Sitravatinib Plus Nivolumab induces lasting responses in advanced NSCLC after IBI, chemotherapy

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According to the results presented at the ESMO 2021 congress, the objective response rate (ORR) was 18%. Three percent of patients had a complete response (CR) and 15% of patients had a partial response (PR). The median duration of response (DOR) was 12.8 months.

The median progression-free survival (PFS) was 5.7 months (95% CI, 4.9-7.6). The median overall survival (OS) was 14.9 months (95% CI, 9.3-21.1). Fifty-six percent of patients were alive at 1 year and 32% were alive at 2 years.

“Up to 70% of patients with NSCLC have disease progression during or after receiving checkpoint inhibitor therapy, leaving these patients with an ongoing unmet medical need,” lead author Ticiana A. Leal, MD, director of the medical thoracic oncology program at the University of Wisconsin Carbon Cancer Center in Madison, said in a press release. “Targeting of TAM and VEGFR receptor tyrosine kinases has been shown to modulate the tumor microenvironment towards a less immunosuppressive state. The encouraging results presented today support the combination of sitravatinib with a checkpoint inhibitor to help increase the anti-tumor response.

All patients with advanced NSCLC without oncologic dependence who are eligible for immunotherapy receive anti-PD-1 / PD-L1 therapy plus a platinum doublet. Further treatment is based on docetaxel and continuing treatment with the checkpoint inhibitor and adding another agent to overcome resistance is an option to improve results. In this study, researchers added sitravatinib, a multikinase inhibitor with strong justification for stimulating anti-PD-1 / PD-L1 activity, to nivolumab.

As of October 2020, 68 patients had received 120 mg sitravatinib per day plus 240 mg nivolumab every 2 weeks or 480 mg nivolumab every 4 weeks in continuous 28-day cycles. Eligible patients had locally advanced, unresectable or metastatic NSCLC and experienced progression after benefiting from or following treatment with a checkpoint inhibitor and / or doublet platinum chemotherapy. Anti-PD-1 / PD-L1 therapy had to be the most recent line of treatment and patients had to have had CR, RP or stable disease (SD) for at least 12 weeks. All patients had an ECOG performance score of 0 to 2.

Patients with uncontrolled brain tumors, exploitable motor mutations, unacceptable toxicity with a checkpoint inhibitor, or impaired cardiac function were not eligible.2

The median age of the patients was 66.0 years (range, 37-87). Most of the patients were women (57%), whites (85%) and previous smokers (69%). Eighteen percent have never smoked.

Seventy-three percent of patients received platinum-based chemotherapy; 7% received cisplatin and 66% received carboplatin.

Nineteen (28%) received nivolumab in the past, 45 (66%) received pembrolizumab, 3 (4%) received azeolizumab, and 1 (2%) received durvalumab. Two (3%) patients had CR, 30 (44%) had PR, and 36 (53%) had SD as the best response to previous treatment with a checkpoint inhibitor.

Most patients (66%) had an ECOG performance score of 1, 27% had a score of 0 and 7% had a score of 2.

The primary endpoint was ORR as defined by RECIST 1.1. Secondary endpoints included safety, tolerability, DOR, PFS, and OS.

Sixty-six percent of patients experienced grade 3/4 treatment-related adverse events, most commonly hypertension (22%) and diarrhea (16%). Sixty percent of patients required sitravatinib dose reductions and 21% discontinued treatment.

“We have encouraging activity of this combination in patients with acquired and non-primary resistance to anti-PD-1 / PD-L1,” said Maurice Perol, MD, of the Léon Bérard Center, Lyon, France, in a speaker. “This advantage appears to be due to some long-lasting responders or long-term stability, but at the cost of a significant level of toxicity.”

Reference

1. Leal TA, Berz D, Rybkin I, et al. MRTX-500: Phase II trial of sitravatinib (sitra) + nivolumab (nivo) in patients (pts) with non-squamous cell lung cancer (NSQ) non-small cell (NSCLC) progressing with or after previous treatment by checkpoint inhibitor (IPC). Presented at: ESMO 2021 Congress; September 16-21, 2021; virtual. Abstract 1191O.

2. Phase 2 study of glesatinib, sitravatinib or moketinostat in combination with nivolumab in non-small cell lung cancer. Accessed September 19, 2021. https://bit.ly/3koQ7MB

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