Kaelin Delivers A Keynote Lecture On The Future Of The Treatment Paradigm In VHL Disease–Associated RCC.
William G. Kaelin Jr, MD, a co-recipient of the 2019 Nobel Prize 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, delivered a keynote address for the International Kidney Cancer Symposium (IKCS 2020). Dr. Kaelin spoke of recent research on effective treatment with the ability to target von Hippel-Lindau (VHL) disease–associated renal cell carcinoma (RCC)1. “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 is both necessary and sufficient for VHL tumor suppression. 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.
“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. Once, p53 was believed as an important target in these patients, however research has revealed 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.
Though single agent TKIs such as bevacizumab (Avastin), sunitinib (Sutent), sorafenib (Nexavar), axitinib (Inlyta), pazopanib (Votrient), cabozantinib (Cabometyx), and lenvatinib (Lenvima) are indicated for RCC treatment, their use as single agents do not lead to responses in all patients, and in those who do, they eventually relapse.
Studies demonstrated that HIF-2 inhibitors alone did not generate responses in all patients. VHL -/- RCC is hypersensitive to the MET ligand hepatocyte growth factor/scatter factor in RCC, emphasizing that MET depletion preferentially kills VHL-/- cells, emphasized Kaelin. 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).2
CRISPR-based lethal screens and utilizing CDK4/6 could be other synthetic lethality methods which appears to be HIF-independent. In an orthotopic VHL-/- kidney cancer mouse model, the CDK4/6 inhibitor palbociclib (Ibrance) was found to prolong survival, Kaelin added. 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 “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.” Kaelin elaborated.
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 a phase 2 study (NCT03401788) 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, investigators evaluated the efficacy of MK-6482, HIF-2α inhibitor. Results showed that treatment with MK-6482 led to a confirmed objective response rate (ORR) of 27.9% (95% CI, 17.1-40.8), which comprised 17 partial responses (PRs).5 43 patients (70.5%) achieved stable disease with the HIF-2α inhibitor. At 52 weeks, the progression-free survival (PFS) rate was 98.3%.6 Any-grade treatment-related adverse effects (TRAEs) TRAEs were mostly grade 1 or grade 2 (83.6%). 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.
1. Kaelin WG. New therapies for kidney cancer based on studies of the Von Hippel-Lindau tumor suppressor gene. Presented at: IKCS 2020 Virtual Experience; November 6-7, 2020; virtual.
2. 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.
3 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.
4. 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
5. 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.
6. 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.
The FDA Granted A Priority Review To Nivolumab Plus Cabozantinib In Advanced Renal Cell Carcinoma.
The FDA has granted a Priority Review designation to supplemental application for the nivolumab (Opdivo) plus cabozantinib (Cabometyx) combination for the treatment of patients with advanced renal cell carcinoma (RCC).1 The designation was granted based on data from the phase 3 pivotal CheckMate-9ER clinical trial (NCT03141177). This trial demonstrated that the combination reduced the risk of disease progression or death by 49% versus sunitinib (Sutent) in treatment-naïve patients with advanced RCC, with a median progression-free survival of 16.6 months versus 8.3 months, respectively (HR, 0.51; P <.0001).2 Additional findings showed that, at a median follow-up of 18.1 months, the median overall survival was not reached in either arm, and there was a 40% reduction in the risk of death with the combination (HR, 0.60; P = .0010).
The ORR was 55.7% with the combination compared with 27.1% with sunitinib (P <.0001). In the nivolumab/cabozantinib arm, the complete response (CR) rate was 8.0%, and the partial response (PR) rate was 47.7%, while 32.2% of patients had stable disease (SD). In the sunitinib arm, CRs occurred in 4.6% of patients, PRs in 22.6%, and SD in 42.1, while 13.7% had PD and 17.1% were not evaluable/assessed.
