VEGF and HIF Pathway Inhibition Point Toward an Increasingly Tolerable RCC Armamentarium

Combination regimens represent the future of metastatic renal cell carcinoma (RCC) management, with immunotherapy doublets and immunotherapy/VEGF TKI combinations at the forefront of a treatment landscape that also includes investigational approaches such as radioligand therapy and CAR T-cell therapy, according to Qian (Janie) Qin, MD.

“There’s much improvement we can do to increase the complete response [CR] rates and decrease the primary progression rates [in RCC],” Qin said.

In an interview with OncLive®, Qin, an assistant professor in the Division of Hematology and Oncology in the Department of Internal Medicine at the Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center in Dallas, Texas, discussed the current RCC treatment landscape, ongoing research with belzutifan (Welireg) combination therapies, and considerations for investigating CAR T-cell therapy in patients with solid tumors.

The phase 3 COSMIC-313 trial (NCT03937219) studied the combination of the VEGF TKI cabozantinib (Cabometyx) plus ipilimumab (Yervoy) and nivolumab (Opdivo) vs placebo plus ipilimumab and nivolumab in patients with treatment-naïve RCC. In this trial, the estimated 12-month progression-free survival rate was 57% (95% CI, 0.50-0.63) in the investigative arm vs 49% (95% CI, 0.42-0.55) in the control arm (HR, 0.73; 95% CI, 0.57-0.94; P = .01). However, 79% of patients who received cabozantinib experienced grade 3 or 4 adverse effects (AEs), compared with 56% of patients who received placebo.¹ In the interview, Qin noted how the unfavorable safety profile of this regimen has spurred further research with other triplet therapies that may be better tolerated.

Qin also shared findings from the phase 2 LITESPARK-003 trial (NCT03634540), in which the HIF2α inhibitor belzutifan plus cabozantinib generated a confirmed overall response rate (ORR) of 30.8% (95% CI, 18.7%-45.1%) in patients with advanced clear cell RCC (ccRCC) who had previously received immunotherapy.²

OncLive: What treatment regimens are emerging for patients with metastatic RCC?

Qin: The field has moved to combination therapy for the treatment of patients with advanced ccRCC. Those combinations include either an immunotherapy/immunotherapy combination with the doublet ipilimumab with nivolumab, or an immunotherapy/VEGF TKI combination, of which we have 4 choices. Pembrolizumab [Keytruda]/axitinib [Inlyta], nivolumab/cabozantinib, and pembrolizumab/lenvatinib [Lenvima] are usually the preferred choices, because the survival data are yet to be mature for avelumab [Bavencio]/axitinib. Although the response rates [with these therapies have] significantly increased, we still have a way to go [to achieve] CRs and increase response rates for patients.

Emerging treatment options are available for patients with advanced or metastatic RCC. Triplet therapy looking at targeting the HIF pathway [has been introduced]. [Additionally], novel immunotherapies and VEGF TKIs are under development. Novel therapies with novel mechanisms of action within the realm of kidney cancer include the COSMIC-313 trial [regimen]. Other trials are also investigating [other] triplet therapies. The HIF2α inhibitor belzutifan [is under investigation as well]. HIF2 pathway resistance [treatment] includes ARO-HIF2. Emerging single-agent, double-agent, or triplet therapies with belzutifan [are under evaluation]. Novel mechanisms [include] CAR T-cell therapy and radioligand therapy.

As HIF2α inhibition appears well tolerated as monotherapy, what are some potential combination partners for HIF2α inhibitors?

For belzutifan, which is currently being investigated in several clinical trials, our [combination] options include known VEGF TKIs. For example, in the LITESPARK-003 trial, belzutifan was combined with cabozantinib. Belzutifan [was administered] at 120 mg [once daily] and cabozantinib [was administered] at 60 mg [once daily] in 2 cohorts of patients. Cohort 1 was [comprised of] treatment-naïve [patients], and cohort 2 [included] patients who had received 2 of fewer lines of therapy, including immunotherapy.

The preliminary efficacy of the combination seems promising. In the treatment-naïve patients, the ORR was 57% in the 35 patients who were enrolled. In cohort 2, the pretreated patients, the ORR, per the latest update by Toni Choueiri, MD, [of Dana-Farber Cancer Institute in Boston, Massachusetts], and colleagues, [which was published] in Lancet Oncology, showed an ORR of 30.8%. That combination is promising.

Then, we’re evaluating additional therapies. The [phase 3] LITESPARK-011 trial [NCT04586231] is investigating belzutifan plus lenvatinib vs cabozantinib. Belzutifan [is administered at] 120 mg [once daily], lenvatinib [is administered at 20 mg once daily], and cabozantinib [is administered] at the full dose of 60 mg [once daily] as the comparator. LITESPARK-011 [enrolled] pretreated patients who have had 2 or fewer lines of therapy.

[Regarding] triplet therapy, the COSMIC-313 trial [regimen] of cabozantinib plus ipilimumab plus nivolumab seems to be difficult to tolerate, with high toxicity. Other triplet therapies with different mechanisms [of action are under investigation], and the question is whether they will be tolerable.

