We report an updated analysis of OS and other efficacy and safety outcomes after a median follow-up of 25.2 months. In addition, we describe outcomes among patients who crossed over from chemotherapy to pembrolizumab per protocol and analyses that adjusted for potential bias introduced by treatment crossover.

KEYNOTE-024 ( ClinicalTrials.gov identifier: NCT02142738) is an international, randomized, open-label, phase III study of pembrolizumab monotherapy versus platinum-based chemotherapy in patients with previously untreated advanced non–small-cell lung cancer (NSCLC) with programmed death ligand 1 (PD-L1) tumor proportion score (TPS) of 50% or greater and without EGFR mutation or ALK translocation. 1 At the second preplanned interim analysis (median follow-up, 11.2 months), pembrolizumab was associated with significantly improved progression-free survival (PFS; hazard ratio [HR], 0.50; 95% CI, 0.37 to 0.68; one-sided P < .001) and overall survival (OS; HR, 0.60; 95% CI, 0.41 to 0.89; one-sided P = .005). Median OS was not reached (NR) in either arm. Importantly, pembrolizumab was generally well tolerated. On the basis of these results, the independent data and safety monitoring committee recommended the trial be stopped early to allow for use of pembrolizumab in patients randomly assigned to chemotherapy. The improvement in OS occurred despite the study design allowing patients randomly assigned to chemotherapy to cross over to pembrolizumab. The observed treatment effect was potentially attenuated because many patients participated in this crossover.

The IPCW method addressed treatment crossover by introducing artificial censoring at time of crossover for each patient. To adjust for potential confounding from artificial censoring, weights were calculated for observations before crossover according to patient baseline and time-varying demographic and disease-related characteristics (as described by Latimer et al 11 ). These were then used in a weighted Cox proportional hazards model to estimate the HR of pembrolizumab versus chemotherapy; the 95% CI was estimated by bootstrapping.

In the RPSFT model, 9 , 10 survival times of patients in the chemotherapy arm who crossed over were adjusted multiplicatively by an acceleration factor determined by G-estimation to estimate the expected survival time if patients had not crossed over. Survival times of all patients randomly assigned to chemotherapy were recensored to maintain the assumption of noninformative censoring. Observed survival times in the pembrolizumab arm were compared with adjusted survival times in the chemotherapy arm using a Cox proportional hazards model. Bootstrapping was used to estimate the 95% CIs of the HR.

Additional analyses for OS, intended to complement the intent-to-treat analysis, were conducted to estimate the treatment difference between pembrolizumab and chemotherapy adjusted for crossover. The following three statistical methods were applied: the simplified two-stage, rank-preserving structural failure time (RPSFT), and inverse probability of censoring weighting (IPCW) methods. In stage 1 of the two-stage model (described by Latimer et al 7 , 8 ), a log-normal parametric survival model accounting for important covariates was developed to estimate the effect of crossover in the chemotherapy arm (acceleration factor) that was then used to adjust survival times for patients who crossed over to pembrolizumab. Patients were eligible for inclusion in stage 1 if they met the following criteria consistent with the clinical criteria for crossover before the second interim analysis: centrally verified disease progression, no discontinuation of chemotherapy for any reason other than progressive disease, ECOG PS of 0 or 1 at progression, survival of 30 days or longer after cessation of chemotherapy, and initiation of pembrolizumab 30 days or more after last chemotherapy dose. In the second stage, observed survival times in the pembrolizumab arm were compared with adjusted survival times in the chemotherapy arm and analyzed with a stratified proportional hazards model. Bootstrapping was used to estimate the 95% CI of the acceleration factor and treatment effect HR.

The final protocol-specified OS analysis was to occur after approximately 170 patients had died, providing approximately 75% power to observe an HR of less than 1, assuming approximately 70% of the patients in the chemotherapy arm crossed over to pembrolizumab. Because OS benefit was confirmed at the second interim analysis (data cutoff, May 9, 2016; 108 of 305 patients had died), this final analysis was not subjected to multiplicity control. Efficacy was assessed in the intent-to-treat population (all randomly assigned patients), and safety was assessed in the as-treated population (patients who were randomly assigned and received one or more doses of study treatment, analyzed by treatment received). The Kaplan-Meier method was used to estimate OS, with censoring of data for patients alive or lost to follow-up at time of last contact. Between-group difference in OS was assessed using a stratified log-rank test. HRs and associated 95% CIs were assessed using a stratified Cox proportional hazards model with Efron’s method of handling ties. Randomization stratification factors were applied to the stratified log-rank and Cox models. After crossover to pembrolizumab, DOR was summarized using the Kaplan-Meier method for patients with confirmed complete or partial responses in this phase.

