Phase 3 KEYNOTE-604 Trial Shows Promise for Pembrolizumab and EP in Patients ES-SCLC

Results from the phase 3 KEYNOTE-604 trial, simultaneously presented at the 2020 ASCO Virtual Scientific Program and published in the Journal of Clinical Oncology, demonstrated modest survival benefits in patients with extensive-stage small cell lung cancer (ES-SCLC) who received the combination of pembrolizumab (Keytruda) and etoposide plus platinum (EP) compared with patients who received EP and placebo.^1,2

However, though progression-free survival (PFS) rates reached the threshold for significance, overall survival (OS) rates failed to reach the prespecified threshold.

"SCLC remains an exceptional aggressive disease. About two-thirds of patients present with metastatic disease at the time of diagnosis and despite a high response rate to initial chemotherapy, these are rarely durable,” Charles M. Rudin, MD, medical oncologist and chief of the Thoracic Oncology Service at Memorial Sloan Kettering Cancer Center, as well as co-chair of the Eastern Cooperative Oncology Group Thoracic Committee, said in a presentation of the data.

In the study, a total of 453 patients were randomized in a 1:1 fashion. In the experimental arm, 228 patients received 220 mg of pembrolizumab on day 1 plus 100mg/m2 of EP on days 1 and 2 and carboplatin AUC 5 on day 1 or 75mg/m2 of cisplatin on day 1. In the control arm, 225 patients received matching doses of placebo, matching EP, and carboplatin or cisplatin. Pembrolizumab and placebo were continued for up to 31 cycles.

The co-primary endpoints of the trial were PFS per RECIST v1.1 by blinded independent central review and OS. Secondary endpoints included overall response rate (ORR) and duration of response (DOR) per RECIST v1.1 by BICR, as well as safety.

KEYNOTE-604 analyzed efficacy in an intention-to-treat (ITT) population and safety in an as-treated population. The analyses included a second interim analysis with a data cutoff of March 29, 2019 and a final analysis with a data cutoff date of December 2, 2019.

For the option of carboplatin or cisplatin, 70.6% of participants in the pembrolizumab group received carboplatin, as did 69.3% of patients (n = 156) in the placebo group.

Following chemotherapy administration, the curves favored pembrolizumab. The median PFS was 4.5 months (95% CI, 4.3-5.4) in the pembrolizumab arm versus 4.3 months (95% CI, 4.2-4.4) in the placebo arm. At 6 months, the PFS rate was 34.1% in the pembrolizumab arm versus 23.8% in the placebo arm. At 12 months, the PFS rate was 13.6% in the pembrolizumab arm compared with 3.1% in the placebo arm.

In the final PFS analysis, the separation of the survival curves was maintained (HR, 0.73; 95% CI, 0.60-0.88). The median PFS was 4.8 months (95% CI, 4.3-5.4) compared with 4.3 months (95% CI, 4.2-4.5) in the placebo arm. The 12-month PFS rate observed with the pembrolizumab combination was 15.9% versus 5.0% with the placebo combination. Even at 18 months, the PFS rate in the pembrolizumab arm was higher than the placebo arm at 10.8% versus 2.1%.

In terms of overall survival in the ITT population, pembrolizumab/EP prolonged OS compared with the control combination (HR, 0.80; 95% CI, 0.64-0.98; P = .0164). Rudin noted, "While the 95% CIs did not cross 1, the P-value of 0.0164 narrowly missed the superiority threshold, which was 0.0128."

The median OS was 10.8 months (95% CI, 9.2-12.9) with the addition of pembrolizumab to EP. On the placebo arm, the median OS was 9.7 months (range, 8.6-10.7 months). The 12-month OS rate was 45.1% in the pembrolizumab arm compared with 39.6% in the placebo arm. At 24 months, the OS rate was 22.5% in the pembrolizumab arm compared with 11.2% in the placebo arm.

In the as-treated population, the OS curves were identical, but the HR decreased to 0.78 (95% CI, 0.63-0.97; nominal P = 0.0124), according to an exploratory analysis.

Survival outcomes in the various subgroups in the study were similar between the 2 arms, with the brain metastases population being the only outlier, by favoring placebo.

