Checkpoint inhibitor therapy (CPI) has demonstrated the potential for eliciting anti-tumor responses and extending survival in non-small cell lung cancer (NSCLC). However, a majority of patients who initially benefit from this therapy eventually develop resistance as the disease progresses. 

Mirati's tyrosine kinase inhibitor, sitravatinib, which had a wide range of potential applications, had always appeared as a risky endeavor. On the other hand, the most unexpected aspect of yesterday's outcome in the SAPPHIRE trial was its failure. Mirati also presented KRYSTAL-7 study’s data at ESMO 2023, where KRAZATI (adagrasib) in combination with pembrolizumab showed a remarkable response rate and less liver toxicity than its competitor.

Sitravatinib, a receptor tyrosine kinase inhibitor, can resensitize tumors to CPI by shifting the tumor microenvironment towards a less immunosuppressive state and, combined with nivolumab, may overcome acquired CPI resistance and improve outcomes vs. chemotherapy. Sitravatinib, one of the most promising assets of Mirati Therapeutics, was in the late stage of its development. Based on Phase II findings, it was thought that immunotherapy rechallenge with the addition of the immune-stimulating effects of sitravatinib may help reverse resistance however, in the Phase III SAPPHIRE study, patients with advanced non-squamous NSCLC who initially benefited from CPI with/after platinum-based chemotherapy with subsequent disease progression indicate no improvements over standard chemotherapy.

As of March 2023, the median OS was not significantly improved by the combination vs. docetaxel, the median PFS was 4.4 vs. 5.4 months for docetaxel. ORR was 15.6% with sitravatinib plus nivolumab vs. 17.2% with docetaxel. Safety profiles were consistent with prior reports for each regimen. The most common any-grade treatment-related adverse events were diarrhea (56%), nausea (31.3%), and decreased appetite (29%) with the combination of sitravatinib plus nivolumab, and diarrhea (36%), fatigue (36%), nausea and decreased neutrophil count (32% each) with docetaxel.

KOL insights

“Unfortunately, SAPPHIRE was a negative trial. No difference in OS (HR 0.86, mOS 12.2 vs 10.6m). PFS is numerically longer with docetaxel. RR similar (16%, 17%). Patients with no smoking history seemed to do better with docetaxel.” -MD, Director of Thoracic Oncology & Developmental Therapeutics, US

“SAPPHIRE evaluating TAM shift in acquired IO resistance. Sadly OS negative and despite huge trials efforts, docetaxel remains SoC after chemo-IO resistance. Can anything beat it? -Thoracic Oncologist, UK

Conclusion

The shift towards using ICIs as first-line treatment for advanced NSCLC has left an unmet need for effective subsequent treatment options. Sitravatinib was Mirati’s one of the most promising therapies in late-stage development. The drug was anticipated to overcome various resistances by reversal of an immunosuppressive tumor microenvironment by inhibiting TAM family receptors and RTKs, despite showing encouraging results in previous clinical studies the combination misses the primary endpoints of the SAPPHIRE study hence proving no clinical benefit. The combination of sitravatinib plus nivolumab did not yield a statistically significant improvement in overall survival when compared to the standard treatment of docetaxel for patients with NSCLC. The safety profiles of both treatment regimens remained consistent with prior findings, with no new safety concerns identified. This setback signals the end of the road for sitravatinib, since the company had intended to utilize the early results to support an FDA application for approval in second- and third-line NSCLC. The need for further research is evident, as identifying effective treatment options for patients who develop resistance to CPI therapy in NSCLC remains a critical and ongoing challenge in the field of oncology.

PD-L1 therapies are mainly utilized in patients without genetic drivers. Merck’s KEYTRUDA is generally considered the ‘gold standard’ of care in 1L NSCLC when combined with platinum chemotherapy, regardless of PD-1 status. DelveInsight estimates that the total PD-L1 in NSCLC market size in the 7MM is expected to reach ~USD 20 million by 2032.

For more insight into the patient's burden/epidemiology, treatment, and changing market landscape-related advancements, refer to the Programmed death-ligand 1 (PD-L1) Non-small Cell Lung Cancer (NSCLC) Market Report