Savolitinib Plus Durvalumab Produces Responses, Tolerability in MET-Driven Papillary Renal Cancer Subset

Cristina Suárez, MD

The combination of savolitinib and durvalumab (Imfinzi) induced high response rates with a manageable safety profile in patients with metastatic papillary renal cancer (PRC) with MET-driven disease enrolled to the phase 2 CALYPSO trial (NCT02819596), although the trial missed its primary end point of confirmed response rate (cRR) for the overall study population, according to findings published in the Journal of Clinical Oncology.¹

At a median follow-up of 26.8 months (95% CI, 19.2-34.3), the cRR was 29% (95% CI, 16%-46%) in all treated patients with advanced PRC (n = 41). In the subset with MET-driven disease (n = 17), the cRR was 53% (n = 9; 95% CI, 28%-77%), and in patients with PD-L1–positive disease (n = 27), the cRR was 33% (n = 9; 95% CI, 17%-54%).

“This is, to our knowledge, the first analysis of MET alterations with immune checkpoint inhibition/MET–targeted therapy,” lead study author, Cristina Suárez, MD, of Vall d’Hebron Barcelona Hospital Campus in Spain, and colleagues, wrote in the paper.

PD-L1 is a promising target in kidney cancer, as evidenced in previous studies such as the phase 2 KEYNOTE-427 trial (NCT02853344), in which treatment with the PD-1 inhibitor pembrolizumab (Keytruda) led to an overall response rate of 26.7% and a median overall survival (OS) of 28.9 months (95% CI, 24.3–not reached [NR]) in patients with non–clear cell renal cell carcinoma (RCC).²

CALYPSO investigated the combination of durvalumab, a PD-L1 inhibitor, and savolitinib, a MET inhibitor, in patients with metastatic PRC and clear cell RCC.¹ The results from the PRC cohort were published in the Journal of Clinical Oncology.

Both previously treated and treatment-naïve patients with advanced, biopsy-proven PRC were enrolled in this single-arm, multisite, international trial. Eligible patients included those with an ECOG performance status of 0 or 1, at least 1 measurable lesion per RECIST v1.1 criteria, and an available tissue sample for biomarker assessment. Patients were eligible regardless of prior VEGF-targeted treatment. Additionally, patients needed to have adequate organ function; no underlying second cancers or other serious illnesses; and no contraindications for savolitinib or durvalumab.

The trial featured a safety run-in where patients received savolitinib alone at 600 mg per day for the first 28 days. On day 29, patients began durvalumab at 1,500 mg once every 4 weeks and continued with savolitinib at 600 mg once daily. Savolitinib dose reductions to 400 mg and 200 mg once daily were permitted; however, dose reductions with durvalumab did not occur. Patients were allowed to discontinue or delay savolitinib and/or durvalumab because of adverse effects (AEs).

Patients were treated until disease progression, unacceptable toxicity, patient request to discontinue, or death. Additionally, patients could continue study treatment upon progression, particularly during the first 4 weeks when they received savolitinib alone, provided the treating physician determined the treatment to be beneficial and the patients did not meet any other discontinuation criteria.

The primary end point of CALYPSO was a cRR of over 50% in the overall study population. A cRR of 30% or less would not warrant further investigation. Secondary end points included progression-free survival (PFS), tolerability, OS, and biomarker end points such as PD-L1 and MET status.

In total, 63% of patients (n = 26) had Heng intermediate risk score. Additionally, 34% of patients (n = 14) had received prior treatment for advanced disease, including sunitinib (Sutent; 50%), pazopanib (Votrient; 29%), and other treatments (21%). Regarding biomarker status, of the patients with available tissue samples, 66% (n = 27) had PD-L1–positive disease and 41% (n = 17) had MET-driven tumors.

In the overall population, 0% had a best response of complete response, 27% had a partial response (PR), 10% had stable disease (SD), 49% had progressive disease (PD), 10% were not evaluable (NE), and 5% were not applicable (NA), respectively.

In treatment-naïve patients (n = 27), the cRR was 37%, and the cRR was 14% in previously treated patients (n = 14).

