Kaelin Speaks to the Future of I/O, HIF-2α, CDK4/6 Inhibitors in VHL Disease–Associated RCC

William G. Kaelin Jr, MD

During a keynote address for the International Kidney Cancer Symposium (IKCS 2020), William G. Kaelin Jr, MD, spoke of recent research on effective treatment with the ability to target von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC). These drugs included immunotherapy, HIF-2α inhibitors, and CDK4/6 inhibitors, which may be the future of the treatment paradigm.¹

“You can start to dream what an eventual kidney cancer curative combination will look like. I suspect that it will contain a VEGF inhibitor, an immune checkpoint inhibitor, maybe a HIF-2α inhibitor, maybe a CDK4/6 inhibitor, [and] maybe even a MET inhibitor,” said Kaelin, the 2019 Nobel Laureate in Physiology or Medicine, Sidney Farber Professor of Medicine, Dana-Farber Cancer Institute and Harvard Medical School, and an investigator at Howard Hughes Medical Institute.

RCC is arising more often in patients with VHL, said Kaelin, who added that inactivation of VHL is not sufficient for renal carcinogenesis, even if it is an initiating event. In sporadic clear cell RCC, however, VHL inactivation is the initiation event and should be targeted. HIF2 inhibition, he explained, is both necessary and sufficient for VHL tumor suppression (pVHL).

“We think HIF-2 is the driver, or oncoprotein, in VHL–associated renal cell carcinoma cells and, if anything, HIF-1 seems to act as a tumor suppressor and is frequently lost in such tumors,” Kaelin said.

Though initially believed that p53 was an important target in these patients, research has shown that an intact p53 pathway is not essential for clear cell RCC HIF2-dependence, and TP53 knockout doesn’t alter PT2399 sensitivity of OSRC2 cells.

“We no longer think p53 status is a biomarker for HIF2 dependence,” said Kaelin.

In preclinical models, a first-generation HIF-2α compound, PT2399,² led to decreased HIF-dependent mRNAs, decreased proliferation, and decreased tumor growth by VHL homozygous negative (-/-) kidney cancer cells. Moreover, tumor formation by some VHL-/- kidney cancer cell lines were not inhibited by PT2399, despite pharmacodynamic response.

“These are all [pull-]down assays—decrease, decrease, decrease,” Kaelin said. “You would worry whether these effects were really on-target or off-target.”

HIF-2 inhibitors however do not generate responses in all patients, and to avoid resistance, Kaelin emphasized the importance of synthetic lethality. VHL -/- RCC he added, is hypersensitive to the MET ligand hepatocyte growth factor/scatter factor in RCC, emphasizing that MET depletion preferentially kills VHL-/- cells.

A number of TKIs are indicated for RCC treatment, such as bevacizumab (Avastin), sunitinib (Sutent), sorafenib (Nexavar), axitinib (Inlyta), pazopanib (Votrient), cabozantinib (Cabometyx), and lenvatinib (Lenvima). However, their use as single agents does not lead to responses in all patients, and in those who do, they eventually relapse.

For example, the dual MET/VEGF inhibitor cabozantinib demonstrated an improvement in overall survival (OS) compared with everolimus (Afinitor), with a median OS of 21.4 months (95% CI, 18.7–not estimable) with cabozantinib and 16.5 months with everolimus (95% CI, 14.7-18.8), leading to a 34% reduction in the risk of death (HR, 0.66; 95% CI, 0.53-0.83; P = .0003).³

However, Kaelin said these data were “a bit unsatisfying; it could be that cabozantinib is a better VEGF inhibitor than the VEGF inhibitors that patients had failed on previously.”

Other synthetic lethality methods are through CRISPR-based lethal screens and utilizing CDK4/6, Kaelin added, which is synthetically lethal with VHL and appears to be HIF-independent. In an orthotopic VHL-/- kidney cancer mouse model, the CDK4/6 inhibitor palbociclib (Ibrance) was found to prolong survival, he said.

When used in combination with the HIF-2α inhibitor PT2399, data showed that the regimen synergistically suppresses VHL -/- cell growth in HIF2-sensitive cell lines, leading to more investigations of this approach. Additionally, the use of palbociclib suppressed orthotopic xenograft growth alone and in combination with PT2399.⁴

“I think we might learn something from our friends in the world of breast cancer, because they already learned that combining tamoxifen with a CDK4/6 inhibitor is a good thing to do, and maybe that’s because when you add an ER agonist you lower cyclin D1 transcription, and cyclin D1 is then the partner for CDK4/6, which you’re now going to inhibit with a small molecule. Maybe we can do something analogous in kidney cancer by combining PT2399 with a CDK4/6 inhibitor at least for those tumors that are still HIF2 dependent.”