Belzutifan seems well tolerated, so the [phase 3] LITESPARK-012 trial [NCT04736706] is evaluating the combination of belzutifan plus lenvatinib and pembrolizumab vs quavonlimab [MK-1308], a novel CTLA-4 inhibitor, plus lenvatinib and pembrolizumab, vs standard-of-care lenvatinib and pembrolizumab. This trial [is evaluating] treatment-naïve patients. I’m interested to see the tolerability and efficacy of this triplet combination as [the trial] reads out.

What are some the properties of the CAR T-cell therapies under evaluation in RCC?

In the hematological realm, CAR T-cell therapy has drastically changed the treatment landscape and has [induced] fantastic responses. However, in solid tumors, there’s unique sets of challenges with using CAR T-cell therapy, which are T cells engineered to look for tumor-associated antigens. [There needs to be a] nonclassical immune synapse between the CAR T cells and the target, so the CAR T cells can identify the tumor cells and lead to cytotoxic killing. In solid tumors, though, the CAR T cells first need to traffic to the tumor, then penetrate layers of extracellular matrix. Once they do that, they might face a hostile tumor microenvironment. There are a few challenges and steps regarding getting CAR T-cell therapy to the [right] areas of the tumor.

The other challenges are identifying tumor-associated antigens. The best tumor-associated antigens are those that are uniformly and highly expressed in tumor cells but are not expressed in normal cells. If they are expressed in normal cells, we could see significant autoimmune AEs. Identifying the right tumor-associated antigen is important and can pose a challenge.

[One overall challenge with] CAR T-cell therapy [stems from] autologous vs allogeneic [CAR T cells]. The former are T cells of the patients that get leukapheresed and engineered into CAR T cells. That can take time, and if a patient has already progressed on several lines of therapy, we may not have time to wait weeks for that engineering.

[Conversely], allogeneic CAR T-cell therapy, or off-the-shelf CAR T-cell therapy, uses healthy donors to engineer the CAR T cells. [This is associated with] concerns such as graft-versus-host disease. However, [with allogeneic CAR T cells], the timing from initial need for CAR T-cell therapy to getting the CAR T-cell therapy is significantly shorter.

Within RCC, multiple studies are investigating CAR T-cell therapy. CD70 is highly expressed in RCC tumor cells, and two trials have read out [that evaluated] allogeneic CD70-directed CAR T-cell therapy: COBALT-RCC [NCT04438083] and TRAVERSE [NCT04696731]. These are phase 1 trials, so the most important thing [they evaluated was] tolerability and the safety profile. Overall, these trials showed that CAR T-cell therapy is safe and tolerable in this patient population. However, the response rates are preliminary, and more work is needed in this area. A few active clinical trials are using CAR T-cell therapy with targets such as CD70 or CA9, which is expressed in over 90% of patients with ccRCC. This is an exciting field, but there are some unique challenges that we need to cross with CAR T-cell therapy in kidney cancer.

What ongoing RCC research is UT Southwestern involved in?

UT Southwestern was crucial in the identification of the HIF pathway and HIF2α inhibitors. That’s an area of high interest within our institution, particularly identifying resistance within the HIF pathway to identify the next generation of HIF inhibitors. There’s also a high interest in biomarkers for the identification of kidney cancer, both in terms of the tumor and responses to specific therapies.

There’s much interest from us regarding novel radiotracers that may help us evaluate or predict responses to immunotherapy vs VEGF TKIs or HIF inhibitors. One such trial is the [phase 2] atezolizumab [Tecentriq] immunoPET/CT trial [NCT04006522]that’s currently active and accruing, where patients get a small, radiolabeled dose of atezolizumab. We want to see whether we can identify PD-L1 expression within the patients’ tumors across metastatic sites. If [this trial is] positive, could a PET scan like this help us predict whether patients will respond to immunotherapy? If there’s high uptake of the radiotracer on the PET scan, do those patients have great responses to immunotherapy? [Do the patients with] low uptake have not as ideal responses to immunotherapy? Novel radiotracers and imaging are of high interest in their ability to noninvasively give us some ideas about patients’ tumors and their potential responses.

What is your main message for academic and community colleagues regarding the future of the RCC treatment landscape?

Doublet immunotherapy [combinations] or immunotherapy with VEGF TKI combinations are now the preferred first-line treatment options for [patients with] advanced RCC. Further increasing the ORRs [and generating] longer survival benefits [are what] we hope to achieve with progress in the field.

Novel therapies are under development, such as novel triplet combinations, HIF2 pathway inhibition, CAR T-cell therapy, and radioligand therapy. It will be important to see the readouts of [these trials to see] how they shape the treatment landscape moving forward. These hold much promise in expanding the arsenal of available therapies for patients with advanced RCC.

References

1. Choueiri TK, Powles T, Albiges L, et al. Cabozantinib plus nivolumab and ipilimumab in renal-cell carcinoma. N Engl J Med. 2023;388(19):1767-1778. doi:10.1056/NEJMoa2212851
2. Choueiri TK, McDermott DF, Merchan J, et al. Belzutifan plus cabozantinib for patients with advanced clear cell renal cell carcinoma previously treated with immunotherapy: an open-label, single-arm, phase 2 study. Lancet Oncol. 2023;24(5):553-562. doi:10.1016/S1470-2045(23)00097-9