As described previously, 1 PD-L1 expression was assessed in formalin-fixed tumor samples (from core-needle or excisional biopsy or tissue resected at time of diagnosis of metastatic disease) using the PD-L1 IHC 22C3 pharmDx assay (Agilent, Santa Clara, CA). 5 , 6 Imaging studies were performed every 9 weeks. Response was assessed per RECIST version 1.1 by blinded, independent, central radiology review (stopped after the second interim analysis [protocol amendment 6]) and by investigator assessment. Patients were contacted every 2 months during follow-up to evaluate OS. All AEs occurring from random assignment until 30 days after the last dose of study treatment (90 days for serious AEs) were graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. The sponsor reviewed all AEs and condensed several AE preferred terms that suggested an immune-mediated etiology for specific categories, regardless of investigator-assessed attribution of the event.

The primary end point was PFS (time since random assignment to disease progression or death from any cause, whichever occurred first). OS (time since random assignment to death from any cause) was an important secondary end point; objective response rate (ORR; confirmed complete and partial responses) and safety were other secondary end points. Exploratory end points included duration of response (DOR), patient-reported outcomes, 3 and time since random assignment to objective tumor progression on next-line treatment or death from any cause, whichever occurred first. 4

Eligible patients were randomly assigned (1:1; stratified by ECOG PS of 0 v 1, squamous v nonsquamous histology, East Asian v non–East Asian enrollment site) to receive intravenous pembrolizumab (200 mg every 3 weeks) for 35 cycles (2 years) or investigator’s choice of platinum-based chemotherapy (carboplatin plus pemetrexed, cisplatin plus pemetrexed, carboplatin plus gemcitabine, cisplatin plus gemcitabine, or carboplatin plus paclitaxel; pemetrexed-containing regimens were only permitted for patients with nonsquamous disease) for four to six cycles, in the absence of radiologic disease progression (per RECIST), treatment-related adverse events (AEs) of unacceptable severity, or patient withdrawal. Pemetrexed-containing chemotherapy regimens and subsequent use of pemetrexed as maintenance therapy were permitted for patients with nonsquamous tumors. Patients assigned to chemotherapy could cross over to pembrolizumab (starting 30 days or more after last chemotherapy dose) if safety eligibility criteria were met; before the second interim analysis that revealed superiority, only patients with progressive disease confirmed by blinded, independent, central radiology review were eligible. The protocol did not include preplanned crossover from pembrolizumab to chemotherapy or postprogression treatment guidelines for pembrolizumab recipients. Patients in either arm who were clinically stable and considered by the investigator to be deriving clinical benefit could continue therapy after disease progression.

As described previously, 1 adult patients eligible for enrollment had untreated stage IV NSCLC with PD-L1 TPS of 50% or greater, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1 or lower, measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, 2 and life expectancy of 3 months or longer. Patients were excluded if they had sensitizing EGFR mutations, ALK translocations, untreated brain metastases, or active autoimmune disease requiring systemic therapy or were receiving systemic glucocorticoids or other immunosuppressive therapy.

During crossover, the rates of any grade, grade 3 to 5, and serious treatment-related AEs were 61.0%, 9.8%, and 8.5%, respectively (discontinuation rate due to treatment-related AEs, 6.1%). There were no grade 5 treatment-related AEs during on-study crossover. Among crossover patients, 16 (19.5%) developed an immune-mediated AE and/or infusion reaction (hypothyroidism, 9.8%; hyperthyroidism, 6.1%; pneumonitis, 4.9%; adrenal insufficiency, 1.2%; and infusion reaction, 1.2%).

The most frequent treatment-related AEs were diarrhea (16.2%) and fatigue (14.3%) in the pembrolizumab arm and anemia (44.0%) and nausea (43.3%) in the chemotherapy arm ( Table 2 ). In the pembrolizumab arm, the most common grade 3 to 5 treatment-related AEs were diarrhea (3.9%) and pneumonitis (3.2%). Immune-mediated AEs and infusion reactions, regardless of relationship to treatment, occurred in 33.8% (grade 3 to 5, 13.6%) and 5.3% (grade 3 to 5, 0.7%) of patients in the pembrolizumab and chemotherapy arms, respectively ( Table 2 ).

