The safety and efficacy achieved with the combination of savolitinib and durvalumab vs standard-of-care sunitinib or durvalumab monotherapy will be evaluated in patients with MET-driven papillary renal cell carcinoma in the phase 3 SAMETA trial.
The safety and efficacy achieved with the combination of savolitinib and durvalumab (Imfinzi) vs standard-of-care sunitinib (Sutent) or durvalumab monotherapy will be evaluated in patients with MET-driven papillary renal cell carcinoma (RCC) in the phase 3 SAMETA trial (NCT05043090).1
The trial’s primary end point is progression-free survival (PFS) according to blinded independent review and RECIST v1.1 criteria.
Patients with papillary RCC often experience worsened clinical outcomes and have a higher likelihood of disease metastasis. This prognosis is further compounded by the lack of approved therapies specifically designed for this disease. A substantial percentage of these cases are determined to be driven by genomic abnormalities that cause dysregulation of the MET-signaling pathway. Accordingly, these abnormalities may be a viable target for treatment.
“As the MET pathway may play a role in immunomodulation, data suggest that combining MET
inhibition [e.g. savolitinib] with a checkpoint inhibitor [e.g. durvalumab] may provide a synergistic, antitumor effect,” lead study author Toni K. Choueiri, MD, of Dana-Farber Cancer Institute, and colleagues, wrote in a poster of the trial.
The highly-selective oral MET inhibitor, savolitinib, was previously found to have acceptable safety and early activity with numerically superior survival vs sunitinib in patients with MET-driven papillary RCC in the phase 3 SAVOIR study (NCT03091192). The median PFS was 5.6 months (95% CI, 4.1-6.9) with sunitinib vs 7.0 months (95% CI, 2.8-not calculated [NC]) with savolitinib monotherapy (HR, 0.71; 95% CI, 0.37-1.36; 2-sided P = .313. The median overall survival (OS) was 13.2 months (95% CI, 7.6-NC) with sunitinib vs NC (95% CI, 11.9-NC) with savolitinib (HR, 0.51; 95% CI, 0.21-1.17; 2-sided P = .110). Savolitinib also produced a partial response rate of 27% (95% CI, 13.3%-45.5%) vs 7% with sunitinib (95% CI, 0.9%-24.3%).2 Notably, premature termination of the SAVIOR study limited sample size and subsequent follow-up.1
Several other non-clinical studies have indicated the potential for MET and PD-L1 inhibitors to have synergistic antitumor effects when administered in combination. For example, initial data from the phase 1/2 CALYPSO studyshowed that savolitinib and durvalumab generated a positive efficacy signal in the MET-driven papillary RCC population, despite producing negative results in those with clear cell histology.3 The overall response rate (ORR) in this subgroup was 57%, with a median PFS of 10.5 months (95% CI, 2.9-15.7) and a median OS of 27.4 months (95% CI, 7.3-not reached).1
“Based on [this] phase 2 study…we know that there’s a significant response rate with that combination only in MET-positive patients, so we [are running] this phase 3 study in those 30% to 40% of patients who [have] MET-driven [disease],” Choueiri explained in an interview with OncLive®.
The open-label, three-arm, multicenter, phase 3 SAMETA study is enrolling patients 18 years of age or older with histologically confirmed unresectable and locally advanced or metastatic PRCC. To be eligible for enrollment, patients must not have had any prior exposure to systemic anticancer therapies in the metastatic setting, or to MET inhibitors, durvalumab, or sunitinib in any disease setting. Centrally confirmed MET-driven disease without co-occurring familial hypercholesterolemia (FH) mutations is also required. This will be assessed with a sponsor-designated, validated, next-generation sequencing assay. MET-driven papillary RCC is defined as detection of chromosome 7 gain, MET amplification, MET kinase domain variations, and/or HGF amplification.
If patients have a history of liver cirrhosis or other serious liver disease, exhibit spinal cord compression or brain metastases, and/or have active or prior cardiac disease or clinically significant electrocardiographic abnormalities, they will be excluded. Other key exclusion criteria include active infection, including COVID-19; active interstitial lung disease; active or previously documented autoimmune and inflammatory disorders; and receipt of live attenuated vaccine within 30 days prior to the first dose of study intervention.
