Study of antibody-Keytruda combination seeds hope for overcoming immune checkpoint inhibitor resistance, use of biomarkers

In a Phase 1 trial, the combination of linavonkibart, a selective anti-latent transforming growth factor-beta 1 (TGFβ1) antibody, and Keytruda (pembrolizumab) exhibited objective response rates of up to 20% in patients with immune checkpoint inhibitor (ICI)-resistant advanced solid tumors, including clear cell renal cell carcinoma (ccRCC). This finding may mean a possible advance in combating ICI resistance, providing optimism for enhanced results in patients for whom treatment choices are limited and perhaps affecting payer approaches for refractory tumors. The researchers also saw an increased role for biomarkers that could be used to help guide treatment decisions.

ICIs have transformed cancer treatment, extending survival in diseases like melanoma and renal cell carcinoma. However, primary or acquired resistance affects 70-80% of patients, often linked to TGFβ1, which fosters an immunosuppressive tumor microenvironment. Linavonkibart, a novel fully human monoclonal antibody developed by Scholar Rock, a Cambridge, Massachusetts, biotech company, selectively inhibits latent TGFβ1 to enhance anti-tumor immunity without the cardiotoxicity seen in pan-TGFβ blockers.

Timothy Yap, Ph.D., from the University of Texas MD Anderson Cancer Center in Houston, and and his colleagues ran a multicenter, open-label study that enrolled 112 patients across the U.S. and South Korea from April 2020 to December 2023. The study had three parts: A1 (linavonkibart monotherapy dose escalation, n=19), A2 (combination dose escalation with Keytruda, n=15), and B (combination dose expansion, n=78). Patients had locally advanced or metastatic solid tumors resistant to prior anti-PD-1/PD-L1 therapy, with a median of three to four prior lines of treatment. Patients in part B included those with ccRCC (n=30), melanoma (n=11), head and neck squamous cell carcinoma (HNSCC, n=11), urothelial cancer (n=11), and non-small cell lung cancer (NSCLC, n=11).

The primary objective of assessing safety and tolerability was met. Linavonkibart showed a manageable profile, with no dose-limiting toxicities in monotherapy or in combination. Treatment-related adverse events occurred in 73% of part B patients, mostly grades 1-2, including rash (33%), pruritus (28%), fatigue (22%), and diarrhea (17%). Grade 3 or higher adverse events affected 32% were dermatological in nature, aligning with Keytruda's known risks but adding skin reactions as a new consideration. No cytokine release syndrome or infusion interruptions were reported. Discontinuation due to adverse events was 27% overall.

Antitumor activity was a key secondary outcome. In part B, confirmed objective response rates were 20% for ccRCC (including one complete response), 18.2% for melanoma, 9.1% for HNSCC, and 9.1% for urothelial cancer, with no responses in NSCLC. Median durations of response ranged from 5.6 months in melanoma to 16 months in HNSCC. Also, disease control rates reached 57% in ccRCC and 64% in melanoma.

Biomarker analyses provided proof of a mechanism during combination therapy.Yap and his colleagues observed increased CD8+ T cell infiltration and activation in tumors, reduced the regulatory T cell-to-activated CD8+ ratio in responders, and lowered circulating granulocytic myeloid-derived suppressor cells.

In their Nature Medicine article, which was published last month, the researchers emphasized linavonkibart's context-independent TGFβ1 inhibition as a strategy to reverse immune exclusion without off-target effects. They highlighted potential biomarkers for ccRCC patient selection, such as baseline elevated CD8+ T cells, regulatory T cells and TGFβ1 expression, which correlated with higher objective response rates and better progression-free survival. This could enable precision medicine, reducing unnecessary exposure and costs for payers facing high costs associated with cancer care. The authors called for phase 2/3 trials to confirm efficacy, noting implications for population health by extending ICI benefits to resistant subgroups, potentially lowering long-term care burdens in oncology.