Immunotherapy for small cell lung cancer: Comparison between PD-1 and PD-L1

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Immunotherapy for small cell lung cancer: Comparison between PD-1 and PD-L1

Immunotherapy for small cell lung cancer: Comparison between 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.

In 2019 and 2020, the U.S. Food and Drug Administration (FDA) respectively approved atelizumab and duvalizumab in combination with first-line platinum and etoposide chemotherapy for the treatment of extensive-stage small cell lung cancer (ES-SCLC) ,

This is the first new treatment approved in decades. The evidence for its application is based on two important studies.

First Section

The IMpower133 study is a phase III study that evaluates the efficacy and safety of atelizumab +etoposide/carboplatin versus placebo+etoposide/carboplatin in the first-line treatment of ES-SCLC.

It is also the first phase III study to compare first-line standard chemotherapy The program significantly improves OS research.

A total of 403 patients with newly treated ES-SCLC were enrolled in this study, and they were divided into a chemotherapy-only group and a chemotherapy combined with ICIs group ( atilizumab , 1200 mg, once every 3 weeks) according to a ratio of 1:1 .

The results showed that compared with standard treatment, atelizumab+etoposide/carboplatin prolonged the median overall survival (mOS) (12.3 months vs 10.3 months, HR=0.70, 95%CI 0.54～0.91, P =0.007) and median progression-free survival (mPFS) (5.2 months vs 4.3 months, HR=0.77, 95CI 0.62～0.96, P=0.02) , the risk of disease progression was reduced by 23%, and the two groups of patients with grade 3/4 AE The incidence is similar.

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.

The CASPIAN study is a randomized, open, global multicenter phase III clinical trial on the first-line treatment of ES-SCLC patients. Efficacy in first-line treatment of ES-SCLC patients. The results showed that the median OS of the duvalimab+etoposide/cisplatin or carboplatin group was significantly better than that of the chemotherapy group (13.0 vs 10.3 months, P=0.0047) , and the risk of death was reduced by 27% (HR=0.73, 95%CI 0.59～0.91) , the incidence of AEs in the two groups was also similar (98.1% vs 97%) .

In November 2019, the FDA granted Duvalimab combined with etoposide/cisplatin or carboplatin as the priority review qualification for the first-line treatment of extensive SCLC. The CSCO guidelines serve as a level III recommendation (type IA evidence).

In 2020, ASCO updated the research data of the study. Compared with the control group, the OS of the first-line treatment group of duvalizumab + EP continued to improve (12.9 months vs 10.5 months, HR=0.75, 95%CI 0.62～0.91, p=0.0032) , thus further supporting the duvalizumab + EP regimen as the first-line standard treatment for ES-SCLC.

Second section:

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

In the Phase I/II CheckMate-032 trial (NCT 01928394) (third-line) , the overall response rate (ORR) of patients treated with nivolumab was 11.9%, of which the partial response (PR) rate was 11%, and the complete response (CR) ) Rate was 0.9%; median duration of response (mDoR) was 17.9 months, of which 62% of patients lasted more than 12 months, and 39% of patients lasted more than 18 months. Based on this data, the FDA approved nivolumab for third-line treatment of ES-SCLC in August 2018.

However, in subsequent large-scale confirmatory trials, CheckMate-451 and CheckMate-331 trials, nivolumab did not reach the ideal endpoint of overall survival.

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

The results of the study showed that there was no significant difference in OS between the three groups (9.2 months vs. 10.4 months vs. 9.6 months), and the 1-year OS rate was similar (41% vs. 44% vs. 40%).

The incidence of treatment-related adverse events of each grade was 86% (52%) in the combination treatment group, 61% (12%) in the nivolumab group, and 50% (8%) in the placebo group.

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.

In this large study of 569 patients, 56% of patients had platinum-sensitive relapses, but the primary study endpoint OS was still negative between the two groups (7.5 vs. 8.4 months, HR=0.86) . in PFS satisfied Wu Li You monoclonal antibody group numerically even worse (1.4 vs. 3.8 months; the HR = 1.41) , the ORR similar between the two groups (13.7% FC vs. 16.5%) , but the reaction duration ICIs group Better (8.3 vs. 4.5 months) .

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

In the KEYNOTE-158 study , patients with advanced tumors including SCLC were included, and all patients received at least one chemotherapy regimen. After enrollment, pembrolizumab was given intravenous injection of 200 mg once every 3 weeks for 2 years.

Final result analysis: After an average of 9.3 months of follow-up of 107 patients, the ORR of pembrolizumab treatment was 18.7%, including 3 cases of CR, 17 cases of PR, 12 cases of stable disease (SD) , and 62 cases of disease progression (PD). .

The disease control rate was 30%; the median PFS was 2.0 months, and the median OS was 8.7 months; among those with positive PD-L1 expression, ORR reached 35.7%, while among those with negative expression, it was 6.0%; PFS was 2.1, respectively Months and 1.9 months.

In particular, it should be noted that the median overall survival time of PD-L1 positive group was significantly higher than that of negative group (14.9 months vs. 5.9 months) .

In the KEYNOTE-028 study , the SCLC cohort enrolled 24 patients with advanced SCLC who had undergone multiple treatments in the past.

The data showed that the ORR of this cohort was 33.3% (n=8/24) , the CR rate was 4.2% (1 case) , and the PR rate was 29.2% (7 cases) . 1 patient had SD and 13 patients had PD.

The relief is durable, with an mDoR of 19.4 months. In addition, mPFS was 1.9 months (PFS rate: 28.6% at 6 months, 23.8% at 12 months) . mOS is 9.7 months (OS rate: 66.0% at 6 months, 37.7% at 12 months) .

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. From the baseline characteristics of the patients, the patients were balanced in age, gender, ECOG score, smoking status, lactate dehydrogenase level, and liver metastasis; 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, the mPFS of pembrolizumab combined with chemotherapy and chemotherapy 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 of patients were 45.1% and 39.6%, and the 24-month OS rates were 22.5% and 11.2%.

Pembrolizumab combined with chemotherapy group has an advantage in 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 the KEYNOTE-604 research data, on March 2, 2021, Pembrolizumab negotiated with the FDA to withdraw its SCLC indication approval application.

Summary

Exploring immunotherapy in SCLC, the first two PD-1 related drugs the FDA’s accelerated approval, but in later clinical trials, we are satisfied that Wu Li You monoclonal antibody and Pabo Li natalizumab study failed to meet expectations, and thus 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.

Immunotherapy for small cell lung cancer: Comparison between PD-1 and PD-L1.

(source:internet, reference only)

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