New Drugs Being Explored in Kidney Cancer

Ongoing research is laying the groundwork for new kidney cancer treatments, according to Dr. Rana R. McKay.

“There are a lot of novel therapies that are being investigated, (and) targeting angiogenesis (stopping cancer cells from growing new blood vessels) continues to be pretty important in RCC cell carcinoma,” McKay, a medical oncologist and an associate professor of medicine at University of California, San Diego Health, 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 antibody drug conjugates — which is a type of drug that attaches to biomarkers on the cancer cell surface, and then delivers therapy directly to the tumor — as well as radiotherapeutics and other agents within the RCC landscape and highlighted novel targets that could inform the development of treatments for this patient population.

Anti-Angiogenics

The phase 1 LITESPARK-001 trial evaluated Welireg (belzutifan) monotherapy in patients with locally advanced or metastatic solid sporadic clear cell RCC (ccRCC) who received at least one prior treatment for ccRCC, had measurable disease per RECIST v1.1 criteria, and were able to perform all of most of their daily tasks independently.

Fifty-five patients who had received a median of three prior lines of therapy, received 120 mg of oral Welireg per day for up to one year, and data showed that they experienced a median progression-free survival (time from treatment until death or disease worsening) of 14.5 months and an overall response rate (percentage of patients whose disease shrinks or disappears from treatment, of 25%.

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

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

ARO-HIF2 was also investigated in a phase 1 trial (NCT04169711) in patients with advanced ccRCC. The agent produced an overall response rate of 8% and a disease control rate of 39%. Investigators observed a reduction in HIF2α expression, which promotes tumor growth.

“(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 — proteins that play a role in the growth and survival of cancer cells. The agent is under evaluation as monotherapy and in combination with Tecentriq (atezolizumab) or Bavencio (avelumab) in patients with solid tumors in the phase 1 STELLAR-001 trial, and in combination with Opdivo (nivolumab) with or without Yervoy (ipilimumab) in patients with solid tumors in the phase 1 STELLAR-002 trial.

"(XL092) does have a similar target profile to (Cabometyx), 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 (Cabometyx). 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 drugs, 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, two partial responses were recorded — one in a patient with advanced RCC and another in a patient with advanced ovarian cancer — among 15 patients evaluable for efficacy. Additionally, nine patients had stable disease.

AGS-16C3F is another novel ADC designed to target ENPP3, which is expressed in 94% of patients with ccRCC. In a phase 2 trial that compared the ADC vs Inlyta (axitinib) in previously treated patients with metastatic RCC, the primary end point of progression-free survival was not met. Patients treated with AGS-16C3F experienced a median progression-free survival of 2.9 months vs 5.7 months for Inlyta.

"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, investigators are evaluating the radioligand in combination with Opdivo in metastatic ccRCC who received at least one prior immunotherapy. Additionally, 177Lu-girentuximab in combination with Opdivo and Cabometyx will be investigated in the phase 2 STARLITE 1 trial in treatment-naïve patients with ccRCC.

"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 is evaluating the addition of Kisqali (Palbociclib) to Bavenxio and Inlyta in patients with advanced RCC who have not received prior systemic therapy.

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

Furthermore, in a phase 1b/2 trial (NCT04300140) showed that the combination of batiraxcept (AVB-S6-500) and Cabometyx 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 (22 patients), and 58% of patients experienced an improved response compared with prior treatment.

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

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