The overall population experienced a median PFS of 4.9 months (95% CI, 2.5-10.0). The median PFS was 12.0 months (95% CI, 2.9-19.4) in the MET-driven population.

The median OS was 14.1 months (95% CI, 7.3-30.7) and 27.4 months (95% CI, 9.3-NR) in the overall and MET-driven populations, respectively. The 1-year OS rates were 54.3% and 70.6% in the overall and MET-driven populations, respectively.

The duration of response was 9.4 months (95% CI, 5.5-NR) and 11.5 months (95% CI, 3.9-NR) in the treated population and patients with MET-driven disease, respectively. Overall, 24% of patients (n = 10) progressed after the first 4 weeks of study therapy. Of these patients, 7 discontinued the study with no subsequent imaging, 2 achieved stable target lesions with the combination, and 1 progressed on the combination. Study authors noted that the 4-week safety run-in with single-agent savolitinib may have contributed to this progression rate.

An exploratory biomarker analysis evaluated DNA alterations from archived tissue in 35 available patients. The gene mutations of interest were PTEN (11%), KRAS (6%), and PIK3CA (3%).

Regarding best responses, of the 2 patients with KRAS mutations, 1 each had a PR and PD. The patient with a PIK3CA mutation had PD as their best response. Of the 4 patients with PTEN mutations, 1 had a PR and 3 had PD as their best responses. OS rates in these cohorts were similar, irrespective of PD-L1 expression.

Overall, 22 patients evaluated for DNA alterations had low tumor mutational burden (TMB) and achieved best responses of PR (n = 7), SD (n = 2), PD (n = 10), NE (n = 1), and NA (n = 2). Additionally, 12 patients in this analysis had high TMB and achieved best responses of PR (n = 4), SD (n = 1), PD (n = 5), and NE (n = 2). The median TMB was 2.52, and TMB was not associated with outcome.

In total, any-grade treatment-related AEs (TRAEs) occurred in 83% of all treated patients, and 41% experienced TRAEs of grade 3 or higher. The most common grade 3 TRAEs were edema (10%), transaminitis (7%), nausea (5%), fatigue (5%), dyspnea (5%) vomiting (2%), rash (2%), diarrhea (2%), mucosal inflammation (2%), infection (2%), pruritus (2%), and increased amylase (2%). One patient each had grade 4 treatment-related transaminitis and grade 5 treatment-related cerebral infection.

Overall, 39% of patients had serious AEs. The most common any-grade serious AEs were infection (n = 7), dyspnea (n = 3) and tachycardia (n = 2). Two grade 5 serious AEs occurred: infection and treatment-related cerebral infarction.

Serious AEs were less frequent in patients with MET-driven disease, occurring in 29% of these patients (n = 5). The most common serious AEs in this subgroup were infection (n = 3) and dyspnea (n = 2).

A total of 27% of all patients had savolitinib dose reductions.

Further evaluation of savolitinib plus durvalumab in MET-driven unresectable and locally advanced or metastatic PRC has begun in the phase 3 SAMETA trial (NCT05043090), which is investigating the combination vs sunitinib and durvalumab monotherapy.³

“[SAMETA] may herald a new era of personalized combination therapy in PRC, where MET-driven tumors are prominent,” study authors concluded.

References

1. Suárez C, Larkin JMG, Patel P, et al. Phase II study investigating the safety and efficacy of savolitinib and durvalumab in metastatic papillary renal cancer (CALYPSO). J Clin Oncol. Published online February 21, 2023. doi:10.1200/JCO.22.01414
2. McDermott DF, Lee JL, Ziobro M, et al. Open-label, single-arm, phase II study of pembrolizumab monotherapy as first-line therapy in patients with advanced non-clear cell renal cell carcinoma. J Clin Oncol. 2021;39(9):1029-1039. doi:10.1200/JCO.20.02365
3. Savolitinib plus durvalumab versus sunitinib and durvalumab monotherapy in MET-driven, unresectable and locally advanced or metastatic PRCC (SAMETA). ClinicalTrials.gov. Updated February 3, 2023. Accessed February 23, 2023. https://www.clinicaltrials.gov/ct2/show/NCT05043090