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Cabozantinib in combination with Atezolizumab in non-clear cell renal cell carcinoma - Results from cohort 10 of the COSMIC-021 study

Non-clear cell renal cell carcinoma ( nccRCC ) encompasses a heterogenous group of histologies comprising approximately 25% of all renal cell carcinoma ( RCC ) diagnoses with worse outcomes than clear cell renal cell carcinoma ( ccRCC ).

Both Cabozantinib ( Cabometyx ) monotherapy and immune checkpoint inhibitors ( ICIs ) have shown preliminary activity in nccRCC, and several phase 2 trials are evaluating Cabozantinib in nccRCC.

Cabozantinib promotes an immune-permissive environment which may enhance response to immune checkpoint inhibitors and has shown encouraging activity in combination with immune checkpoint inhibitors in tumor types including ccRCC, urothelial carcinoma ( UC ), metastatic castration-resistant prostate cancer ( mCRPC ), and hepatocellular carcinoma ( HCC ).

COSMIC-021, a multicenter phase 1b study, is evaluating the combination of Cabozantinib with Atezolizumab ( Tecentriq ) in various solid tumors.

Initial results from cohort 10 in nccRCC were reported.

Eligible patients had ECOG PS 0-1 and had received less than or equal to 1 prior VEGFR tyrosine kinase inhibitor ( VEGFR-TKI ) therapy for advanced nccRCC.
Prior immune checkpoint inhibitor or Cabozantinib therapy was not allowed.
Patients received Cabozantinib 40 mg per os ( PO ) daily ( QD ) and Atezolizumab 1200 mg IV once every 3 weeks ( Q3W ).

The primary endpoint is objective response rate ( ORR ) per RECIST v1.1 by investigator. Other endpoints include safety, duration of response ( DOR ), progression-free survival ( PFS ), and overall survival ( OS ).

As of Mar 27, 2020, 30 patients were enrolled with a median follow-up of 9.2 months ( range 4, 16 ); histological subtypes were papillary, n=15; chromophobe, n=7; and other, n=8.
Median age was 61 years, 87% were male, 70% had ECOG PS 0, 80% had prior nephrectomy, and 57% had greater than or equal to 3 sites of disease.
Five patients ( 17% ) had received prior VEGFR-TKI therapy ( two in combination with Everolimus ).
37% were favorable, 50% were intermediate, and 13% were poor risk by IMDC criteria.

Grade 3/4 TRAEs occurred in 30%, with no grade 5 TRAEs. Hypophosphatemia was the most common grade 3/4 TRAE ( 4 [ 13% ] ).

Confirmed objective response rate per RECIST v1.1 was 33%; 10 patients had partial responses ( PRs ) ( papillary, n=6; chromophobe, n=1; ccRCC, n=1; translocation, n=1; and unclassified, n=1 ).
Responses occurred in all IMDC risk groups.
DCR ( CR+PR+SD ) was 93%.

Median duration of response was 7.9 months ( range 1.0+, 8.3+ ).

Increased median levels of activated peripheral cytotoxic T ( +13% ) and NK ( +34% ) cells were observed at day 21 with a concomitant decrease in immunosuppressive cells.

In conclusion, Cabozantinib + Atezolizumab demonstrated encouraging clinical activity in patients with nccRCC with an acceptable safety profile.
Responses were observed in multiple histologies.
Antitumor immunomodulatory effects were observed in peripheral blood with Cabozantinib + Atezolizumab. ( Xagena )

Source: European Society for Medical Oncology ( ESMO ) Virtual Meeting, 2020