The ORR in the ITT population for pembrolizumab/EP was 70.6% (95% CI, 64.2%-76.4%), which included complete responses (CRs) in 1.8% (4) of patients, partial responses (PRs) in 68.9% (157) of patients, stable disease (SD) in 17.5% (40) of patients, and progressive disease (PD) in 3.5% (8) of patients. The best response was not evaluable (NE) in 2.6% (5) of patients in the pembrolizumab arm, and not applicable (NA) in 5.7% (13) of patients.

The ORR observed with placebo/EP was 61.8% (95% CI, 55.1%-68.2%) of which best response were, CRs in 0.9% (2), PRs in 60.9% 137) of patients, SD in 24.9% (56) of patients, and PD in 5.3% of patients (12). Best responses were NE in 2.2% of patients who received the placebo combination (5) and NA in 5.8% (13).

Responses were more durable among those who received pembrolizumab. Similar to the survival activity, the DOR curves overlapped at first, then separated in favor of pembrolizumab after about 5 months. The median DOR in the pembrolizumab/EP arm was 4.2 months (95% CI, 1.0-26.0) and the median DOR in the placebo/EP arm was 3.7 months (95% CI, 1.4-25.8). The DOR rate at 12 months was 19.3% with pembrolizumab versus 3.3% with the control and at 18 months, the DOR rate was 16.3% versus 1.3%, respectively.

The safety analysis showed that adverse events (AEs) of any-grade occurred in 100% of patients in the pembrolizumab arm and 99.6% of patients in the placebo arm, in the as-treated population. AEs were grade 3/4 in 76.7% of subjects who received the addition of pembrolizumab to EP compared with 74.9% of those who received the placebo combination.

Grade 5 AEs, which led to death were also observed in 6.3% of patients in the pembrolizumab arm versus 5.4% in the control arm. Additionally, a higher percentage of patients in the pembrolizumab arm discontinued treatment on any study drug (14.8% versus 6.2%), and the percentage of patients who discontinued all treatments was 4.0% versus 3.6%, respectively.

The most common AEs were hematologic and were not intensified by the addition of pembrolizumab. AEs in the pembrolizumab arm versus the control arm, respectively were neutropenia (57.0% vs. 53.4%), anemia (48.4% vs. 46.6%), nausea (38.6% vs. 43.0%), alopecia (33.6% vs. 37.7%) decreased appetite (30.9% vs. 24.7%), constipation (29.6% vs. 26.5%), fatigue (27.4% vs. 27.4%), thrombocytopenia (26.5% vs. 22.0%), leukopenia (22.4% vs. 20.6%), diarrhea (21.1% vs. 18.8%), and cough (19.7% vs. 20.2%).

Any grade immune-related AEs in the as-treated population were experienced by 24.7% of patients in the pembrolizumab arm and 10.3% of those in the placebo arm. Immune-related AEs were grade 3 or 4 in severity for 7.2% of the pembrolizumab group, and 1.3% of the placebo group.

No events caused death in the pembrolizumab group, but 0.4% of immune-related AEs led to death in the placebo arm. In terms of treatment discontinuation, 5.8% of patients who received pembrolizumab discontinued any study treatment versus 0.9% of patients who received the placebo combination. Discontinuation of all treatment in the study occurred in 0.9% of patients in the pembrolizumab arm and no patients in the placebo arm.

Of the immune-related AEs, the most common were hypothyroidism (10.3% vs. 2.2%), hyperthyroidism (6.7% vs. 2.7%), and pneumonitis (4.0% vs. 2.2%).

Overall, Rudin concluded that this safety profile was expected with pembrolizumab and the toxicities were manageable.

The efficacy and safety data taken together support the use of pembrolizumab to improve upon the capabilities of EP as treatment of patients with ES-SCLC.

References:

1. Rudin CM, Awad MM, Navarro A, et al. KEYNOTE-604: Pembrolizumab (pembro) or placebo plus etoposide and platinum (EP) as first-line therapy for extensive-stage (ES) small-cell lung cancer (SCLC). J Clin Oncol. 2020;38(suppl):9001. doi:10.1200/JCO.2020.38.15_suppl.9001

2. Rudin CM, Awad MM, Navarro A, et al. Pembrolizumab or Placebo Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer: Randomized, Double-Blind, Phase III KEYNOTE-604 Study. J Clin Oncol. Published online May 29, 2020. doi:10.1200/JCO.20.00793