Dr. Escudier points out that the future of immune-oncology in his opinion is the use of combination strategies. The highlight of combination strategies to date certainly is the CheckMate 214 study lead by Dr. Escudier, reported last year at ESMO 2017 . This landmark phase III RCT tested nivolumab + ipilimumab vs sunitinib in 1,096 mRCC patients who were previously untreated. The ORR in intermediate/poor risk patients was 42% (9.4% complete response) vs 27% (1.2% CR) for nivolumab + ipilimumab vs sunitinib (p<0.0001). Furthermore, the median duration of response was not reached for the nivolumab + ipilimumab arm (NR; 95%CI 22-NR months) vs 18 months (95%CI 15-NR) in the sunitinib arm. The median PFS for intermediate/poor risk patients was 11.6 months for nivolumab + ipilimumab vs 8.4 months for sunitinib (HR 0.82, 99.1%CI 0.64-1.05), while median OS was not reached for nivolumab + ipilimumab compared to 26.0 months for sunitinib (HR 0.63, 99.8%CI 0.44-0.89). In the intention to treat group the results were as follows: (i) ORR: 39% (95%CI 35-43) for nivolumab + ipilimumab compared to 32% (95%CI 28-36) for sunitinib (p=0.02); (ii) median PFS: 12.4 months (95%CI 9.9-16.5) for nivolumab + ipilimumab compared to 12.3 months (95%CI 9.8-15.2) for sunitinib (p=0.85); (iii) median OS: not reached for nivolumab + ipilimumab compared to 32.9 months for sunitinib (HR 0.68, 99.8%CI 0.49-0.95). Interestingly, for IMDC favorable risk patients, ORR and PFS both significantly favored sunitinib. Efficacy outcomes differed by PD-L1 expression and IMDC risk group. ORR favored nivolumab + ipilimumab vs sunitinib in intermediate/poor risk patients with baseline PD-L1 expression <1% and ≥1%. Importantly, a significant PFS benefit with nivolumab + ipilimumab vs sunitinib was seen in patients with PD-L1 ≥1% (HR 0.48, 95%CI 0.28-0.82). Baseline PD-L1 expression was lower in favorable risk patients (≥1% in 11% nivolumab + ipilimumab vs 12% sunitinib) than in intermediate/poor risk patients. According to Dr. Escudier, nivolumab + ipilimumab should be the new standard of care in 2018, but only in intermediate and poor risk patients and not in good risk patients. He surmises that PD-L1 expression should be used to help determine those most likely benefit from combination therapy.
A current RCT ongoing in Europe is the Tailored Immunotherapy Approach with Nivolumab in RCC (TITAN) phase III study, which should provide additional clarity as to who may benefit from upfront combinatorial therapy. This study is aiming to recruit 200 patients with mRCC who are previously untreated or pretreated with one prior TKI and intermediate or high risk by IMDC criteria. These patients will undergo nivolumab induction (3 mg/kg IV every 2 weeks for 8 treatments) and patients with complete/partial response will undergo nivolumab maintenance every two weeks. Those with stable/progressive disease after induction will be given an “ipilimumab boost” with nivolumab 3mg/kg + ipilimumab 1mg/kg every 3 weeks for two doses. Those responders will then receive nivolumab maintenance whereas those that are either stable/progressive will receive a second ipilimumab boost with nivolumab.
Dr. Escudier feels that the PD-1/PD-L1 + VEGF inhibitor combinatorial regimens are also promising. The results of several phase III trials in the first-line setting are expected soon, including:
- Javelin Renal 101 (n=583): randomizing patients to avelumab + axitinib vs sunitinib
- Randomizing patients (n=735) to lenvatinib + pembrolizumab vs lenvatinib + everolimus vs sunitinib
- KEYNOTE-426 (n=840): randomizing patients to axitinib + pembrolizumab vs sunitinib
- IMMOTION 151 (n=915): randomizing patients to atezolizumab + bevacizumab vs sunitinib (reporting results this afternoon)
Studies moving forward will make use of prospective predictive biomarkers, according to Dr. Escudier. One such trial in Europe is the BIONIKK Trial, enrolling previously untreated mRCC patients who will submit to a metastatic site biopsy to determine their “molecular subgroup.” Based on these results, patients will then be randomized to nivolumab vs nivolumab + ipilimumab vs TKI (sunitinib vs pazopanib) and treated until RECIST 1.1 disease progression.
The future of immuno-oncology will also rely on enhancing the efficacy of immunotherapy, with a potential role for the microbiota and food. The mouse model has shown that feces composition may play a role in antitumor efficacy of immunotherapy, noting differences in the microbiome between responders and non-responders. Fecal transplantation studies have successfully enhanced the efficacy of immunotherapy in these non-responders. Finally, the role of food has been implicated with preliminary data suggesting improved responses to immunotherapy among animal models focusing on a ketogenic diet.
There are several key questions that must be answered as we move forward with immunotherapy in RCC:
- Are PD1 and PD-L1 inhibitors equivalent?
- Duration of therapy – when should be stop in responders and who should we treat beyond progression?
- What is the appropriate schedule of treatment (every 2 weeks? 3 weeks? 4 weeks?)
- What is the appropriate dose? Why use a flat dose?
- Can we use steroids up front to decrease toxicity?
Presented by: Bernard Escudier, MD, Gustave Roussy Cancer Campus, Villejuif, France
Written by: Zachary Klaassen, MD, Urologic Oncology Fellow, University of Toronto, Princess Margaret Cancer Centre, @zklaassen_md at the 2018 American Society of Clinical Oncology Genitourinary (ASCO GU) Cancers Symposium, February 8-10, 2018 - San Francisco, CA
2018 ASCO GU - Renal Cell Cancer: Keynote Lecture: Tyrosine Kinase Inhibitors for Renal Cell Carcinoma: Past, Present, and Future
1. Motzer RJ, Escudier B, McDermott DF, et al. Nivolumab versus Everolimus in Advanced Renal-Cell Carcinoma. N Engl J Med 2015;373(19):1803-1813.
2. Escudier B, Tannir N, McDermott D, et al. CheckMate 214: Efficacy and safety of Nivolumab + Ipilimumab vs Sunitinib for treatment-naïve advanced or metastatic renal cell carcinoma, including IMDC risk and PD-L1 expression subgroups. ESMO 2017 abst LBA5.