After Immunotherapy Fails, What's Next?

( In conjunction with the Scientific Congress held as part of the American Society of Clinical Oncology’s (ASCO) Annual Meeting in May 2020, an Educational Symposium was convened on August 8 to 10th. In a session entitled “Too Many Choices: How to Select the Best Treatment for Your Patient With Kidney Cancer”, Toni Choueiri, MD, from Dana-Farber Cancer Institute and Harvard Medical School presented a plenary talk discussing the subsequent lines of therapy for patients with metastatic renal cell carcinoma (RCC) who have previously received immunotherapy.

As highlighted in a prior presentation by Dr. Lara in this session, immunotherapy-based approaches are the standard of care for most patients with mRCC.

Dr. Choueiri began with a case of a patient with metastatic clear cell RCC who progressed following sunitinib and subsequent nivolumab. He presented a number of treatment options included VEGF-TKI, nivolumab and ipilimumab, VEGF-TKI, and PD-1 inhibitor, a clinical trial of a novel agent or approach, or all of the above and suggested that all of the approaches may be considered.

He then highlighted options for progression following immunotherapy approaches including single-agent VEGF-TKIs, other immunotherapy approaches [single agent immunotherapy, doublet immunotherapy approaches (e.g. nivolumab and ipilimumab), the addition of a second immunotherapy agent to monotherapy (e.g. adding ipilimumab to existing nivolumab), or immunotherapy and VEGF combination therapy], or novel targets (e.g. HIF-2 inhibitors).

Dr. Choueiri then highlighted emerging experience with the use of VEGF-TKI agents for patients who have progressed following immunotherapy. These data demonstrate objective response rates ranging from 13 to 45% and progression-free survival of 6 to 13 months. Additionally, preliminary safety data demonstrate no new concerning signals of toxicity with the use of these agents following immunotherapy.
He highlighted data from the TIVO-3 trial of tivozanib versus sorafenib, demonstrating improved progression-free survival for those receiving tivozanib (hazard ratio 0.73, 95% confidence interval 0.5 to 0.94). In a subgroup of patients with prior immunotherapy treatment, a similar benefit to the use of tivozanib (median progression-free survival 7.3 months) as compared to sunitinib (median progression-free survival 5.1 months) (hazard ratio 0.55, 95% confidence interval 0.32 to 0.94). TIVO-3_trial_of_tivozanib_versus_sorafenib.png

Dr. Choueiri then considered a number of other immunotherapeutic approaches. Preliminary data regarding immunotherapy re-challenge suggest reasonable response with objective response rates of approximately 30% (7 of 23 patients). Combination therapy using nivolumab and ipilimumab following progression on immunotherapy suggest similar results with essentially no complete responses and objective response rates of 15-20%.
He then highlighted the HCRN GU16-260 trial assessing the sequential addition of ipilimumab for patients who have partial response or stable disease following initial treatment with nivolumab monotherapy.

This trial, and two other similar trials, have been presented over the past year demonstrating generally poor complete response rates (0 to 3%) and objective response rates (4 to 13%).

As a result of these data, the approach using nivolumab followed by ipilimumab cannot be recommended in patients with mRCC due to low activity.

While combinations of VEGF-TKI therapy with immunotherapy have now become standard of care for first-line therapy for patients with mRCC, such approaches can also be considered for those who have progressed on immunotherapy. Dr. Choueiri highlighted data from a phase II trial of lenvatinib and pembrolizumab in combination for patients who progressed on PD-1 or PD-L1 inhibitors. These phase II data are promising with objective response rates in 52% of patients.

He then highlighted the phase III CONTACT-03 trial. This phase III randomized trial assessed the combination of VEGF-TKI therapy in combination with PD-L1 inhibition compared to VEGF-TKI therapy alone in the second and third-line setting for patients with mRCC. Patients will be randomized to atezolizumab and cabozantanib or cabozantanib alone. This trial aims to accrue 500 patients to assess primary endpoints of progression-free survival and overall survival.

Finally, Dr. Choueiri discussed novel treatment approaches for patients with progression following immunotherapy. There are a number of ongoing and early-phase studies of at least twelve different treatment approaches, as highlighted below.
One of the foremost targets among these novel approaches is targeting of HIF-2alpha: VHL deficiency results in HIF-2alpha activation and this contributes to the carcinogenesis of approximately 90% of sporadic clear cell renal cell carcinomas. MK-6482 is a potent, selective small molecular inhibitor of HIF-2alpha which is currently under investigation. Early data presented at the 2020 ASCO GU Cancer symposium demonstrated promising objective response rates and progression-free survival.
Results presented at the 2020 ASCO Meeting demonstrate even more promising results in Von Hippel-Lindau Disease-associated renal cell carcinoma with 87% of patients having a decrease in the size of target lesions. MK-6482 is now under investigation in phase III randomized controlled trial of patients with metastatic clear cell RCC following VEGF and immunotherapy. Patients will be randomized to MK-6482 or everolimus with a targeted accrual of 736 patients and a primary endpoint of progression-free survival.

In summary, Dr. Choueiri concluded that there is moderate data supporting VEGF-TKI, combination immunotherapy, and combination immunotherapy with VEGF-TKI approaches in patients who have progressed following initial immunotherapy. Novel targets remain welcome to add new therapeutic approaches for these patients.

Presented by: Toni K. Choueiri, MD, Dana Farber Cancer Institute, Harvard University, Cambridge, MA

Written by: Christopher J.D. Wallis, Urologic Oncology Fellow, Vanderbilt University Medical Center, @WallisCJD on Twitter at the ASCO20 Virtual Education Program, #ASCO20, August 8-10, 2020