Immunotherapy for small cell lung cancer: the PK of PD-1 and PD-L1

In recent years, the treatment and prognosis of non-small cell lung cancer (NSCLC) have rapidly benefited from the approval of PD-1 and PD-L1 related drugs, but the progress in the treatment of small cell lung cancer (SCLC) has been much slower

One

1.

Based on the results of IMpower133, in 2019 the FDA approved the PD-L1 inhibitor atelizumab + etoposide/carboplatin as the first-line indication for the treatment of ES-SCLC, and the CSCO guidelines are also used as a level I recommendation

2.

In 2020, ASCO updated the study data of the study.

Second

However, two other PD-1 drugs , nivolumab and pembrolizumab , were withdrawn by the FDA for the treatment of SCLC in 2020 and 2021, respectively

1.

The CheckMate-451 study is a global, double-blind, phase III clinical study that aims to investigate whether nivolumab ± ipilimumab will improve OS in maintenance treatment of ES-SCLC patients who have not progressed to first-line chemotherapy

CheckMate-331 is an open, randomized phase III clinical trial, mainly for ES-SCLC patients who relapse after first-line platinum chemotherapy, using nivolumab versus standard chemotherapy

On December 30, 2020, Bristol-Myers Squibb Company announced that it withdrew the indication of nivolumab for ES-SCLC

2.

Based on the ORR and DOR data (third-line) of KEYNOTE-158 (G group) and KEYNOTE-028 (C1 group), Pembrolizumab received accelerated FDA approval in June 2019

In January 2020, the results of the phase III confirmatory trial KEYNOTE-604 for SCLC indications were announced.
The results showed that it reached the primary endpoint of PFS, but the primary endpoint of OS was not statistically significant
.

The KEYNOTE-604 study compares the efficacy and safety of pembrolizumab combined with standard chemotherapy (carboplatin or cisplatin/etoposide) and placebo combined with standard chemotherapy in the first-line treatment of ES-SCLC
.
In this study, 453 patients were randomized, 228 patients in the pembrolizumab plus chemotherapy group, 225 patients in the placebo plus chemotherapy group, and 223 and 222 patients in the two groups received at least one dose of study treatment
.
Judging from the baseline characteristics of the patients, the patient’s age, gender, ECOG score, smoking status, lactate dehydrogenase level, and liver metastasis were balanced; the pembrolizumab combined chemotherapy group accounted for 14.
5% of patients with brain metastases, and the chemotherapy group Accounted for 9.
8%; pembrolizumab combined with chemotherapy group had a PD-L1 combined score ≥ 1 in 38.
6%, and chemotherapy group accounted for 43.
1%
.

This study conducted two interim analyses.
In the second interim analysis, in the intention-to-treat population, mPFS of pembrolizumab plus chemotherapy group and chemotherapy group were 4.
5 months and 4.
3 months, respectively (HR: 0.
75, P=0.
0023), reaching the preset one-sided P=0.
0048; in the final analysis, mPFS of pembrolizumab combined with chemotherapy group and chemotherapy group were 4.
8 months and 4.
3 months (HR: 0.
75), respectively; mOS They were 10.
8 and 9.
7 months respectively (HR: 0.
80, P=0.
0164), but the final OS did not meet the preset P=0.
0128
.
The 12-month OS rates of the two groups were 45.
1% and 39.
6%, and the 24-month OS rates were 22.
5% and 11.
2%.
Pembrolizumab combined with chemotherapy has an advantage in the OS rate
.
In terms of ORR, the pembrolizumab combined chemotherapy group and the chemotherapy group were 70.
6% and 61.
8%, respectively, and the mDOR was 4.
2 months and 3.
7 months, respectively
.

Based on KEYNOTE-604 research data, on March 2, 2021, Pembrolizumab negotiated with the FDA to withdraw its SCLC indication approval application
.

Summarize

In the exploration of SCLC immunotherapy, the first two PD-1 related drugs received accelerated approval from the FDA, but in later clinical trials, both nivolumab and pembrolizumab did not meet the research expectations.
Withdraw SCLC treatment
.

Although the immunotherapy of SCLC has suffered a blow in the application of PD-1 related drugs, it has succeeded in subsequent PD-L1 related drugs (atifalizumab and duvalizumab)
.
These two victories established a new treatment model for SCLC patients and ultimately benefited SCLC patients
.