During treatment with initially assigned therapy, treatment-related AEs occurred in 76.6% (grade 3 to 5, 31.2%) and 90.0% (grade 3 to 5, 53.3%) of patients in the pembrolizumab and chemotherapy arms, respectively ( Table 2 ). Incidences of serious treatment-related AEs (22.7% and 20.7% in the pembrolizumab and chemotherapy arms, respectively) and treatment discontinuation as a result of treatment-related AEs (13.6% and 10.7% in the pembrolizumab and chemotherapy arms, respectively) were similar between the arms. There were five treatment-related fatal AEs (pembrolizumab, n = 2; chemotherapy, n = 3; four were previously reported 1 [pembrolizumab: sudden death of unknown cause; chemotherapy: pulmonary sepsis, pulmonary alveolar hemorrhage, and death of unknown cause]). With longer follow-up in this analysis, there was one additional death in the pembrolizumab arm (pneumonitis occurring on day 181 of pembrolizumab treatment with significant delay in start of immunosuppressive therapy).

Seventy-seven patients randomly assigned to chemotherapy met the prespecified criteria for inclusion in stage 1 of the two-stage analysis (centrally verified progression, no discontinuation of chemotherapy other than for progressive disease, ECOG PS of 0 or 1 at time of progression, and survival of 30 days or more after cessation of chemotherapy). This is less than the number of patients who qualified for on-study crossover (n = 82), as described earlier, as a result of the requirement for disease progression. Sixty-three of these 77 patients crossed over to pembrolizumab on study; 14 of these patients did not, although four patients received anti–PD-1 treatment outside the study (pembrolizumab, n = 2; nivolumab, n = 2). The estimated acceleration factor was 4.00 (95% CI, 1.59 to 11.30), indicating the survival period after disease progression was reduced by 75% in the chemotherapy arm versus unadjusted outcomes, resulting in an adjusted median OS of 8.7 months (95% CI, 7.3 to 11.5 months). In stage 2, the adjusted HR for the adjusted OS in the chemotherapy arm versus the observed OS in the pembrolizumab arm was 0.49 (95% CI, 0.34 to 0.69; Fig 4 ). Similar results were obtained with the RPSFT and IPCW methods; RPSFT-adjusted median OS was 11.8 months (95% CI, 8.7 months to NR; adjusted HR, 0.52; 95% CI, 0.33 to 0.75) and IPCW-adjusted median OS was 11.8 months (95% CI, 8.7 to 21.3 months; adjusted HR, 0.52; 95% CI, 0.33 to 0.80).

Baseline characteristics for the 82 patients who crossed over to on-study pembrolizumab were similar to those for the overall study population (Appendix Table A1 , online only). Seventeen of 82 patients who crossed over had an objective response per investigator assessment (ORR, 20.7%; 95% CI, 12.6% to 31.1%). Nineteen patients (23.2%) had stable disease. Median time to response was 2.0 months (range, 1.1 to 8.4 months), and median DOR was NR (range, 2.1 [ongoing] to 22.9 [ongoing] months) after on-study crossover ( Fig 3 ).

At data cutoff, 169 patients had died (pembrolizumab, n = 73; chemotherapy, n = 96). Median OS was 30.0 months (95% CI, 18.3 months to NR) in the pembrolizumab arm and 14.2 months (95% CI, 9.8 to 19.0 months) in the chemotherapy arm (HR, 0.63; 95% CI, 0.47 to 0.86; one-sided nominal P = .002). Kaplan-Meier estimates of OS at 12 months for pembrolizumab and chemotherapy were 70.3% (95% CI, 62.3% to 76.9%) and 54.8% (95% CI, 46.4% to 62.4%), respectively, with corresponding 24-month rates of 51.5% (95% CI, 43.0% to 59.3%) and 34.5% (95% CI, 26.7% to 42.4%; Fig 2A ), respectively. An OS benefit for pembrolizumab compared with chemotherapy was observed in all subgroups evaluated ( Fig 2B ).

