CALYPSO: combined MET and PD-L1 inhibition shows promise in a cohort of patients with MET-driven metastatic papillary renal cancer.

 

• Results of the phase II single arm, multi-site international CALYPSO study point to the efficacy of combining potent MET inhibitor savolitinib with PD-L1 inhibitor durvalumab in a cohort of patients with MET-driven metastatic papillary renal cancer. First authored by VHIO’s Cristina Suárez, these data have now published in the Journal of Clinical Oncology ⁽¹⁾.

 

• Metastatic papillary renal cancer has a poor prognosis with few treatment options available. Based on preclinical data suggesting positive interaction between MET and PD-L1 inhibition, the CALYPSO investigators, led by Thomas Powles, Barts Cancer Institute, London, UK, assessed the safety and clinical activity of this dual therapeutic strategy.

 

• While the combination of savolitinib and durvalumab did not reach the primary endpoint of a response rate higher than 50% in the global treated population, responses observed in patients presenting alterations in the MET gene show promise.

 

• Considering the observed tolerability of this combination and initial efficacy in patients with MET-driven tumors, this combined approach is now being tested in the randomised phase III SAMETA study.

 

Advanced papillary renal cancer (PRC) has a poor prognosis with few treatment options available. Approximately 30% of patients with this disease present alterations in the MET gene that encodes a hepatocyte growth factor receptor. Mutations in this gene are implicated in disease progression and can also contribute to cancer drug resistance. While the association of MET mutations with the development of this kidney cancer subtype has been well described, the effect of specifically targeting this gene is unclear.

Aimed at identifying new and more potent treatment avenues for these patients, the CALYPSO investigators spearheaded by Thomas Powles, Barts Cancer Institute, London (UK), have assessed the efficacy of different treatment combinations in patients with metastatic renal carcinoma, including the combination of savolitinib, a potent MET inhibitor, plus immunotherapy durvalumab which is already used to treat several tumor types, but not approved for renal cancer. 

Results of the papillary renal cancer cohort, which was part of a wider study assessing the efficacy and toxicity of this combined approach in clear cell and papillary subsets that split into two separate expansion phases, have now published online ahead of print in the Journal of Clinical Oncology ⁽¹⁾. 

“Here we report he results of the metastatic papillary renal cancer cohort. Based on previous single arm studies showing that savolitinib monotherapy achieved response rates of 18% in patients with MET gene alterations ⁽²⁾, as well as promising preclinical data ⁽³⁾ suggesting a positive interaction between MET and PD-L1 inhibition, this single arm study included 41 patients with advanced PRC, 17 of which had MET-driven tumors,” says Cristina Suárez, a Clinical Investigator of the Vall d’Hebron Institute of Oncology’s (VHIO) Genitourinary, Central Nervous System (CNS) Tumors, and Sarcoma Group, and first author of this study.

MET-driven status was defined as chromosome 7 gain, MET amplification, MET kinase domain variations, or hepatocyte growth factor amplification, which expanded the clinical trial population given that all these alterations can be implicated in the progression of papillary renal cancer and influence cancer drug resistance. Treatment naïve or previously treated patients with metastatic PCR participated in this study and the primary endpoint was a confirmed response rate of higher than 50%.

The combination of savolitinib and durvalumab did not achieve the primary endpoint in the global treated population, but a positive response was observed in those patients with MET-driven tumors, with reported response rates of 29% and 53%, respectively. A median progression-free survival of 12 months was observed in the patients with MET-driven status versus 4.9 months in the global treated population. Adverse events were in line with expectations for these two agents with grade 3 or 4 adverse events in 17 (41%) patients.

“Our results show that this combination is tolerable and shows promising activity in patients with MET mutations. While the prognostic significance of MET alterations and PD-L1 expression is not well-defined, data from our exploratory biomarker analysis point to MET as a more promising new biomarker over PD-L1 for this treatment combination,” adds Suárez.

 

She concludes, “While the numbers are small, the results of our subset study justify further evaluation of MET-driven tumors. Based on our data, the phase III SAMETA study is currently underway to investigatae savolitinib plus durvalumab versus sunitinib and durvalumab monotherapy in MET-driven, unresectable and locallly advanced or metastatic PRC.”
 

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Acknowledgments:

The authors thank the patients and their families as well as all of the investigators and their staff involved in CALYPSO. The Experiment Cancer Medicine Centre at Barts Cancer Institute organized and had oversight of all aspects of the study. T.P. was the chief investigator, AstraZeneca performed aspects of the biomarker analysis. Queen Mary University of London was the Sponsor of the study. AstraZeneca granted QMUL funding for the study and supplied the study drug.

They express gratitude to the members of the Data Monitoring Committee: M. Bower, Chelsea and Westminster Hospital NHS Foundation Trust; P. Schmid, Queen Mary University London, and the following people who helped with the study: C. Lawrence, R. Boussiga, C. Tyson and M. McLaughlin-Callan of the Experiment Cancer Medicine Centre at Barts Cancer Institute; Júlia Calonge Comas and Olga Sánchez-Maroto Carrizo of the Academic Research Organization, Vall d’Hebron Institut de Recerca, Spain. They acknowledge Cancer Research UK, the UK Experimental Cancer Medicine Network and AstraZeneca for funding.

References:

1.Cristina Suárez, James M. G. Larkin, Poulam Patel, Begoña P. Valderrama , Alejo Rodriguez-Vida, Hilary Glen, Fiona Thistlethwaite, Christy Ralph, Gopalakrishnan Srinivasan, Maria Jose Mendez-Vidal, Ryan Hartmaier, Aleksandra Markovets, Aaron Prendergast, Bernadett Szabados, Kelly Mousa, Thomas Powles. Phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). DOI: 10.1200/JCO.22.01414 J Clin Oncol. Published online February 21, 2023.

2. Choueiri TK, Plimack E, Arkenau HT, Jonasch E, Heng DYC, Powles T, Frigault MM, Clark EA, Handzel AA, Gardner H, Morgan S, Albiges L, Pal SK. Biomarker-Based Phase II Trial of Savolitinib in Patients With Advanced Papillary Renal Cell Cancer. J Clin Oncol. 2017 Sep 10;35(26):2993-3001.

3. Balan M, Mier y Teran E, Waaga-Gasser AM, Gasser M, Choueiri TK, Freeman G, Pal S. Novel roles of c-Met in the survival of renal cancer cells through the regulation of HO-1 and PD-L1 expression. J Biol Chem. 2015 Mar 27;290(13):8110-20. 

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