Rationale and Design of the Phase III KEYLYNK-012 Study of Pembrolizumab and Concurrent Chemoradiotherapy Followed by Pembrolizumab With or Without Olaparib for Stage III Non-Small-Cell Lung Cancer.

BACKGROUND: Concurrent chemoradiotherapy is a standard therapy for patients with stage III non-small-cell lung cancer (NSCLC). Durvalumab is an approved treatment option following concurrent chemoradiotherapy in the absence of disease progression. The multicenter, phase III, randomized, placebo- and active-controlled, double-blind KEYLYNK-012 study evaluates whether initiation of immunotherapy with pembrolizumab concurrently with chemoradiotherapy, followed by post-chemoradiotherapy pembrolizumab with or without olaparib improves outcomes for participants with stage III NSCLC. (ClinicalTrials.gov: NCT04380636) METHODS: Eligible participants are aged ≥18 years with previously untreated, pathologically confirmed, stages IIIA-C, squamous or nonsquamous NSCLC not suitable for surgery with curative intent. Participants will be randomized 1:1:1 to platinum-doublet chemotherapy plus radiotherapy with pembrolizumab (Groups A and B) or concurrent chemoradiotherapy alone (Group C) for 3 cycles. In the absence of disease progression, participants will receive pembrolizumab plus olaparib placebo (Group A), pembrolizumab plus olaparib (Group B), or durvalumab monotherapy (Group C). Dual primary endpoints are progression-free survival per RECIST version 1.1 by independent central review and overall survival. RESULTS: Enrollment began on July 6, 2020, and is ongoing at approximately 190 sites. CONCLUSION: KEYLYNK-012 will provide important information on the efficacy and safety of pembrolizumab combined with concurrent chemoradiotherapy and subsequent pembrolizumab with or without olaparib in participants with unresectable stage III NSCLC.

Estimands for overall survival in clinical trials with treatment switching in oncology.

An addendum of the ICH E9 guideline on Statistical Principles for Clinical Trials was released in November 2019 introducing the estimand framework. This new framework aims to align trial objectives and statistical analyses by requiring a precise definition of the inferential quantity of interest, that is, the estimand. This definition explicitly accounts for intercurrent events, such as switching to new anticancer therapies for the analysis of overall survival (OS), the gold standard in oncology. Traditionally, OS in confirmatory studies is analyzed using the intention-to-treat (ITT) approach comparing treatment groups as they were initially randomized regardless of whether treatment switching occurred and regardless of any subsequent therapy (treatment-policy strategy). Regulatory authorities and other stakeholders often consider ITT results as most relevant. However, the respective estimand only yields a clinically meaningful comparison of two treatment arms if subsequent therapies are already approved and reflect clinical practice. We illustrate different scenarios where subsequent therapies are not yet approved drugs and thus do not reflect clinical practice. In such situations the hypothetical strategy could be more meaningful from patient's and prescriber's perspective. The cross-industry Oncology Estimand Working Group (www.oncoestimand.org) was initiated to foster a common understanding and consistent implementation of the estimand framework in oncology clinical trials. This paper summarizes the group's recommendations for appropriate estimands in the presence of treatment switching, one of the key intercurrent events in oncology clinical trials. We also discuss how different choices of estimands may impact study design, data collection, trial conduct, analysis, and interpretation.

Independent drug action and its statistical implications for development of combination therapies.

Researchers have long sought to find combinations of cancer drugs that might achieve synergy. However, while observed in some preclinical tumor models, synergistic effects are rarely seen in clinical trials. In fact, growing evidence in clinical trial data shows that the treatment effect of most approved combination therapies can be largely explained by the independent drug action model at the patient level. Previous statistical research on drug combinations mainly centered on experimental designs for dose-finding followed by measure of combination efficacy. In this paper, we introduce the independent drug action model to those working in late stage clinical development, propose a new approach to predict the progression-free survival of combination therapies, and discuss its statistical implications for trial design and monitoring. The discussion is enriched with real data examples.

Assessing the Impact of COVID-19 on the Clinical Trial Objective and Analysis of Oncology Clinical Trials-Application of the Estimand Framework.

Abstract-Coronavirus disease 2019 (COVID-19) outbreak has rapidly evolved into a global pandemic. The impact of COVID-19 on patient journeys in oncology represents a new risk to interpretation of trial results and its broad applicability for future clinical practice. We identify key intercurrent events (ICEs) that may occur due to COVID-19 in oncology clinical trials with a focus on time-to-event endpoints and discuss considerations pertaining to the other estimand attributes introduced in the ICH E9 addendum. We propose strategies to handle COVID-19 related ICEs, depending on their relationship with malignancy and treatment and the interpretability of data after them. We argue that the clinical trial objective from a world without COVID-19 pandemic remains valid. The estimand framework provides a common language to discuss the impact of COVID-19 in a structured and transparent manner. This demonstrates that the applicability of the framework may even go beyond what it was initially intended for.

Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Pembrolizumab is a humanized monoclonal antibody against programmed death 1 (PD-1) that has antitumor activity in advanced non-small-cell lung cancer (NSCLC), with increased activity in tumors that express programmed death ligand 1 (PD-L1). METHODS: In this open-label, phase 3 trial, we randomly assigned 305 patients who had previously untreated advanced NSCLC with PD-L1 expression on at least 50% of tumor cells and no sensitizing mutation of the epidermal growth factor receptor gene or translocation of the anaplastic lymphoma kinase gene to receive either pembrolizumab (at a fixed dose of 200 mg every 3 weeks) or the investigator's choice of platinum-based chemotherapy. Crossover from the chemotherapy group to the pembrolizumab group was permitted in the event of disease progression. The primary end point, progression-free survival, was assessed by means of blinded, independent, central radiologic review. Secondary end points were overall survival, objective response rate, and safety. RESULTS: Median progression-free survival was 10.3 months (95% confidence interval [CI], 6.7 to not reached) in the pembrolizumab group versus 6.0 months (95% CI, 4.2 to 6.2) in the chemotherapy group (hazard ratio for disease progression or death, 0.50; 95% CI, 0.37 to 0.68; P<0.001). The estimated rate of overall survival at 6 months was 80.2% in the pembrolizumab group versus 72.4% in the chemotherapy group (hazard ratio for death, 0.60; 95% CI, 0.41 to 0.89; P=0.005). The response rate was higher in the pembrolizumab group than in the chemotherapy group (44.8% vs. 27.8%), the median duration of response was longer (not reached [range, 1.9+ to 14.5+ months] vs. 6.3 months [range, 2.1+ to 12.6+]), and treatment-related adverse events of any grade were less frequent (occurring in 73.4% vs. 90.0% of patients), as were grade 3, 4, or 5 treatment-related adverse events (26.6% vs. 53.3%). CONCLUSIONS: In patients with advanced NSCLC and PD-L1 expression on at least 50% of tumor cells, pembrolizumab was associated with significantly longer progression-free and overall survival and with fewer adverse events than was platinum-based chemotherapy. (Funded by Merck; KEYNOTE-024 ClinicalTrials.gov number, NCT02142738 .).

Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial.

BACKGROUND: Despite recent advances in the treatment of advanced non-small-cell lung cancer, there remains a need for effective treatments for progressive disease. We assessed the efficacy of pembrolizumab for patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. METHODS: We did this randomised, open-label, phase 2/3 study at 202 academic medical centres in 24 countries. Patients with previously treated non-small-cell lung cancer with PD-L1 expression on at least 1% of tumour cells were randomly assigned (1:1:1) in blocks of six per stratum with an interactive voice-response system to receive pembrolizumab 2 mg/kg, pembrolizumab 10 mg/kg, or docetaxel 75 mg/m(2) every 3 weeks. The primary endpoints were overall survival and progression-free survival both in the total population and in patients with PD-L1 expression on at least 50% of tumour cells. We used a threshold for significance of p<0.00825 (one-sided) for the analysis of overall survival and a threshold of p<0.001 for progression-free survival. This trial is registered at ClinicalTrials.gov, number NCT01905657. FINDINGS: Between Aug 28, 2013, and Feb 27, 2015, we enrolled 1034 patients: 345 allocated to pembrolizumab 2 mg/kg, 346 allocated to pembrolizumab 10 mg/kg, and 343 allocated to docetaxel. By Sept 30, 2015, 521 patients had died. In the total population, median overall survival was 10.4 months with pembrolizumab 2 mg/kg, 12.7 months with pembrolizumab 10 mg/kg, and 8.5 months with docetaxel. Overall survival was significantly longer for pembrolizumab 2 mg/kg versus docetaxel (hazard ratio [HR] 0.71, 95% CI 0.58-0.88; p=0.0008) and for pembrolizumab 10 mg/kg versus docetaxel (0.61, 0.49-0.75; p<0.0001). Median progression-free survival was 3.9 months with pembrolizumab 2 mg/kg, 4.0 months with pembrolizumab 10 mg/kg, and 4.0 months with docetaxel, with no significant difference for pembrolizumab 2 mg/kg versus docetaxel (0.88, 0.74-1.05; p=0.07) or for pembrolizumab 10 mg/kg versus docetaxel (HR 0.79, 95% CI 0.66-0.94; p=0.004). Among patients with at least 50% of tumour cells expressing PD-L1, overall survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 14.9 months vs 8.2 months; HR 0.54, 95% CI 0.38-0.77; p=0.0002) and with pembrolizumab 10 mg/kg than with docetaxel (17.3 months vs 8.2 months; 0.50, 0.36-0.70; p<0.0001). Likewise, for this patient population, progression-free survival was significantly longer with pembrolizumab 2 mg/kg than with docetaxel (median 5.0 months vs 4.1 months; HR 0.59, 95% CI 0.44-0.78; p=0.0001) and with pembrolizumab 10 mg/kg than with docetaxel (5.2 months vs 4.1 months; 0.59, 0.45-0.78; p<0.0001). Grade 3-5 treatment-related adverse events were less common with pembrolizumab than with docetaxel (43 [13%] of 339 patients given 2 mg/kg, 55 [16%] of 343 given 10 mg/kg, and 109 [35%] of 309 given docetaxel). INTERPRETATION: Pembrolizumab prolongs overall survival and has a favourable benefit-to-risk profile in patients with previously treated, PD-L1-positive, advanced non-small-cell lung cancer. These data establish pembrolizumab as a new treatment option for this population and validate the use of PD-L1 selection. FUNDING: Merck & Co.