More than 50% of patients in the combination arm required a dose reduction of cabozantinib due to adverse events (AEs). The most common any-grade and high-grade treatment-related AEs (TRAEs) appeared similar between the 2 arms. TRAEs led to treatment discontinuations in 15.3% of patients in the combination arm versus 8.8% in the control arm, and 3.1% discontinued the combination due to AEs, 5.6% discontinued nivolumab, and 6.6% discontinued only the cabozantinib. The overall rate of serious AEs was similar between the 2 arms, but liver toxicity was more common with the combination regimen compared with sunitinib. In addition, 19% of patients in the combination arm had required corticosteroids due to immune-related AEs, 4% of which required corticosteroids for at least 30 days.
The data from CheckMate-9ER study were presented during the 2020 European Society for Medical Oncology (ESMO) Virtual Congress. “With their complementary mechanisms of action and evidence that cabozantinib may promote a more immune-permissive environment, we believe there is opportunity for additive or synergistic effects with this potential combination regimen,” stated Gisela Schwab, MD, president, product development and medical affairs and chief medical officer, Exelixis.1/sup>
Cabozantinib was approved by the FDA in December 2017 for use in previously untreated patients with advanced RCC. The FDA approved nivolumab in November 2015 for use in patients with metastatic RCC who progressed on an angiogenesis inhibitor. Nivolumab also has an FDA-approved RCC indication in the frontline setting for use in combination with ipilimumab (Yervoy) as a treatment for intermediate- and poor-risk patients with advanced disease.
1. U.S. Food and Drug Administration accepts for Priority Review applications for Opdivo® (nivolumab) in combination with Cabometyx® (cabozantinib) in advanced renal cell carcinoma. News Release. Bristol Myers Squibb. Accessed October 19, 2020. https://bit.ly/3jac9z6
2. Choueiri TK, Powles T, Burotto M, et al. Nivolumab + cabozantinib vs sunitinib in first-line treatment for advanced renal cell carcinoma: first results from the randomized phase 3 CheckMate 9ER trial. Ann Oncol. 2020;31(4). Abstract 696O.
Pembrolizumab Plus Lenvatinib Demonstrated Statistically Significant Improvement in Progression-Free Survival, Overall Survival and Objective Response Rate Versus Sunitinib as First-Line Treatment for Patients with Advanced Renal Cell Carcinoma
In the pivotal Phase 3 KEYNOTE-581/CLEAR trial (Study 307) trial, combinations of KEYTRUDA®, Merck’s anti-PD-1 therapy, plus LENVIMA, the orally available multiple receptor tyrosine kinase inhibitor discovered by Eisai, and LENVIMA plus everolimus were evaluated versus sunitinib for the first-line treatment of patients with advanced renal cell carcinoma (RCC).
KEYTRUDA plus LENVIMA met the trial’s primary endpoint of progression-free survival (PFS) and its key secondary endpoints of overall survival (OS) and objective response rate (ORR), demonstrating a statistically significant and clinically meaningful improvement in PFS, OS, and ORR versus sunitinib in the intention-to-treat (ITT) study population. LENVIMA plus everolimus also met the trial’s primary endpoint of PFS and a key secondary endpoint of ORR, demonstrating a statistically significant and clinically meaningful improvement in PFS and ORR versus sunitinib in the ITT study population. The ITT population included patients across all Memorial Sloan Kettering Cancer Center (MSKCC) risk groups (favorable, intermediate, and poor). The safety profiles of both KEYTRUDA plus LENVIMA and LENVIMA plus everolimus were consistent with previously reported studies. Merck and Eisai will discuss these data with regulatory authorities worldwide, with the intent to submit marketing authorization applications based on these results, which will be presented at an upcoming medical meeting.
“The results for KEYTRUDA plus LENVIMA versus sunitinib, which showed a statistically significant improvement in progression-free survival, overall survival, and objective response rate, build on the growing scientific evidence that supports the investigation of KEYTRUDA-based combinations for the first-line treatment of advanced renal cell carcinoma,” said Dr. Gregory Lubiniecki, Associate Vice President, Oncology Clinical Research, Merck Research Laboratories.
