizumab. 38 (39%) of 97 patients received extracranial radiotherapy and 24 (25%) of 97 patients received thoracic radiotherapy. Median follow-up for surviving patients was 32·5 months (IQR 29·8-34·1). Progression-free survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (hazard ratio [HR] 0·56 [95% CI 0·34-0·91], p=0·019; median progression-free survival 4·4 months [95% CI 2·1-8·6] vs 2·1 months [1·6-2·3]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (HR 0·50 [0·30-0·84], p=0·0084; median progression-free survival 6·3 months [95% CI 2·1-10·4] vs 2·0 months [1·8-2·1]). Overall survival with pembrolizumab was significantly longer in patients who previously received any radiotherapy than in patients without previous radiotherapy (HR 0·58 [95% CI 0·36-0·94], p=0·026; median overall survival 10·7 months [95% CI 6·5-18·9] vs 5·3 months [2·7-7·7]) and for patients who previously received extracranial radiotherapy compared with those without previous extracranial radiotherapy (0·59 [95% CI 0·36-0·96], p=0·034; median overall survival 11·6 months [95% CI 6·5-20·5] vs 5·3 months [3·0-8·5]). 15 (63%) of 24 patients who had previously received thoracic radiotherapy had any recorded pulmonary toxicity versus 29 (40%) of 73 patients with no previous thoracic radiotherapy. Three (13%) patients with previous thoracic radiotherapy had treatment-related pulmonary toxicity compared with one (1%) of those without; frequency of grade 3 or worse treatment-related pulmonary toxicities was similar (one patient in each group).nnnINTERPRETATIONnOur data suggest that previous treatment with radiotherapy in patients with advanced NSCLC results in longer progression-free survival and overall survival with pembrolizumab treatment than that seen in patients who did not have previous radiotherapy, with an acceptable safety profile. Further clinical trials investigating this combination are needed to determine the optimal treatment strategy for patients with advanced NSCLC.nnnFUNDINGnUS National Institutes of Health.

The Value of PD-L1 Testing in Non–Small-Cell Lung Cancer

Overview Two agents, nivolumab and pembrolizumab, directed against the programmed cell death 1 (PD-1) immune checkpoint have been approved by the US Food and Drug Administration for treatment of previously treated non–small-cell lung cancer (NSCLC).1-3 Nivolumab is approved with no requirement for programmed cell death 1 ligand 1 (PD-L1) expression, whereas pembrolizumab is approved only in patients whose tumors express PD-L1. As a result of these differing approvals, substantial debate has arisen regarding the appropriate role of PD-L1 testing to select patients for therapy.

Treatment-Related Adverse Events Predict Improved Clinical Outcome in NSCLC Patients on KEYNOTE-001 at a Single Center

A retrospective analysis of non–small cell lung carcinoma patients treated with pembrolizumab found that treatment-related adverse events predicted improved clinical outcome. This observation could identify the patients most likely to benefit from anti–PD-1 therapy. We retrospectively analyzed non–small cell lung cancer (NSCLC) patients from a single center treated with pembrolizumab on the KEYNOTE-001 trial and evaluated the association between treatment-related adverse events (trAEs) and clinical outcomes. Investigators reported AEs on trial and graded them according to Common Terminology Criteria for Adverse Events v4.0, labeling them as unlikely, possibly, or probably treatment-related. AEs labeled as possibly/probably related were considered trAEs for this analysis. The relationship between the incidence of a trAE and clinical outcomes was evaluated. Ninety-seven NSCLC patients treated on KEYNOTE-001 at the University of California, Los Angeles were evaluated. Ten percent (85/826) of AEs were trAEs, occurring in 40% (39/97) of patients. The most frequent trAEs were rash (21% patients), fatigue (6% patients), and hypothyroidism (6% patients). The 39 patients that experienced a trAE had increased objective response rate (ORR, 38.5%), progression-free survival (PFS: median, 248 days), and overall survival (OS: median, 493 days), compared with the 58 patients that did not (ORR: 8.9%, PFS: median 60 days, OS: median 144.5 days). The observed association between trAEs and improved clinical outcome persisted when using Cox proportional hazards regression models to assess the confounding effect of covariates and mitigate guarantee-time bias. The association also remained when data were substratified by grade, degree of association, and treatment-related select AE designation. This single-center analysis revealed that trAEs predicted for improved clinical outcome with pembrolizumab, and when controlling for guarantee-time bias and plausible confounders, this association remained. This observed relationship adds to our understanding of anti–PD-1 therapy and could aid clinicians in identifying patients most likely to benefit from therapy. Cancer Immunol Res; 6(3); 288–94. ©2018 AACR.

