Sitravatinib Plus Nivolumab Induces Durable Responses in Advanced NSCLC After ICIs, Chemotherapy

Maurice Perol, MD

Post-hoc analysis results from the MRTX-500 trial (NCT02954991) show that the TAM and VEGFR2 targeted spectrum-selective tyrosine kinase inhibitor, sitravatinib (Sitra) administered in combination with nivolumab (Opdivo) elicited durable response and showed robust survival outcomes for patients with non-small cell lung cancer (NSCLC) who progressed after deriving benefit from treatment with a checkpoint inhibitor and/or platinum doublet chemotherapy.¹

According to results presented during the ESMO Congress 2021, 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.

“As many as 70% of patients with NSCLC have progression of their disease on or after receiving checkpoint inhibitor therapy, leaving these patients with a continued unmet medical need,” lead author Ticiana A. Leal, MD, director of the medical thoracic oncology program at the University of Wisconsin Carbone Cancer Center in Madison, said in a news release. “Targeting the TAM and VEGFR receptor tyrosine kinases has been shown to modulate the tumor microenvironment toward a less immunosuppressive state. The encouraging results presented today support combining sitravatinib with a checkpoint inhibitor to help augment the antitumor response.”

All patients with advanced NSCLC without oncologic addiction who are eligible for immunotherapy receive anti–PD-1/PD-L1 therapy plus a platinum-based doublet. Subsequent treatment is based on docetaxel and continuing treatment with the checkpoint inhibitor and adding another agent to overcome resistance is one option for improving outcomes. In this study, investigators added sitravatinib, a multikinase inhibitor with a strong rationale for boosting anti–PD-1/PD-L1 activity, to nivolumab.

As of October 2020, 68 patients had received 120 mg daily sitravatinib 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 deriving benefit on or after treatment with a checkpoint inhibitor and/or platinum doublet chemotherapy. The anti–PD-1/PD-L1 treatment had to be the most recent line of therapy and patients had to have displayed CR, PR, 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, actionable driver mutations, unacceptable toxicity with a checkpoint inhibitor, or impaired heart function were not eligible.²

The median patient age was 66.0 years (range, 37-87). Most patients were women (57%), White (85%), and prior smokers (69%). Eighteen percent were never smokers.

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

Nineteen (28%) received prior nivolumab, 45 (66%) received prior pembrolizumab, 3 (4%) received prior atezolizumab, and 1 (2%) received prior durvalumab. Two (3%) patients had CR, 30 (44%) had PR, and 36 (53%) had SD as the best response to prior therapy 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 end point was ORR as defined by RECIST 1.1. Secondary end points included safety, tolerability, DOR, PFS, and OS.

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

“We have encouraging activity of this combination in patients with acquired and not primary resistance to anti–PD-1/PD-L1,” Maurice Perol, MD, of Centre Léon Bérard, Lyon, France, said in a discussant. “This benefit seems to be driven by some long-lasting responders or long lasting 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 (NSQ)non-small cell lung cancer (NSCLC) progressing on or after prior checkpoint inhibitor (CPI) therapy. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract 1191O.}

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