Novel targets for refractory kidney cancer: Where are we heading?

Targeted therapy with HIF-2a antagonists

Close to 90% of Clear cell Renal Cell Carcinomas (ccRCC) display the loss of function of the pVHL tumor suppressor protein, consequently causing an aberrant activation of the hypoxia inducible factor 2-alpha (HIF-2α) transcription factor. ³ HIF-2α is known to facilitate angiogenesis, cell migration, and tumor proliferation. ⁴ Being a DNA-binding transcription factor that lacks a ligand-binding domain, HIF-2α was for many years considered undruggable. So for the past two decades drugs were and are still developed to target the downstream effects of HIF-2α activity, mainly implicated in angiogenesis. This is the case of VEGFA inhibitors (Bevacizumab) and tyrosine-kinase inhibitors TKI (sorafenib and sunitinib at first, lenvatinib and cabozantinib more recently). Nevertheless, complete responses to these drugs are rare especially for VEGFA inhibitors and first generation TKI, with most ccRCC tumors eventually activating angiogenic escape pathways to restore tumor perfusion. ⁵ With the recent discovery of a microcavity within the PAS-B domain of HIF-2α that can bound to small molecules,^6,7 targeted anti-HIF-2α therapy became a possibility. ⁸ The direct inhibition of HIF-2a potentially causes the inhibition of the whole HIF cascade: apart from tumor angiogenesis inhibition by stopping HIF-2a–induced upregulation of VEGFA expression, HIF-2α antagonists also impede tumor growth by inhibiting HIF-2a–induced upregulation of genes such as CCND1 and TGFA, which promote tumor cell proliferation but are independent of the VEGF signaling pathway. Therefore, HIF-2a antagonism in ccRCC may provide greater efficacy than what is currently achieved with VEGF receptor kinase inhibitors. ¹

Two HIF-2α inhibitors, PT2385 and PT2977, have already showed positive results in phase I^1,9 and phase II^10,11 trials with an acceptable safety profile. PT2977, also known as ‘MK-6482’, has showed however better pharmacokinetics over PT2385 and is actually moving forward as the HIF2α inhibitor of choice for future trials. ¹² A Phase 3 trial (NCT04195750) has already started and is currently testing MK-6482 monotherapy versus everolimus in patients with refractory metastatic ccRCC, with PFS and OS as primary endpoints. A phase II trial (NCT03634540) is testing the potential benefits of combination therapy, studying the effect of MK-6482 + cabozantinib in first-line ccRCC. These trials will eventually shed more lights on the efficacy of HIF-2α inhibitors. It is however certain that HIF-2α inhibitors will have a primary role in the future of targeted therapy for renal cell carcinoma.

Metabolic pathways inhibitors

Following the work of Otto Warburg in the 1950’s, cancer cells are known to metabolize glucose to lactate under aerobic conditions despite this process being far less efficient than oxidative phosphorylation in terms of net ATP production. ¹³ This paradoxical phenomenon is also observed in renal cancer cells and causes an excess uptake of glutamine, which is converted to glutamate by the enzyme glutaminase, to feed the TCA cycle. ¹⁴ Telaglenastat is an oral glutaminase inhibitor that specifically blocks glutamine consumption in tumor cells, and also targets growth factor signaling. ¹⁵

Encouraging data from phase I studies showing a 92% disease control rate and a median progression-free survival (PFS) of 5.8 months in metastatic RCC patients treated with telaglenastat combination ¹⁶ have led to the development of the phase II ENTRATA (NCT03163667) trial. In this randomized study, investigators compared telaglenastat + everolimus combination to Everolimus alone in 69 heavily pre-treated advanced ccRCC patients. Apart from inhibiting glutamine metabolic pathways, preclinical studies found that this combination had an additional synergistic antiproliferative activity in vitro as well as in vivo. In 2019, the trial met its primary endpoint, with the telaglenastat plus everolimus combination achieving an improvement in PFS relative to everolimus alone (3.8 months versus 1.9 months, HR, 0.64; 95% CI, 0.34–1.20; one-sided P = 0. 079). The secondary endpoint of overall survival was not yet reached.

Following these promising results and in line with the current trend of combination therapy in advanced renal cell carcinoma, the ongoing CANTATA (NCT03428217) trial is studying the telaglenastat + cabozantinib combination. This randomized, double-blind phase II study comparing telaglenastat in combination with cabozantinib versus placebo with cabozantinib in patients with advanced RCC will have its efficacy and safety data communicated in late 2020. With more data incoming on the mechanism of action of telaglenastat, glutaminase inhibition is representing a new therapeutic option that has not yet been applied to metastatic kidney cancer.

New immune checkpoint targets

Immunotherapies such as programmed death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) and cytotoxic T-lymphocyte–associated protein 4 (CTLA-4) inhibitors are already playing a central role in mRCC treatment.^17,18 But with the rising interest in combination immunotherapies, the need to develop new immune pathways inhibitors to prevent tumor evasion is a must. Two novel immune drug classes have been developed to this extent: indoleamine 2,3-dioxygenase 1 (IDO1) and adenosine 2 A receptor (A2AR) inhibitors. The first one, epacadostat, acts by depleting intracellular tryptophan causing cycle arrest, anergy, and apoptosis of effector T cells, contributing to immunosuppression within the tumor microenvironment. ¹⁹ The A2AR inhibitor CPI-444, on the other hand, acts on the CD39-CD73-A2AR pathway by inhibiting the action of the immunosuppressive metabolite adenosine. ²⁰

The integration of both drugs in immunotherapy combinations can be promising in the future, but data is still premature. Epacadostat, for example, showed discordant results: early clinical studies reported a positive safety profile and an encouraging antitumor activity when combined to pembrolizumab in advanced RCC (objective response rate and disease control rate of 47% and 58% for patients with 0–1 prior treatment in phase I/II ECHO-202 study ¹⁹ ). But despite those positive results and the clear biological rationale, the same combination did not improve PFS versus pembrolizumab alone in melanoma patients, causing the ECHO-302 study that compared epacadostat plus pembrolizumab versus TKIs in the first-line treatment of RCC to stop prematurely. CPI-444 has the advantage of proving encouraging results as a monotherapy (as opposed to epacadostat) with an objective response rate (ORR) of 14% in a phase I trial. The addition of atezolizumab, however, had small or no effect (ORR = 13%), warranting investigations with other checkpoint inhibitors.

In conclusion, new promising therapeutic options are emerging in the management of advanced RCC. These options include drugs that act on new cancer pathways (e.g. glutamine metabolic pathways inhibitors), new immune checkpoint inhibitors (e.g., epacadostat and CPI-444) as well as direct HIF-2α antagonists. The latter is rapidly gaining in importance, with MK-6482 recently gaining FDA approval for the treatment of patients with VHL disease-associated RCC with nonmetastatic RCC tumors <3 cm (based on phase II study results (NCT03401788)). Trials with combination therapies as well as ongoing investigations in biomarkers predicting treatment response will give us more insight and evidence about the future place of these therapies.