“The results from KEYNOTE-581/CLEAR (Study 307) support the potential use of KEYTRUDA plus LENVIMA for the first-line treatment of advanced RCC. These data also support the potential first-line use of LENVIMA plus everolimus, which is already approved in advanced RCC following prior antiangiogenic therapy,” said Dr. Takashi Owa, Vice President, Chief Medicine Creation and Chief Discovery Officer, Oncology Business Group at Eisai.
Source: "KEYTRUDA® (Pembrolizumab) Plus LENVIMA® (Lenvatinib) Demonstrated Statistically Significant Improvement In Progression-Free Survival (PFS), Overall Survival (OS) And Objective Response Rate (ORR) Versus Sunitinib As First-Line Treatment For Patients… - Merck.Com". 2020. Merck.Com.
Novel HIF-2α Inhibitor Achieved Durable Responses in VHL-Associated RCC
Treatment with MK-6482, an investigational HIF2α inhibitor, demonstrated durable efficacy as treatment of patients with Von Hippel-Lindau-associated renal cell carcinoma and non-renal lesions, according to phase 2 data presented during the 21st Annual Meeting of the Society of Urologic Oncology.
In the open-label phase 2 study, MK-6482 (NCT03401788), an investigational small molecule HIF-2α inhibitor, has shown demonstrated durable efficacy as treatment of patients with Von Hippel-Lindau (VHL)-associated renal cell carcinoma (RCC) and non-renal lesions, according to presented during the 21st Annual Meeting of the Society of Urologic Oncology (SUO).
Patients received 120 mg of oral MK-6482 once daily. At a median follow-up of 68.7 weeks (range, 18.3-104.7), the objective response rate (ORR) in RCC lesions among 60 evaluable patients was 36.1%, comprising 22 confirmed partial responses (PRs). There were also 7 unconfirmed PRs. Overall, 91.8% (n = 56) of patients had at least some decrease in the size of target lesions. The median time to response in renal tumors was 31 weeks, although responses were observed as long as 61 weeks after the start of therapy. The median duration of response had not yet been reached and the progression-free survival rate at 52 weeks was 98.3%. Thirty-eight (62.3%) patients reached stable disease, 1 patient was not evaluable for response, and 0 patients had progressive disease. Fifty patients had an ECOG performance status of 0, 10 patients had a performance status of 1, and 1 patient had a performance status of 2. In addition to renal tumors, all 61 patients had pancreatic lesions, 43 patients had brain hemangioblastomas, and 16 patients had retinal lesions. Key eligibility criteria for the open-label phase 2 study (NCT03401788) included a confirmed diagnosis of VHL disease (based on germline mutation), at least 1 measurable RCC tumor, and an ECOG performance status of 0 or 1. Prior systemic anticancer therapy was not allowed and patients with metastatic disease were excluded from enrollment. At a minimum follow-up of 60 weeks, 56 (91.8%) patients remained on treatment.
“Promising clinical activity was observed with MK-6482 in treatment-naïve patients with VHL-associated RCC,” said lead study author Ramaprasad Srinivasan, MD, PhD, National Cancer Institute, Bethesda, Maryland.
Clinical activity with MK-6482 was observed in non-RCC lesions. The confirmed ORR in pancreatic lesions was 63.9%, including 4 complete responses. The confirmed ORR in brain hemangioblastomas was 30.2%, with a CR rate of 11.6%. Also, 11 (68.8%) of 15 patients with retinal lesions demonstrated improvement in these lesions, with the 4 other patients reaching stable disease. Safety data showed that 60 of the 61 patients had at least 1 treatment-related adverse event (TRAE). The most common all-cause AE was grade 1/2 anemia, occurring in 51 (83.6%) patients. Eight (13.1%) patients had a grade 3 TRAE. Four (6.6%) patients had grade 3 anemia. There were no grade 4/5 TRAEs. There was 1 discontinuation due to a TRAE (grade 1 dizziness).
