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

Author: Wang Fudong

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.

In the field of small cell lung cancer, PD-L1 outperforms PD-1

However, PD-1 treatment of small cell lung cancer is not completely without positive signals.

In this article, we will provide a list of key clinical data of several PD-(L)1 products in the field of small cell lung cancer

PD-L1 monoclonal antibody: one step ahead, two approved first-line indications

Atelizumab

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

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

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

Duvalizumab

The CASPIAN study is a randomized, open, global multi-center phase III clinical trial on the first-line treatment of ES-SCLC patients.

In November 2019, the FDA granted Duvalvumab combined with etoposide/cisplatin or carboplatin as the priority review qualification for the first-line treatment of extensive SCLC

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

PD-1 mAb: Two indications have been withdrawn, but dawn is beginning

On December 30 last year, nivolumab withdrew its indication for small cell lung cancer due to the successive failures of the two phase III clinical trials of CheckMate-331 and CheckMate-451.

However, in the first-line SCLC, Fuhong Henlius' PD-1 inhibitor has achieved positive results for OS in phase 3 clinical trials, which may be expected to bring dawn to the treatment in this field

Navulimab

Nivolumab's indications for the third-line treatment of small cell lung cancer were approved by the FDA in August 2018 based on data from the Phase I/II CheckMate-032 trial (NCT01928394)

In the CheckMate-032 study, the overall response rate (ORR) of patients treated with nivolumab was 11.

After approval, Bristol-Myers Squibb also conducted a large-scale confirmatory phase III clinical trial for small cell lung cancer to evaluate overall survival data

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

CheckMate-331 is an open, randomized phase III clinical trial, mainly for ES-SCLC patients who relapse after first-line platinum chemotherapy.
The use of nivolumab and standard chemotherapy is a comparative trial
.
In this large study of 569 patients, 56% of patients had platinum-sensitive relapses, but the main study endpoint OS was still negative between the two groups (7.
5 vs.
8.
4 months, HR=0.
86).
PFS was even worse in the nivolumab group (1.
4vs.
3.
8 months; HR=1.
41), ORR was similar between the two groups (13.
7%vs.
16.
5%), but the duration of response was in the ICIs group Better (8.
3vs.
4.
5 months)
.

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

Pembrolizumab

Pembrolizumab was approved by the FDA for the third-line treatment of SCLC in June 2019, based on the ORR and DOR data (third-line) of KEYNOTE-158 (G group) and KEYNOTE-028 (C1 group)
.
It was approved for one and a half years.
Because the phase 3 clinical KEYNOTE-604 study failed to meet the OS focus, Merck voluntarily withdrew this indication
.

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 107 patients were followed up for an average of 9.
3 months, 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 the people with positive PD-L1 expression, the ORR reached 35.
7%, while among the negative people, 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 remission 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 was 9.
7 months (OS rate: 66.
0% at 6 months, 37.
7% at 12 months)
.

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 compared 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 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 the pembrolizumab combined chemotherapy group and the 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%, respectively, 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, pembrolizumab combined with chemotherapy group and chemotherapy group were 70.
6% and 61.
8%, respectively, and 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
.

Slulimumab

On December 7th, Henlius announced a randomized, double-blind, international multi-center for the PD-1 inhibitor slulimumab combined with chemotherapy in previously untreated extensive-stage small cell lung cancer (ES-SCLC) Phase III clinical study ASTRUM-005 (NCT04063163) reached the primary study endpoint of overall survival (OS) in the first interim analysis
.

The ASTRUM-005 study was conducted by Professor Cheng Ying from Jilin Provincial Tumor Hospital as the main investigator and was conducted in 128 test centers in China, EU Poland, Russia, Turkey, Ukraine, Georgia and other countries
.
The primary endpoint of the study is overall survival (OS), and secondary endpoints include progression-free survival (PFS), PFS2, objective response rate (ORR), duration of response (DOR), safety, pharmacokinetic characteristics, and immunity Originality and so on
.

As of October 22, 2021, a total of 585 qualified subjects were enrolled in the study (slulimumab group: n=389; placebo group: n=196), and the median follow-up time was 12.
3 months
.
The median OS of the slulimumab group and the placebo group were 15.
38 months and 11.
10 months, respectively, and the hazard ratio (HR) was 0.
62 (95%CI: 0.
48, 0.
80), p<0.
001
.
The 2-year overall survival rate (OSR) of the two treatment groups was 43.
2% and 8.
0%, respectively
.
In the Asian population, the median OS of the slulimumab group and the placebo group were 16.
03 months and 11.
10 months, respectively, and the hazard ratio (HR) was 0.
59 (95%CI: 0.
44, 0.
79), p<0.
001
.

The test results show that slulimumab combined with carboplatin-etoposide can significantly improve the OS of first-line ES-SCLC patients, and has good safety
.
On December 7, according to a preset interim analysis conducted by the Independent Data Monitoring Committee (IDMC), IDMC recommended that the results of the validity analysis be reported in advance
.
Based on the positive test results of this research, Henlius will submit an application for listing and registration for this indication as soon as possible
.

summary

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

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
.

However, according to the Insight database, domestic PD-1 R&D companies have not given up the field of small cell lung cancer
.
In addition to Fuhong Henlius, which has officially announced positive results, BeiGene and Junshi Biologics PD-1 monoclonal antibody has also initiated phase 3 clinical trials for small cell lung cancer, and Xinda has launched an evaluation of its PD- 1/PD-L1 double anti-IBI318 in the treatment of small cell lung cancer phase Ib/III clinical
.

Domestic PD-1 monoclonal antibody & double antibody for SCLC Phase III clinical development

picture

From: Insight database (http://db.
dxy.
cn/v5/home/)