A Phase II Study of Pembrolizumab in EGFR-Mutant, PD-L1+, Tyrosine Kinase Inhibitor Naïve Patients With Advanced NSCLC

Background: Despite the significant antitumor activity of pembrolizumab in NSCLC, clinical benefit has been less frequently observed in patients whose tumors harbor EGFR mutations compared to EGFR wild‐type patients. Our single‐center experience on the KEYNOTE‐001 trial suggested that pembrolizumab‐treated EGFR‐mutant patients, who were tyrosine kinase inhibitor (TKI) naïve, had superior clinical outcomes to those previously treated with a TKI. As TKI naïve EGFR‐mutants have generally been excluded from pembrolizumab studies, data to guide treatment decisions in this patient population is lacking, particularly in patients with programmed death ligand 1 (PD‐L1) expression ≥50%. Methods: We conducted a phase II trial (NCT02879994) of pembrolizumab in TKI naive patients with EGFR mutation–positive, advanced NSCLC and PD‐L1–positive (≥1%, 22C3 antibody) tumors. Pembrolizumab was administered 200 mg every 3 weeks. The primary endpoint was objective response rate. Secondary endpoints included safety of pembrolizumab, additional pembrolizumab efficacy endpoints, and efficacy and safety of an EGFR TKI after pembrolizumab. Results: Enrollment was ceased due to lack of efficacy after 11 of 25 planned patients were treated. Eighty‐two percent of trial patients were treatment naïve, 64% had sensitizing EGFR mutations, and 73% had PD‐L1 expression ≥50%. Only 1 patient had an objective response (9%), but repeat analysis of this patient’s tumor definitively showed the original report of an EGFR mutation to be erroneous. Observed treatment‐related adverse events were similar to prior experience with pembrolizumab, but two deaths within 6 months of enrollment, including one attributed to pneumonitis, were of concern. Conclusions: Pembrolizumab’s lack of efficacy in TKI naïve, PD‐L1+, EGFR‐mutant patients with advanced NSCLC, including those with PD‐L1 expression ≥50%, suggests that it is not an appropriate therapeutic choice in this setting.

Non–small cell lung cancer clinical trials requiring biopsies with biomarker-specific results for enrollment provide unique challenges

Clinical trials in lung cancer increasingly require patients to provide fresh tumor tissue as a prerequisite to enrollment. The effects of this requirement on enrollment rates, enrollment durations, and patient selection have not been fully elucidated.

High-profile studies frequently and repetitively present data on the same patients, particularly in immunotherapy studies

BackgroundnTraditionally, study results have been presented as abstracts at major scientific meetings at the conclusion of the analysis. Recently, presentations of studies in progress and updates to previously presented data have been allowed at major meetings. The frequency and implications of a single study being presented multiple times, particularly in high profile oral presentations, have not been fully evaluated.nnnMethodsnTo identify studies presented multiple times, abstracts from an approximately 1-year period from international conferences for three major societies devoted largely or in part to lung cancer research were assessed (ASCO 2015, World Lung 2015, ESMO 2015 and ASCO 2016). Abstracts were selected in a two-step process. The first step was for subject matter based on keywords: non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC) or immunotherapy. Searches differed slightly based on individual website functionality, with ASCO searched by track, World Lung by session and ESMO by individual abstract. In a second step, abstracts for which clinical outcome data was presented from a trial with an identifiable National Clinical Trial (NCT) number were selected. Immunotherapy abstracts that did not include the treatment of NSCLC or SCLC were excluded in the second step.nnnResultsnA total of 851 abstracts were identified that were related to NSCLC, SCLC or immunotherapy. Of these, 357 referred to a clinical trial. In total, 110 of 357 (31%) described clinical trials that were presented multiple times (mean 2.75, range 2-7), and in 44 (12%), this occurred at the same conference. Of the 113 oral presentations, 75 (66%) presented data from clinical trials, either as posters or oral presentations. Further, 35 of the 113 (31%) oral presentations presented data from clinical trials that had generated other oral presentations. Of the 16 unique clinical trials leading to multiple oral presentations, a variety of issues led to the duplicate presentations, including different cohorts of the same trial, biomarker analysis, analysis by one study variable, or simply updated data. Moreover, 107 of the 357 (30%) clinical trial abstracts pertained to immunotherapy, including 4 of the 16 clinical trials generating multiple oral presentations. Of the 16 trials generating multiple oral presentations, 11 (69%) lead to a full-length publication by July 2017, including all of those pertaining to immunotherapy.nnnConclusionsnThere is a pattern of multiple presentations of clinical trials, particularly in oral presentations, at major meetings. In most cases, data presented in subsequent oral presentations related entirely to patients whose data was presented in the previous oral presentation.

Epidermal growth factor tyrosine kinase inhibitor therapy inferior to second-line chemotherapy in EGFR wild-type non-small cell lung cancer patients: results of French nationwide observational study

In the recent issue of The European Respiratory Journal , Tomasini et al. report on an observational study comparing the clinical, biological, treatment and outcome data for epidermal growth factor wild-type (EGFR-wt) advanced non-small cell lung cancer (NSCLC) patients who received second-line treatment with an EGFR tyrosine kinase inhibitor (TKI) versus those that received second-line chemotherapy, collected in France over a 1 year period (1). Their central finding, that clinical outcomes with second-line EGFR TKI therapy in EGFR-wt patients were inferior to those with second-line chemotherapy, underscores the ineffectual nature of the treatment of EGFR-wt NSCLC with an EGFR TKI.