Srinivasan R, Donskov F, IIiopoulos O, et al. Oral HIF-2α inhibitor MK-6482 for Von Hippel-Lindau (VHL) disease–associated clear cell renal cell carcinoma: evaluation of RCC and non-RCC disease. Presented at: 21st Annual Meeting of the Society of Urologic Oncology; December 2-5, 2020; Virtual. Abstract 10
Neoadjuvant Nivolumab Safe for Nonmetastatic High-Risk RCC
In a phase 1 trial (NCT02575222), Nivolumab (Opdivo) given as a Neoadjuvant has demonstrated tolerability in patients with nonmetastatic high-risk clear cell renal cell carcinoma as reported in a poster presentation during the 21st Annual Meeting of the Society of Urologic Oncology (SUO).1
Currently, Nivolumab plus ipilimumab (Yervoy) has demonstrated significant efficacy in treating patients with treatment-naïve metastatic RCC compared with the prior standard-of-care sunitinib (Sutent).2 The investigators sought to discover if the benefit of PD-1/PD-L1 inhibitors could be extended to the neoadjuvant setting, as an earlier study of neoadjuvant treatment with the multikinase inhibitor axitinib (Inlyta) had demonstrated significant shrinking of RCC tumors prior to surgery.3
The study was a prospective, open-label, single arm phase 1 trial that explored the safety and tolerability of nivolumab prior to surgery in patients with resectable nonmetastatic high-risk RCC. Patients with T2a-T4 with or without positive lymph nodes were eligible for the study if they were scheduled to undergo a partial or radical nephrectomy, had an ECOG performance status of 0 or 1, and adequate organ and bone marrow function. Nivolumab was administered at 3 mg/kg on day 1 of each of a total of 3 consecutive 14-day cycles. Treatment was followed by surgery within 7 days of completion of the third cycle. A total of 17 patients were included in the early-phase trial consisting of 16 with ccRCC and 1 with papillary disease. Fifteen had stage cT3a disease, 2 had cT3b, and all were negative for lymph node involvement.
At 24.7 months of median follow-up, the 2-year metastasis-free survival rate was 85.1%, and the overall survival rate was 100%. The 15 patients with ccRCC were restaged prior to surgery, but an overall minimal difference was observed in both the long and short axes from baseline to after treatment with nivolumab. However, 1 patient had an immune-related pathologic response and the rest had stable disease by radiographic criteria. The 1 patient who achieved a pathologic response demonstrated a regression bed with features of wound healing as well as immune infiltration.
Grade 3 adverse events (AEs) were reported in 11.8% of patients, and no grade 4 or 5 events were reported. AEs of any grade were reported in 82.4% of patients and were considered potentially due to nivolumab in 58.8%. The most common AEs reported were fatigue (41.2%), pruritis (29.4%), and rash (29.4%), all grade 1 in severity. No delays were reported in surgery, and no postoperative complications of Clavien grade 3 or higher were observed. “Early phase trial demonstrates the safety of neoadjuvant PD-1 blockade with preserved [quality of life] when administered to patients with nonmetastatic high risk ccRCC,” the study authors, led by Hiten D. Patel, MD, MPH, of the Department of Urology at Loyola University Medical Center, wrote in their poster.
Neoadjuvant nivolumab is also currently being studied in the phase 3 PROSPER RCC study in comparison with observation for patients with RCC undergoing nephrectomy (NCT03055013).
1. Patel HD, Gorin MA, Rowe SP, et al. Neoadjuvant nivolumab in patients with high-risk non-metastatic renal cell carcinoma. Presented at: 2020 SUO Annual Meeting; December 2-5, 2020; Virtual. Abstract 92.
2. Motzer RJ, Tannir NM, McDermott DF, et al; CheckMate 214 Investigators. Nivolumab plus Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N Engl J Med. 2018;378:1277-1290. doi:10.1056/NEJMoa1712126
3. Karam JA, Devine CE, Urbauer DL, et al. Phase 2 trial of neoadjuvant axitinib in patients with locally advanced nonmetastatic clear cell renal cell carcinoma. Eur Urol. 2014;66(5):874-880. doi:10.1016/j.eururo.2014.01.035