Voice of China | sitravatinib + tislelizumab in the treatment of advanced melanoma, DCR reaches 88%!

The 2021 American Association for Cancer Research (AACR) Annual Meeting will be held online on April 10-15 and May 17-21, 2021.

This annual conference covers the most cutting-edge research results in the field of oncology.

In this conference, the results of a number of major studies in the field of melanoma were announced.
This article compiled a phase Ib study by Professor Guo Jun's team from Peking University Cancer Hospital and a study on adjuvant treatment of melanoma.

The details are as follows: sitravatinib combined with tislelizumab in the treatment of advanced melanoma has a DCR of 88%! Background Although PD-1/PD-L1 inhibitors can improve the treatment effect of melanoma, some patients still have not been relieved or have drug resistance.

Sitravatinib is a selective tyrosine kinase inhibitor (TKI) that can target to inhibit TAM receptors (Tyro3, ​​Axl, MerTK) and VEGFR2, reduce the number of suppressor cells and regulatory T cells derived from bone marrow, and increase M2 at the same time The ratio of macrophages transformed into M1 macrophages can overcome the tumor immunosuppressive microenvironment and enhance the anti-tumor effect.

Tilelizumab is a PD-1 inhibitor that can reduce the binding of FcγR on the surface of macrophages and avoid antibody-dependent phagocytosis.

Tilelizumab monotherapy and combination chemotherapy have shown clinical activity in patients with advanced solid tumors, including melanoma.

Methods Researchers report the results of the melanoma cohort in an ongoing multi-cohort phase Ⅰb study (BGB-900-103; NCT03666143), which aims to evaluate sitravatinib combined with tislelizumab in advanced solid tumors Safety/tolerability and preliminary anti-tumor activity.

Eligible patients are patients with PD-1/PD-L1 refractory/resistant, unresectable or metastatic melanoma, and have not received other immunotherapy (such as anti-CTLA-4, anti-OXO40 or anti-CD137) or Anti-BRAF/MEK treatment.

The patient received 120mg sitravatinib orally once a day, combined with tislelizumab 200mg intravenously once every three weeks, until the drug withdrawal standard was reached.

The primary endpoint is safety/tolerability, and secondary endpoints include the objective response rate (ORR), disease control rate (DCR), and progression-free survival (PFS) assessed by the investigator.

Results As of October 13, 2020, a total of 25 patients were enrolled, of which 16 (64%) were still receiving treatment.

All patients had previously received first-line PD-1/PD-L1 treatment, with a median age of 51 years (23-79 years).

Baseline histology included skin (n=12; 48%), acral (n=7; 28%), and mucosal (n=4; 16%) subtypes.

The median follow-up time was 5.
5 months (1.
5-13.
3 months).

Twenty-five patients (100%) reported adverse events (AEs); the most commonly reported grade ≥3 AE was hypertension (n=3; 12%).

Serious AEs were reported in 4% of patients (n=1/25).

In 13 patients, the dose of sitravatinib was reduced due to AEs.

No deaths caused by AEs occurred.

Six patients achieved partial remission.

ORR was 24.
0% (95% CI, 9.
36-45.
13), DCR was 88% (95% CI, 68.
78-97.
45), and median PFS was 6.
7 months (95% CI, 4.
07-not evaluable).

Conclusion Sitravatinib combined with tislelizumab is well tolerated, with controllable safety/tolerability, and shows preliminary antitumor activity in patients with refractory/drug-resistant unresectable or metastatic melanoma.

The combined effect of the two drugs needs further research.

CheckMate 915 update: Nivolumab is still the standard solution for adjuvant treatment! Background Nivolumab has been shown to have a significant benefit over ipilimumab (AJCC v7) in the adjuvant treatment of patients with stage IIIB/C or IV resectable melanoma.

Compared with nivolumab as a single agent, nivolumab + ipilimumab has numerically shown a long-term survival benefit in patients with metastatic melanoma.

The CheckMate 915 study evaluated the results of nivolumab + ipilimumab (1mg/kg Q6W) adjuvant therapy vs.
nivolumab monotherapy.

Methods CheckMate -915 is a randomized, double-blind, placebo-controlled Phase III study.

Patients with stage ⅢB/C/D or stage Ⅳ melanoma (AJCC v8) who were ≥12 years old and completely resected were enrolled.

Stratified according to tumor PD-L1 expression status and stage.

Patients received nivolumab 240 mg every 2 weeks in combination with ipilimumab 1 mg/kg once every 6 weeks (nivolumab + ipilimumab group), or nivolumab 480 mg every 4 Single-agent treatment once a week ≤ 1 year.

The common endpoint is the recurrence-free survival (RFS) of PD-L1<1% and the intention-to-treat population (ITT), and the exploratory endpoint is the distant metastasis-free survival (DMFS) of stage III patients.

Results A total of 920 patients were randomly assigned to the nivolumab + ipilimumab group, and 924 patients to the nivolumab monotherapy group.
Most patients were stage IIIB (31% vs 31%) or IIIC Stage (53% vs 52%), and complete lymph node dissection (64% vs 64%).

The median duration of treatment in the combination group was shorter than that in the single-agent group (7.
6 months vs 11.
1 months), so the median cumulative dose of nivolumab was lower (3840 mg vs 6240 mg).

In at least 24 months of follow-up, there was no significant difference in RFS and DMFS between the two groups (table).

The incidence of grade 3/4 treatment-related adverse events (TRAEs) in the nivolumumab+ipilimumab group and the nivolumumab single-agent group were 33% and 13%, respectively.
Any grade of TRAEs resulted in the discontinuation of treatment The incidence was 32% and 10%, respectively.

A total of 4 patients with treatment-related deaths (all in the nivolumab + ipilimumab group).

Conclusion In patients with stage IIIB/C/D or stage IV resectable melanoma, nivolumab + ipilimumab did not show significant improvement in RFS and DMFS compared with nivolumumab alone; safety and safety The results of previous studies remain consistent.

In the CheckMate 915 study, the results of nivolumab 480 mg once every 4 weeks are similar to the previous results of nivolumab, which further supports the standard of nivolumab as an adjuvant treatment for the study population, including those who have received and have not received complete lymph node dissection.
patient.

Reference: CT035-Safety/tolerability and preliminary antitumor activity of sitravatinib plus tislelizumab in patients with PD-(L)1 refractory/resistant unresectable or metastatic melanoma from a phase 1b study.
CT004-Adjuvant therapy with nivolumab (NIVO) combined with ipilimumab (IPI) vs NIVO alone in patients (pts) with resected stage IIIB-D/IV melanoma (CheckMate 915)