The first results of the phase 3 COSMIC-313 trial demonstrated that triple therapy (nivolumab plus ipilimumab plus cabozantinib) improved progression-free survival (PFS) versus dual checkpoint inhibition (nivolumab plus ipilimumab) in patients with previously untreated advanced renal cell carcinoma (RCC).
Dual immune checkpoint inhibition with nivolumab plus ipilimumab is the first-line standard-of-care for patients with advanced RCC of IMDC intermediate or poor risk . However, approximately 20% of patients deteriorate to progressive disease as the best response, representing an unmet medical need. Additionally, first-line cabozantinib plus nivolumab has demonstrated clinical effectiveness in patients with advanced RCC . In a phase 1 trial, triplet therapy (nivolumab plus ipilimumab plus cabozantinib) showed clinical activity and manageable toxicity . Based on this background, the COSMIC-313 (NCT03937219) evaluated the efficacy and safety of first-line triple therapy (nivolumab plus ipilimumab plus cabozantinib) in patients with advanced RCC of poor or intermediate IMDC risk. Prof Toni Choueiri (Dana-Farber Cancer Institute, MA, USA) presented the first results .
The COSMIC-313 trial randomised 855 previously untreated advanced RCC patients with poor (25%) or intermediate IMDC (75%) risk to receive cabozantinib (40 mg once daily) or placebo plus standard-of-care 4 cycles of nivolumab (3 mg/kg every 4 weeks) and ipilimumab (1 mg/kg every 3 weeks), followed by nivolumab (480 mg every 3 weeks) up to 2 years. The primary endpoint of the study was PFS in the 550 first randomised patients. Secondary endpoints were overall survival (OS) in the total intention-to-treat (ITT) population, objective response rate (ORR), duration of response, and safety.
Triple therapy significantly improved median PFS versus dual therapy (not reached vs 11.3 months; HR 0.73; P=0.013, see Figure). PFS rates at 12 months were 57% and 49% for triple and dual therapy, respectively. Triple therapy favoured PFS in all pre-specified subgroups, except participants with IMDC poor risk (HR 1.04). ORR was 43% (3% complete response, 40% partial response) in participants treated with triple therapy versus 36% (3% complete, 33% partial) in participants treated with dual therapy. The median duration of response was not reached in either study arm. The safety profile of the triple therapy was generally manageable and consistent with the profiles of the treatment components.
“This first study to use dual immune checkpoint inhibition as the control demonstrated a significant benefit in PFS for triple therapy consisting of nivolumab plus ipilimumab plus cabozantinib in previously untreated patients with IMDC intermediate risk,” concluded Prof. Toni Choueiri. Follow-up for assessing the OS is ongoing.
- Motzer RJ, et al. New Engl J Med. 2018;378(14):1277–1290.
- Choueiri TK, et al. N Eng J Med. 2021;384(9):829–841.
- Apolo AB, et al. J Clin Oncol. 2020;38(31):3672–3684.
- Choueiri TK, et al. Phase III study of cabozantinib (C) in combination with nivolumab (N) and ipilimumab (I) in previously untreated advanced renal cell carcinoma (aRCC) of IMDC intermediate or poor risk (COSMIC-313). Abstract LBA8, ESMO Congress 2022, 09–13 September, Paris, France.
Figure: Progression-free survival analysis of the total ITT population .
Cabo, cabozantinib. Nivo, nivolumab. Ipi, ipilimumab. NR, not reached. NE, not estimatable.
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Table of Contents: ESMO 2022
Letter from the Editor
High pathological responses to neoadjuvant immune checkpoint inhibition in locally advanced dMMR colon cancer
Fruquintinib: a potential new treatment for patients with refractory mCRC
Second-line avelumab is effective in patients with MSI-H/dMMR mCRC
Upper Gastrointestinal Cancer
Deep learning models predict the risk of relapse and the mutational profile in GIST
Addition of pembrolizumab to lenvatinib does not improve OS in advanced HCC
New, highly selective inhibitor of FGFR2 driver alterations and resistance mutations
Chemo-immunotherapy in gastric cancer is more effective when administered in parallel
Tumour infiltrating lymphocytes identify patients with immunogenic triple-negative breast cancer
OS benefit of abemaciclib in HR-positive/HER2-negative advanced breast cancer not (yet) statistically significant
OS benefit of sacituzumab govitecan in pre-treated HR-positive/HER2-negative metastatic breast cancer
A pathway from air pollution to lung cancer in non-smokers identified
Selective KRASG12C inhibitor sotorasib demonstrates superior PFS and ORR compared to docetaxel in previously treated patients with NSCLC
Promising clinical activity of tepotinib plus osimertinib in NSCLC with MET amplification after progression on first-line osimertinib
High pathological responses in borderline resectable NSCLC patients after induction with dual immunotherapy and concurrent chemoradiotherapy
Treatment with tumour-infiltrating lymphocytes for advanced melanoma outperforms ipilimumab
Neoadjuvant pembrolizumab outperforms adjuvant pembrolizumab in resectable stage III–IV melanomas
Survival-benefit of neoadjuvant T-VEC maintained over 5 years of follow-up
Baseline ctDNA predicts survival in resected stage III–IV melanoma
Genitourinary Cancer – Prostate Cancer
Overall survival benefit of abiraterone in mHSPC is maintained for 7 years
Limited benefit of adding long-term ADT to post-operative radiotherapy in prostate cancer
Intensified ADT benefits biochemical progression-free survival in biochemically relapsed prostate cancer
Genitourinary Cancer – Non-Prostate Cancer
Adjuvant nivolumab plus ipilimumab does not improve survival in patients with localised RCC at high risk of relapse after nephrectomy
Triple therapy improves progression-free survival in patients with advanced RCC versus dual therapy
Adjuvant atezolizumab does not improve outcomes for patients with RCC and increased risk of recurrence
OS benefit for advanced ovarian cancer patients treated with maintenance olaparib
Maintenance tegafur-uracil does not improve survival in locally advanced cervical cancer
Head and Neck Cancer
Adding first-line pembrolizumab to CRT in locally advanced HNSCC does not significantly prolong survival or event-free survival
5-FU-free chemotherapy combination as an alternative for first-line treatment of recurrent or metastatic HNSCC
Epstein Barr virus-specific autologous cytotoxic T lymphocytes do not improve survival in nasopharyngeal carcinoma