KEYNOTE-024 included 305 randomly assigned patients (pembrolizumab, n = 154; chemotherapy, n = 151) from 142 sites in 16 countries; all except one patient in the chemotherapy arm received study treatment ( Fig 1 ). At data cutoff (July 10, 2017), median follow-up was 25.2 months (range, 20.4 to 33.7 months); 235 treated patients across both arms had discontinued initially assigned study treatment. Median treatment duration was 7.9 months (range, 1 day to 28.8 months) in the pembrolizumab arm and 3.5 months (range, 1 day to 30.5 months) in the chemotherapy arm. In the chemotherapy arm, 82 patients had crossed over to pembrolizumab on study; 15 additional patients received anti–PD-1 treatment outside of the crossover (second line, n = 12; third or later line, n = 3), for a crossover rate of 64.2% (97 of 151 patients) in the intent-to-treat population and an effective crossover rate of 65.1% (97 of 149 patients) excluding patients remaining on therapy. Median treatment duration for patients receiving on-study pembrolizumab crossover was 3.9 months (range, 1 day to 23.7 months; Fig 1 ). In the pembrolizumab arm, 56 patients went on to receive one or more subsequent oncologic treatments, including surgery, radiation therapy, chemotherapy, and immunotherapy (pembrolizumab, n = 3; nivolumab, n = 5), after discontinuation. Patient demographic and baseline clinical characteristics were generally well balanced between the arms ( Table 1 ).

DISCUSSION Section: Choose Top of page Abstract INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION << REFERENCES

In this updated analysis of KEYNOTE-024, pembrolizumab continues to show an OS benefit as first-line therapy for advanced NSCLC with PD-L1 TPS of 50% or greater compared with platinum-based chemotherapy (HR, 0.63; 95% CI, 0.47 to 0.86; nominal P = .002). The improvement in OS first reported at the second interim analysis 1 was maintained despite significant crossover to pembrolizumab in the chemotherapy arm, with a notable median OS of 30.0 months for patients randomly assigned to pembrolizumab compared with 14.2 months for patients in the chemotherapy arm. This efficacy outcome is more favorable than that described in trials evaluating platinum-based chemotherapy as first-line treatment of NSCLC. 12 To our knowledge, KEYNOTE-024 is the first study to show an OS benefit with anti–PD-1 monotherapy compared with platinum-based chemotherapy as first-line treatment in patients with advanced NSCLC and has changed the treatment paradigm of this disease.

With median exposure of 7.9 months in the pembrolizumab arm at the time of analysis (more than double that in the chemotherapy arm), pembrolizumab continues to demonstrate a favorable safety profile. The incidence, severity, and nature of AEs were consistent with those described previously, 1 with no evidence of cumulative toxicity with longer exposure and no new safety signals when comparing incidence of AEs during pembrolizumab treatment with those among patients who received chemotherapy (notwithstanding the longer treatment duration with initial therapy in the pembrolizumab arm). In the updated analysis, there was one additional fatal immune-mediated AE as a result of pneumonitis. Although median time to the first pneumonitis event was 100 days in the pembrolizumab arm, this AE developed at day 181. Initially confused with disease progression, immunosuppression was delayed until after the patient underwent two separate biopsies.

Whereas at the second interim analysis 66 patients had received pembrolizumab crossover therapy, at the time of this analysis 82 patients had crossed over and 15 additional patients had received subsequent anti–PD-1 therapy (crossover rate, 64.2% in the intent-to-treat population; effective crossover rate, 65.1% excluding patients remaining on therapy). Outcomes in the crossover population are indicative of treatment benefit for second-line pembrolizumab monotherapy (ORR, 20.7%; median DOR, NR) and are consistent with outcomes for patients with PD-L1 TPS of 50% or greater in the phase III KEYNOTE-010 (ClinicalTrials.gov identifier: NCT01905657) study of pembrolizumab versus docetaxel in patients with previously treated NSCLC. 13

The high rate of crossover in this study (reflecting both the study design and decision of the data and safety monitoring committee to stop the trial analysis early) and apparent activity of pembrolizumab during the crossover period likely attenuated the observed OS effect. We used three statistical methods to adjust for the influence of crossover on OS, and all three supported an HR more strongly favoring the pembrolizumab arm. The two-stage model was preferred, as a result of evidence of deviation from the common treatment effect assumed in RPSFT and because the IPCW method is more prone to bias in the presence of relatively small sample sizes. 7,11 Overall, the crossover-adjusted analyses complement the primary efficacy analysis and reinforce the potential to improve outcomes with early use of pembrolizumab as first-line treatment.

