ADCs and Radiotherapeutics Represent Novel Treatment Methods in RCC

The investigation of treatment regimens featuring antibody-drug conjugates (ADCs) or radiotherapeutics are part of the ongoing wave of research in renal cell carcinoma (RCC), according to Rana R. McKay, MD.

“There are a lot of novel therapies that are being investigated, [and] targeting angiogenesis continues to be pretty important in RCC cell carcinoma,” McKay said. “There are a lot of novel drug delivery mechanisms that are being explored, as well. We need more drugs, and we need more targets.”

In a presentation at the 2023 Kidney Cancer Research Summit, McKay highlighted ongoing research with ADCs, radiotherapeutics, and other agents within the RCC landscape and highlighted novel targets that could inform the development of treatments for this patient population.¹ McKay is a medical oncologist and an associate professor of medicine at University of California, San Diego Health.

Anti-Angiogenics

The phase 1 LITESPARK-001 trial (NCT02974738) evaluated belzutifan monotherapy in patients with locally advanced or metastatic solid sporadic clear cell RCC (ccRCC) who received at least 1 prior treatment for ccRCC, had measurable disease per RECIST v1.1 criteria, and had an ECOG performance status of 0 or 1.²

Patients (n = 55), who had received a median of 3 prior lines of therapy, received 120 mg of oral belzutifan per day for up to 1 year, and data showed that they experienced a median progression-free survival (PFS) of 14.5 months and an overall response rate of 25%.

The agent has also been evaluated in combination with cabozantinib (Cabometyx) in the phase 2 LITESPARK-003 trial (NCT03634540), which showed that treatment-naïve patients with RCC achieved an ORR of 57%. In patients who received prior immune-oncology treatment, the ORR was 31%.³

Further belzutifan-based combinations are being investigated in the phase 3 MK-6482-012 trial (NCT04736706), which is evaluating belzutifan plus lenvatinib (Lenvima) vs pembrolizumab (Keytruda) plus lenvatinib in patients with advanced RCC.

ARO-HIF2, a synthetic double-stranded RNA interference trigger designed to silence HIF2a expression, was also investigated in a phase 1 trial (NCT04169711) in patients with advanced ccRCC. The agent produced an ORR of 8% and a disease control rate of 39%. Investigators observed a reduction in HIF2α expression by quantitative PCR and immunohistochemistry.⁴

“[There is a] concept of targeting HIF2 in different mechanisms, not just through small molecule inhibitors, but through directly silencing the RNA,” McKay said. “You would think that we would see higher responses...and it's going to be interesting to see how the integration of the strategy moves into the clinic.”

McKay also highlighted XL092, which is a novel, oral multi-targeted inhibitor of MET, VEGFR2, and TAM. The agent is under evaluation as monotherapy and in combination with atezolizumab (Tecentriq) or avelumab (Bavencio) in patients with solid tumors in the phase 1 STELLAR-001 trial (NCT03845166), and in combination with nivolumab (Opdivo) with or without ipilimumab (Yervoy) in patients with solid tumors in the phase 1 STELLAR-002 trial (NCT05176483).⁵

"[XL092] does have a similar target profile to cabozantinib, targeting VEGF and cMET. It has a shorter half-life and pharmacokinetic properties that are suitable for once-daily dosing. The pharmacokinetic profile of this drug is a little bit different, and I don't think we mechanistically understand the differences between this agent and cabozantinib. Hopefully, further studies will begin to tease that out."

ADCs and Radiotherapeutics

Other ongoing trials are investigating agents such as ADCs and radiotherapeutics designed to induce direct killing of tumor cells through the leverage of delivering specific payloads, McKay said.

DS-6000a is a CDH6-targeted ADC that consists of a humanized anti-CDH6 IgG1 monoclonal antibody attached to a topoisomerase I inhibitor payload. In a phase 1 trial (NCT04707248), 2 partial responses were recorded—1 in a patient with advanced RCC and another in a patient with advanced ovarian cancer—among 15 patients evaluable for efficacy. Additionally, 9 patients had stable disease.⁶

AGS-16C3F is another novel ADC designed to target ENPP3, which is expressed in 94% of patients with ccRCC. In a phase 2 trial (NCT02639182) that compared the ADC vs axitinib (Inlyta) in previously treated patients with metastatic RCC, the primary end point of PFS was not met. Patients treated with AGS-16C3F experienced a median PFS of 2.9 months vs 5.7 months for axitinib (HR, 1.676; 95% CI, 1.107-2.537; P = .015).⁷

"We still have a lot to learn about ADCs. They're very provocative and certainly have demonstrated a lot of activity across multiple other tumor [types] with a lot of excitement,” McKay noted. “However, RCC is a tumor type that does not traditionally respond to chemotherapy, so we need to understand what [would be] the right payload.”

In the radioligand realm, 177Lu-girentuximab is the first antibody-radioisotope designed for the treatment of patients with ccRCC. The agent targets carbonic anhydrase IX-expressing cells, which includes more than 90% of ccRCC cells. In the phase 2 STARLITE 2 trial (NCT05239533), investigators are evaluating the radioligand in combination with nivolumab in metastatic ccRCC who received at least 1 prior immunotherapy.⁸ Additionally, 177Lu-girentuximab in combination with nivolumab and cabozantinib will be investigated in the phase 2 STARLITE 1 trial in treatment-naïve patients with ccRCC.¹ "These are going to be critically important studies,” McKay noted.

