August 13, 2022

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Immunotherapy for small cell lung cancer: PD-1 vs PD-L1

Immunotherapy for small cell lung cancer: PD-1 vs PD-L1



Immunotherapy for small cell lung cancer: PD-1 vs 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. For non-small cell lung cancer (NSCLC), PD-1 therapy has become the preferred recommendation .

However, the research progress in the treatment of small cell lung cancer (SCLC) has been much slower and has suffered successive setbacks.

In the field of small cell lung cancer, PD-L1 outperforms PD-1. In 2019 and 2020, the FDA approved atelizumab (Tecentriq, Roche) and duvalizumab (Imfinzi, A (Silicon), however, in sharp contrast, the small cell lung cancer indications of PD-1 monoclonal antibody K and O drugs have been withdrawn.

However, PD-1 treatment of small cell lung cancer is not completely without positive signals. On December 7th, Henlius announced the PD-1 inhibitor slulimumab combined with chemotherapy for extensive-stage small cell lung cancer that has not previously been treated.

(ES-SCLC) randomized, double-blind, international multi-center phase 3 clinical (NCT04063163) positive results, in the first interim analysis reached the main research endpoint of overall survival (OS).

This also means that the world’s first anti-PD-1 monoclonal antibody for the first-line treatment of SCLC is expected to be born.

This article 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 atelizumab+etoposide/carboplatin versus placebo+etoposide/carboplatin in the first-line treatment of ES-SCLC.

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

A total of 403 patients with newly treated ES-SCLC were included in this study, and they were divided into a chemotherapy-only group and a chemotherapy combined with ICIs group (atelizumab, 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 3 The incidence of grade /4 AE is similar.

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.  Efficacy in first-line treatment of ES-SCLC patients.

The results showed that the median OS of the duvalizumab+etoposide/cisplatin or carboplatin group was significantly better than that of the chemotherapy group (13.0vs10.3 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 is also similar (98.1% vs 97%).

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. The CSCO guidelines serve as level III recommendations (IA type 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), which further supports the duvalizumab+EP regimen as the first-line standard treatment for ES-SCLC.


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.

On March 2 this year, pembrolizumab was also withdrawn. The indications. The two indications for withdrawal are third-line treatments for small cell lung cancer.

However, in the first-line SCLC, Fuhong Hanlius’ 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 11.9%, with a partial response (PR) rate of 11% and a complete response (CR) rate of 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 had remission lasted more than 18 months.

After approval, Bristol-Myers Squibb also carried out a large-scale confirmatory phase III clinical trial for small cell lung cancer to evaluate overall survival data. However, in the CheckMate-451 and CheckMate-331 trials, nivolumab did not reach the ideal end point of overall survival, and the controversy eventually led to the withdrawal of this indication. This is also the first of the six indications withdrawn this year.

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 also similar (41% vs. 44% vs. 40%). The incidence of treatment-related adverse events in each grade was 86% (52%) in the combined 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 main study endpoint OS was still a negative result between the two groups (7.5 vs. 8.4 months, HR=0.86). PFS was even worse in value in the nivolumab group (1.4 vs. 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 study of KEYNOTE-604 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. Pembrolizumab 200 mg was given intravenously after enrollment, 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 combined chemotherapy group, and 225 patients in the placebo combined chemotherapy group. 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, 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 7, Henlius announced a randomized, double-blind, international multi-center for the PD-1 inhibitor slulimumab combined with chemotherapy in 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 Cancer 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 7th, in accordance with the 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 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.

Immunotherapy for small cell lung cancer: PD-1 vs PD-L1

(source:internet, reference only)


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