Investigators aim to enroll approximately 200 patients onto the study across 25 countries at 165 global centers. Screening will be conducted prior to randomization in 2 parts. In part 1, patients will undergo prospective testing to confirm that their tumor is driven by MET and determine PD-L1 status. Patients with confirmed MET-driven papillary RCC will proceed to part 2 screening, which will determine whether the patient meets remaining inclusion criteria.
Study participants will be randomly assigned 2:1:1 to savolitinib and durvalumab (arm A), sunitinib monotherapy (arm B), or durvalumab monotherapy (arm C).
“Why sunitinib? The simple reason is that this is a global study where sometimes cabozantinib [Cabometyx] hasn’t been accepted or isn’t available,” Choueiri notes in the interview.
Patients will be stratified according to International Metastatic RCC Database Consortium risk group (poor vs intermediate vs favorable), as well as PD-L1 expression (1% or greater vs less than 1%).
In arm A, patients will receive a daily 600-mg dose of savolitinib with 1500 mg of durvalumab every 4 weeks. Those in arm B will be given 50 mg of sunitinib daily for 4 weeks, followed by 2 weeks off treatment. Treatment in arm C consists of 1500 mg of durvalumab administered every 4 weeks.
Imaging assessments will also be performed for all participants approximately every 4 weeks for the first 54 weeks after randomization, and then approximately every 12 weeks. This will continue until radiologic disease progression, as confirmed by RECIST v1.1 criteria and an additional follow-up scan, or other discontinuation criterion are met.
Notably, those in arm C will be allowed to crossover to arm A in the event of disease progression. No intervening systemic anticancer therapy will be necessary to administer following the discontinuation of single-agent durvalumab. Crossover will not be permitted in any other circumstances.
Secondary end points in the trial include OS, ORR as determined by BICR and per RECIST 1.1 criteria, duration of response, and pharmacokinetics. Adverse effects will also be assessed to determine safety.
During biomarker pre-screening, approximately 28% of patients with papillary RCC who submitted a sample were found to have eligible MET-driven status. Approximately 70% of these patients also met other eligibility criteria during the second round of screening and were accordingly randomly assigned to a treatment group.
Study enrollment is ongoing, with the first participant enrolled onto the study in October 2021.
Disclosures: Choueiri listed the following disclosures: stock ownership and honoraria with Curesponse, Osel, Pionyr, Precede Bio, and Tempest Therapeutics; consulting or advisory roles with Alkermes, Analysis Group, Aravive, Arcus Biosciences, ASCO, AstraZeneca, Bayer, Bristol-Myers Squibb, Clinical Care Options, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, Gilead Sciences, GlaxoSmithKline, Harborside Press, Infinity Pharmaceuticals, Ipsen, Janssen Oncology, Kanaph Therapeutics, Lancet Oncology, Lilly, Merck, MJH Life Sciences, Navinata Health, NCCN, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Precede Bio, Prometheus, Roche/Genentech, Sanofi/Aventis, Scholar Rock, Tempest Therapeutics, The New England Journal of Medicine, and UpToDate.
Research funding was received from Agensys, Arcus Biosciences, AstraZeneca, AVEO, Bayer, Bristol-Myers Squibb, Calithera Biosciences, Eisai, Exelixis, GlaxoSmithKline, Ipsen, Merck, NiKang Therapeutics, Novartis, Peloton Therapeutics, Pfizer, Roche, Roche/Genentech, Seattle Genetics/Astellas, Takeda, and TRACON Pharma. Patents and royalties were provided by Biomarkers of Clinical Response and Benefit to Immune Checkpoint Inhibitor Therapy, ctDNA technologies, and PBRM1 Biomarkers Predictive of Anti-Immune Checkpoint Response; and travel expenses were received from Alexion Pharmaceuticals, Allegiant, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Cerulean Pharma, Clinical Care Options, Corvus Pharmaceuticals, Eisai, EMD Serono, ESMO, Exelixis, Foundation Medicine, GlaxoSmithKline, Harborside Press, HERON, Ipsen, Kidney Cancer Association, Lancet Oncology, Lilly, Lpath, Merck, MJH Life Sciences, Navinata Health, NCCN, Novartis, Peloton Therapeutics, Pfizer, PlatformQ Health, Prometheus, Roche/Genentech, Sanofi/Aventis, The New England Journal of Medicine, and UpToDate. Medical writing and editorial assistance support may have been funded by communications companiesfunded by pharmaceutical companies such as ClinicalThinking, Health Interactions, Envision Pharma Group, Fishawack Group of Companies, and Parexel.