Phase 3 COSMIC-313 Trial Explores Triplet Therapy in Advanced Renal Cell Carcinoma

The safety and efficacy of cabozantinib (Cabometyx) in combination with nivolumab (Opdivo) plus ipilimumab (Yervoy) versus nivolumab/ipilimumab will be evaluated in 676 treatment-naïve patients with International Metastatic RCC Database Consortium (IMDC) intermediate- or poor-risk, advanced or metastatic renal cell carcinoma (RCC) in the phase 3 COSMIC-313 trial (NCT03937219). The information was revealed in a poster presented during the 35th Annual Meeting & Pre-Conference Programs of the Society for Immunotherapy of Cancer (SITC 2020).¹

“Preclinical and clinical studies show that cabozantinib may have immunomodulatory activity and may promote an immune-permissive tumor environment that enhances response to immune checkpoint inhibitors,” stated first author Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology, director of the Kidney Cancer Center, and senior physician at Dana-Farber Cancer Institute, and colleagues.

Treatment with tyrosine kinase inhibitors (TKIs) and immune checkpoint inhibitors have become the standard of care for patients with advanced disease. The TKI cabozantinib was developed to hinder tyrosine kinases that play a role in tumor progression, angiogenesis, metastasis, and immune regulation, including the MET, VEGFR, and TAM kinases.

In December 2017, the FDA approved cabozantinib for use in treatment-naive patients with advanced RCC, based on a meaningful improvement in progression-free survival (PFS) versus sunitinib (Sutent) in the CABOSUN trial (NCT01835158).² The agent also received regulatory approval in Europe in May 2018 for previously untreated patients with intermediate- or poor-risk advanced disease based on data from the trial. Specifically, the TKI was found to reduce the risk of progression or death by 52% versus sunitinib in this population; the median PFS was 8.6 months and 5.3 months, respectively (HR, 0.48; 95% CI, 0.31-0.74; P =.0008).³

The anti–PD-1 monoclonal antibody nivolumab is approved for use as a monotherapy in patients with advanced disease who have received prior antiangiogenic therapy;⁴ it is also approved for use in combination with the anti–CTLA-4 monoclonal antibody ipilimumab in treatment-naive patients with advanced intermediate- or poor-risk RCC, based on data from CheckMate 214 (NCT02231749).⁵ In this phase 3 trial, nivolumab plus ipilimumab reduced the risk of death by 32% compared with sunitinib in patients with metastatic disease. The risk reduction was 37% in patients with intermediate- and poor-risk RCC.

Findings from early-phase clinical trials have indicated that the combination of cabozantinib and immune checkpoint inhibitors such as nivolumab (Opdivo) and atezolizumab (Tecentriq) is safe and has clinical activity.^6,7 Notably, data from the phase 3 CheckMate 9ER trial (NCT03141177)demonstrated that the frontline combination of cabozantinib and nivolumab significantly improved PFS, overall survival (OS), and objective response rate (ORR) when compared with sunitinib in patients with advanced RCC.⁸ The FDA has since granted a priority review designation to a supplemental biologics license application and supplemental new drug application for the combination.

To be eligible for enrollment, patients needed to be 18 years or older, have advanced RCC with a clear cell component, be intermediate or poor risk per IMDC score, and have measurable disease via RECIST 1.1 assessment. Patients also had to have archival or fresh tumor tissue available for analysis, a Karnofsky Performance Status score of 70% or greater, and acceptable organ and marrow function.

If patients had received previous systemic therapy for advanced disease, radiation treatment within 4 weeks or within 2 weeks for bone metastasis, or uncontrolled and significant illnesses such as autoimmune diseases, they were excluded. Those with brain metastases or cranial epidural disease were not permitted unless they were adequately treated. Moreover, patients could not be receiving concomitant oral anticoagulants except for low-dose aspirin. Anticoagulation with low-dose low-molecular-weight heparin was permitted, but corticosteroid use was not.

In the trial, patients are randomized in a 1:1 fashion. Those on the investigational arm will receive oral cabozantinib at 40 mg once daily, intravenous (IV) nivolumab at 3 mg/kg every 3 weeks for 4 cycles, and IV ipilimumab at 1 mg/kg every 3 weeks for 4 cycles; this will then be followed by oral cabozantinib at 40 mg once daily and IV nivolumab at 480 mg every 4 weeks. Those in the control arm will receive placebo plus nivolumab/ipilimumab at the same dose and schedule as those in the investigational arm.

Investigators will conduct a tumor assessment at week 10 of the trial, then every 8 weeks for the first 50 weeks, followed by every 12 weeks there-after. Treatment will continue until either loss of clinical benefit or unacceptable toxicity. However, nivolumab will be given for a maximum of 2 years. Also, if a clinical benefit is present per investigator assessment, patients may receive treatment beyond disease progression.