Beyond its potential use in combination with HIF-2a inhibitors, CDK4/6 inhibitors could also be used as a way to enhance immunotherapy in solid tumors.⁵

Transplantation could also be an intriguing approach to target this population. Additional data have shown that transcriptional upregulation of hERV-E in clear cell RCC is driven by HIF2, and therefore recognition of an hERV-derived antigen by allogenic T cells leads to disease regression.6 Following allogeneic stem cell transplant, 48% of patients with metastatic clear cell histology had a disease response.​

The most recent data, presented at the 2020 ASCO Virtual Scientific Program, showed that the HIF-2a inhibitor MK-6482 led to favorable efficacy and tolerability in patients with VHL disease–associated RCC.

In this open-label, phase 2 study (NCT03401788), investigators evaluated the efficacy of MK-6482, a potent, selective, small molecule HIF-2α inhibitor, in patients with VHL disease who have at least 1 measurable RCC tumor, did not receive prior systemic anticancer therapy, did not have metastatic disease, and had an ECOG performance status of either 0 or 1.

Data comprised 61 adult patients who received 120 mg of oral MK-6482 once daily until progression or intolerable toxicity. Results showed that treatment with the agent led to a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8), which comprised 17 partial responses (PRs).⁷ Eight other patients (13%) experienced an unconfirmed PR. Responses were also seen with central nervous system, retinal, and pancreatic lesions.

Forty-three patients (70.5%) achieved stable disease with the HIF-2α inhibitor. Additionally, the median duration of response had not yet been reached (95% CI, 11.9-62.3). Notably, most of the patients on the trial (86.9%) experienced a reduction in the size of their target lesions. At 52 weeks, the progression-free survival (PFS) rate was 98.3%.⁸

With regard to safety, any-grade treatment-related adverse effects (TRAEs) occurred in 96.7% of patients. TRAEs were mostly grade 1 or grade 2 (83.6%) and primarily anemia (86.9%), fatigue (52.5%), and headache (36.1%). Grade 3 TRAEs were reported in 9.8% of patients and were primarily fatigue (4.9%) and anemia (3.3%).

Based on these data, the FDA granted a breakthrough therapy designation to MK-6482 for the treatment of patients with VHL disease–associated RCC who have nonmetastatic tumors of less than 3 centimeters, unless immediate surgery is necessitated.

The HIF-2α inhibitor also showed promising single-agent activity in patients with heavily pretreated clear cell RCC. An ORR of 24% and a disease control rate of 80% was observed in the 55 patients enrolled in the dose-escalation/expansion cohort.⁹ The ORR consisted of 13 confirmed PRs. Additionally, the median PFS for the total population was 11.0 months. At 12 months, 49% of patients remained progression free.

_References

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_{3. Choueiri TK, Escudier B, Powles T, et al. Cabozantinib versus everolimus in advanced renal cell carcinoma. N Engl J Med. 2015;373(19):1814-1823. doi:10.1056/NEJMoa1510016}

_{4. Nicholson HE, Tariq Z, Housden BE, et al. HIF-independent synthetic lethality between CDK4/6 inhibition and VHL loss across species. Sci Signal. 2019;12(601):eaay0482. doi:10.1126/scisignal.aay0482}

_{5. Goel S, DeCristo MJ, Watt AC, et al. CDK4/6 inhibition triggers anti-tumour immunity. Nature. 2017;548(7668):471-475. doi:10.1038/nature23465.}

_{6. Takahashi Y, Harashima N, Kajigaya S, et al. Regression of human kidney cancer following allogeneic stem cell transplantation is associated with recognition of an HERV-E antigen by T cells. J Clin Invest. 2008;118(3):1099-1109. doi:10.1172/JCI34409}

_{7. Jonasch E, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-α inhibitor for Von Hippel-Lindau disease–associated renal cell carcinoma. J Clin Oncol. 2020;38(suppl 15):5003. doi:10.1200/JCO.2020.38.15_suppl.5003}

_{8. Srinivasan R, Donskov F, Iliopoulos O, et al. Phase II study of the oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease-associated clear cell renal cell carcinoma (ccRCC): update on RCC and non-RCC disease. Ann Oncol. 2020;31(suppl 4):S1158. doi:10.1016/j.annonc.2020.08.2255}

_{9. Choueiri TK, Plimack ER, Bauer TM, et al. Phase I/II of the oral HIF-2α inhibitor MK-6482 in patients with advanced clear cell carcinoma (RCC). J Clin Oncol. 2020;38(suppl 6):611. doi:10.1200/JCO.2020.38.6_suppl.611}