Given the OS and PFS benefits observed in KEYNOTE-024, pembrolizumab remains the only checkpoint inhibitor approved in the first-line setting as monotherapy for patients with PD-L1 TPS of 50% or greater. Recently, results from the KEYNOTE-042 (ClinicalTrials.gov identifier: NCT02220894) study confirmed and extended those from KEYNOTE-024 by demonstrating significantly improved OS with pembrolizumab versus platinum-based chemotherapy not only in treatment-naive patients with PD-L1 TPS of 50% or greater (HR, 0.69; 95% CI, 0.56 to 0.85; P = .0003), but also in those with PD-L1 TPS of 20% or greater (HR, 0.77; 95% CI, 0.64 to 0.92; P = .002) and 1% or greater (HR, 0.81; 95% CI, 0.71 to 0.93; P = .0018). 14 In contrast, administration of nivolumab 3 mg/kg every 2 weeks in the CheckMate 026 (ClinicalTrials.gov identifier: NCT02041533) study did not improve PFS or OS among patients with previously untreated advanced NSCLC with PD-L1 expression of 5% or greater. 15 Although cross-trial comparisons should be approached with caution, different PD-L1 assays (with different anti–PD-L1 antibodies) and thresholds were used in CheckMate 026 relative to KEYNOTE-024 and KEYNOTE-042, which may, in part, explain the opposing outcomes. 16

Pembrolizumab with platinum chemotherapy has been evaluated in several trials. In the randomized cohort G of the phase I/II KEYNOTE-021 (ClinicalTrials.gov identifier: NCT02039674) study, pembrolizumab plus carboplatin and pemetrexed in patients with newly diagnosed, advanced, nonsquamous NSCLC without EGFR/ALK alterations irrespective of PD-L1 TPS demonstrated improved ORR and PFS compared with carboplatin and pemetrexed alone, 17 leading to approval in the United States. The phase III KEYNOTE-189 (ClinicalTrials.gov identifier: NCT 02578680) study evaluated first-line pembrolizumab plus pemetrexed and platinum in patients with nonsquamous metastatic NSCLC irrespective of PD-L1 tumor expression and showed significant improvement in OS (HR, 0.49; 95% CI, 0.38 to 0.64; P < .001) and PFS (HR, 0.52; 95% CI, 0.43 to 0.64; P < .001) compared with placebo plus chemotherapy. 18 Pembrolizumab in combination with carboplatin and paclitaxel or nab-paclitaxel resulted in improved OS and PFS compared with placebo plus carboplatin and paclitaxel or nab-paclitaxel in patients with squamous histology regardless of PD-L1 expression (OS HR, 0.64; 95% CI, 0.49 to 0.85; P < .001; PFS HR, 0.56; 95% CI, 0.45 to 0.70; P < .001) in the phase III KEYNOTE-407 (ClinicalTrials.gov identifier: NCT02775435) study. 19 Together with our current analyses, these data show that for all patients with advanced NSCLC without EGFR/ALK alterations, a first-line treatment regimen containing pembrolizumab (either as monotherapy or in combination with platinum chemotherapy) is available that can improve OS compared with platinum doublet chemotherapy.

In addition, other anti–programmed death 1 or anti–PD-L1 antibodies have been evaluated in combination with chemotherapy or immunotherapy in patients with NSCLC. Atezolizumab with bevacizumab, carboplatin, and paclitaxel improved OS (HR, 0.78; 95% CI, 0.64 to 0.96; P = .02) and PFS (HR, 0.62; 95% CI, 0.52 to 0.74; P < .001) compared with bevacizumab, carboplatin, and paclitaxel in patients with nonsquamous histology, 20 and atezolizumab with carboplatin and nab-paclitaxel improved median PFS (HR, 0.715; 95% CI, 0.603 to 0.848; P = .0001) but not OS (HR, 0.96; 95% CI, 0.78 to 1.18; P = .6931) compared with carboplatin plus nab-paclitaxel in patients with squamous NSCLC. 21 Nivolumab with chemotherapy improved PFS compared with chemotherapy alone in patients whose tumors did not express PD-L1 (HR, 0.74; 95% CI, 0.58 to 0.94). 22 Finally, nivolumab plus ipilimumab demonstrated longer PFS compared with chemotherapy (HR, 0.83; 95% CI, 0.72 to 0.96), particularly in patients with high tumor mutational burden (HR, 0.58; 97.5% CI, 0.41 to 0.81). 23 At present, tumor mutational burden does not have a role in guiding treatment decisions, because an OS benefit has not been shown.

In conclusion, in this updated analysis of KEYNOTE-024, pembrolizumab continued to provide improved OS relative to platinum-based chemotherapy, notwithstanding the high rate of crossover. There was no evidence of cumulative toxicity. These results support pembrolizumab monotherapy as a standard-of-care regimen for first-line treatment of advanced NSCLC with PD-L1 TPS of 50% or greater and without EGFR/ALK alterations.