The primary end point of the trial is PFS per RECIST 1.1 assessment by blinded independent radiology committee (BIRC), whereas the secondary end point is OS. Further end points to be evaluated include PFS per RECIST 1.1 by investigator assessment; ORR and duration of response per RECIST 1.1, BIRC, and investigator assessment; PFS and ORR per RECIST 1.1 byBIRC assessment, according to PD-L1 status; safety; and pharmacokinetics of cabozantinib. Moreover, investigators will examine the immunogenicity of nivolumab and ipilimumab, along with the correlation of biomarkers and clinical outcomes. Health-related quality of life (HRQOL) and health care resource use serves as an additional end point of the trial.

Assessments

Investigators will evaluate radiographic response and disease progression in patients through the use of RECIST 1.1. A CT of the chest, abdomen, and pelvis or a CT of the chest and an MRI of the abdomen and pelvis will be completed at baseline, week 10 of the trial, and then every 8 weeks through week 50; this will then be done every 12 weeks thereafter until radiographic disease progression.

The safety of the combination will be examined through the incidence of toxicities, performance status, vital signs, electrocardiograms, and standard laboratory tests.

Moreover, at week 1 day 1 (W1D1), W4D1, W7D1, W10D1, W14D1, and W26D1, investigators will collect blood samples from patients to conduct pharmacokinetic and immunogenicity assessments; they will also do this 30 days and 100 days after study treatment has been stopped. Specifically, they will analyze these samples to learn more about cabozantinib plasmaconcentrations and antibodies to nivolumab and ipilimumab. Serum concentrations for nivolumab/ipilimumab will also be measured.

Additionally, the investigators will collect tumor samples from patients at baseline. Optional tumor biopsies can potentially be collected at 6 weeks following the first dose of treatment. In this case, investigators will look at potential biomarkers and PD-L1 tumor expression.

Finally, using the EuroQoL health questionnaire instrument EQ-5D-5L, investigators will per-form HRQOL assessments at baseline and every 3 weeks following randomization; this will continue until week 10. Thereafter, they will do this every 4 weeks until the date of the last tumor assessment.

COSMIC-313 is open for enrollment in North America, Europe, the Asia-Pacific region, and South America, the authors of the poster concluded.

_REFERENCES:

_{1. Choueiri TK, Albiges L, Powles T, et al. A phase III study (COSMIC-313) of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in patients (pts) with previously untreated advanced renal cell carci-noma (aRCC) of intermediate or poor risk. J Clin Oncol. 2020;38(suppl 6):TPS767. doi: 10.1200/JCO.2020.38.6_suppl.TPS767}

_{2. Choueiri TK, Halabi S, Sanford BL, et al. Cabozantinib versus sunitinib as initial targeted therapy for patients with metastatic renal cell carcinoma of poor or intermediate risk: the Alliance A031203 CABOSUN trial. J Clin Oncol. 2017;35(6):591-597. doi:10.1200/JCO.2016.70.7398}

_{3. Choueiri TK, Hessel C, Halabi S, et al. Progression-free survival (PFS) by independent review and updated overall survival (OS) results from Alliance A031203 trial (CABOSUN): cabozantinib versus sunitinib as initial targeted therapy for patients (pts) with metastatic renal cell carcinoma (mRCC). Ann Oncol. 2017;28(suppl 5):V623. doi:10.1093/annonc/mdx440.032}

_{4. Motzer RJ, Escudier B, McDermott DF, et al; CheckMate 025 Investi-gators. Nivolumab versus everolimus in advanced renal-cell carcinoma. N Engl J Med. 2015;373(19):1803-1813. doi:10.1056/NEJMoa1510665}

_{5. Escudier B, Tannir NM, McDermott DF, et al. CheckMate 214: efficacy and safety of nivolumab + ipilimumab (N+I) v sunitinib (S) for treatment-na-ive advanced or metastatic renal cell carcinoma (mRCC), including IMDC risk and PD-L1 expression subgroups. Ann Oncol. 2017;28(suppl 5):621-622. doi:10.1093/annonc/mdx440}

_{6. Apolo AB, Nadal R, Girardi DM, et al. Phase 1 study of cabozantinib and nivolumab alone or with ipilimumab for advanced or metastat-ic urothelial carcinoma and other genitourinary tumors.l J Clin Oncol. 2020;38(31):3672-3684. doi:10.1200/JCO.20.01652}

_{7. Pal S, Tsao CK, Suarez C, et al. Cabozantinib (C) in combination with atezolizumab (A) as first-line therapy for advanced clear cell renal cell carcinoma (ccRCC): results from the COSMIC-021 study. Ann Oncol. 2020;31(suppl 4):S554. doi:10.1016/annonc/annonc274}

_{8. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase III CheckMate 9ER trial. Ann Oncol. 2020;31(4):S1159. doi:10.1016/j.annonc.2020.08.2257}