Other Novel Targets

CDK4/6 inhibition, which currently plays a role in the treatment of patients with hormone receptor–positive breast cancer, is also being investigated in the RCC space. The multicenter, single-arm phase 2 APART trial (NCT05176288) is evaluating the addition of palbociclib (Kisqali) to avelumab and axitinib in patients with advanced RCC who have not received prior systemic therapy.⁹

CBM588, a live probiotic comprised primarily of Clostridium butyricum, was evaluated in combination with nivolumab and ipilimumab in previously untreated patients with metastatic RCC in a phase 1b trial (NCT03829111), where the triplet elicited achieved an ORR of 58% (n = 19) compared with 20% for those given nivolumab/ipilimumab alone (n = 10).¹⁰

Furthermore, in a phase 1b/2 trial (NCT04300140) showed that the combination of batiraxcept (AVB-S6-500) and cabozantinib generated safety and early signs of efficacy in pretreated patients with advanced or metastatic ccRCC. Batiraxcept is a highly potent and specific first-in-class AXL inhibitor, and the combination led to a reduction in target lesions in 85% of all patients (n = 22), and 58% of patients experienced an improved response compared with prior treatment.¹¹

Finally, McKay pointed to the investigation of TPST-1120, which is a first-in-class oral PPARa inhibitor. In a phase 1 study (NCT03829436), single-agent treatment produced an ORR of 23% in patients with solid tumors (n = 13). Among the 3 partial responses observed, 2 patients had RCC and progressed on prior anti–PD-1 therapy.¹²

References

1. McKay RR. Novel Therapies. Presented at: 2023 Kidney Cancer Research Summit; July 13-14, 2023; Boston, MA.
2. Jonasch E, Bauer TM, Papadopoulos KP, et al. Phase 1 LITESPARK-001 (MK-6482-001) study of belzutifan in advanced solid tumors: update of the clear cell renal cell carcinoma (ccRCC) cohort with more than 3 years of total follow-up. J Clin Oncol. 2022;40(suppl 16):4509. doi:10.1200/JCO.2022.40.16_suppl.4509
3. Choueiri TK, Bauer T, Merchan J, et al. Phase II study of belzutifan plus cabozantinib as first-line treatment of advanced renal cell carcinoma (RCC): cohort 1 of LITESPARK-003. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072
4. Brugarolas J, Beckermann K, Rini BI, et al. Initial results from the phase 1 study of ARO-HIF2 to silence HIF2-alpha in patients with advanced ccRCC (AROHIF21001). J Clin Oncol. 2022;40(suppl 6):339. doi:10.1200/JCO.2022.40.6_suppl.339
5. Sharma M, Subbiah V, Shapiro G, et al. A phase 1 first-in-human study of XL092 administered alone or in combination with immune checkpoint inhibitors (ICIs) in patients (pts) with inoperable locally advanced or metastatic solid tumors: Description of genitourinary (GU) expansion cohorts. J Clin Oncol. 2022;40(suppl 6):TPS401. doi:10.1200/JCO.2022.40.6_suppl.TPS401
6. Hamilton EP, Jauhari S, Moore KN, et al. Phase I, two-part, multicenter, first-in-human (FIH) study of DS-6000a in subjects with advanced renal cell carcinoma (RCC) and ovarian tumors (OVC). J Clin Oncol. 2022;40(suppl 16):3002. doi:10.1200/JCO.2022.40.16_suppl.3002
7. Kollmannsberger C, Choueiri TK, Heng DYC, et al. A randomized phase II study of AGS-16C3F versus axitinib in previously treated patients with metastatic renal cell carcinoma. Oncologist. 2021;26(3):182-e361. doi:10.1002/onco.13628
8. Study of nivolumab in combination with 177Lu-girentuximab for kidney cancer. ClinicalTrials.gov. Updated February 17, 2023. Accessed July 14, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05239533
9. Avelumab, palbociclib and axitinib in advanced RCC (APART). ClinicalTrials.gov. Updated June 28, 2023. Accessed July 14, 2023. https://classic.clinicaltrials.gov/ct2/show/NCT05176288
10. Dizman N. Clinical outcomes with nivolumab/ipilimumab (nivo/ipi) with or without CBM588 in metastatic renal cell carcinoma (mRCC): long-term follow-up of a randomized phase Ib clinical trial. Presented at: International Kidney Cancer Symposium; November 4-5, 2022. Austin, Texas. Abstract 9.
11. Shah NJ, Campbell MT, Mao SS, et al. A phase 1b/2 study of batiraxcept (AVB-S6-500) in combination with cabozantinib in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC). J Clin Oncol. 2023;41(6):666. doi:10.1200/JCO.2023.41.6_suppl.666
12. Yarchoan M, Powderly JD, Bastos BR, et al. A phase 1 study of TPST-1120 as a single agent and in combination with nivolumab in subjects with advanced solid tumors. J Clin Oncol. 2022;40(suppl 16):3005. doi:10.1200/JCO.2022.40.16_suppl.3005