New Data Bring Excitement, Raise Questions in Advanced RCC

Brian I. Rini, MD, FASCO

Although renal cell carcinoma (RCC) remains a difficult-to-treat disease, with patients with clear cell histology experiencing a median overall survival (OS) of approximately 13 months and a 5-year OS rate of less than 10%,¹ updated results from clinical trials examining emerging therapeutic strategies have spurred optimism. This has led to discussion about treatment sequencing and selection based on adverse effect (AE) profiles and efficacy among patient subgroups.

An estimated 431,288 new kidney cancer cases were diagnosed globally in 2020, with RCC accounting for approximately 90% of these instances. The 3 most common subtypes of RCC are clear cell RCC (70%), papillary RCC (10%-15%), and chromophobe RCC (5%).²

“Clear cell RCC is a disease that happens predominantly to men in their 50s and 60s,” Brian I. Rini, MD, FASCO, said. “We see a lot of these
patients. They can present asymptomatically, incidentally, [and] with hematuria symptoms. The [treatment] landscape [for this population] has been immune-based doublets.”

During a recent OncLive Peer Exchange®, expert clinicians in the field of kidney cancer highlighted updates from clinical trials evaluating frontline treatment options for patients with advanced clear cell RCC, therapeutic choices in the second line and beyond, and options for patients with non–clear cell RCC, presented during the 2023 American Society of Clinical Oncology Annual Meeting (ASCO 2023).

Optimizing Frontline Advanced ccRCC Treatment

In recent years, there have been multiple posi- tive trials in advanced clear cell RCC, providing several options for patients that can be selected based on safety profiles, efficacy in different subgroups, and other factors.

During ASCO 2023, investigators presented findings from the final prespecified OS analysis of the phase 3 CLEAR trial (NCT02811861).

CLEAR enrolled treatment-naïve patients with advanced RCC with a clear cell component and randomly assigned them to receive the multire- ceptor tyrosine kinase inhibitor (TKI) lenvatinib (Lenvima) in combination with PD-1 inhibitor pembrolizumab (Keytruda; n = 355) or sunitinib (Sutent; n = 357).³

At a median follow-up of 49.8 months (range, 41.4-53.1), patients in the combination arm experienced a median OS of 53.7 months (95% CI, 48.7-not estimable [NE]) compared with 54.3 months (95% CI, 40.9-NE) at a median follow-up of 49.4 months (95% CI, 41.6- 52.8) in the sunitinib arm (HR, 0.79; 95% CI, 0.63-0.99; P = .0424). However, the 24- (80.4% vs 69.6%, respectively), 36- (66.4% vs 60.2%), and 48-month (55.9% vs 52.5%) OS rates all favored the combination arm, although the benefit was driven more by the intermediate- and poor-
risk (HR, 0.74; 95% CI, 0.57-0.96) subgroup than the favorable-risk (HR, 0.94; 95% CI, 0.58-1.52) subgroup (Table 1)³.

Table 1

Additionally, lenvatinib plus pembrolizumab provided a significant benefit in terms of progression-free survival (PFS), at 23.9 months (95% CI, 20.8-27.7) vs 9.2 months (95% CI, 6.0-11.0), respectively (HR, 0.47; 95% CI, 0.38- 0.57; P < .0001), and overall response rate (ORR), at 71.3% (95% CI, 66.6%-76.0%) vs 36.7% (95% CI, 31.7%-41.7%), respectively (relative risk, 1.94; 95% CI, 1.67-2.26; P < .0001).

Safety results from CLEAR showed that any-grade treatment-related AEs (TRAEs) occurred in 96.9% and 92.1% of patients in the combination and monotherapy arms, respectively. Grade 3 or higher TRAEs were reported
in both arms (74.1% vs 60.3%, respectively) as were deaths (1.1% vs 0.3%). The most common any-grade TRAEs in the investigational arm were diarrhea (56.0%), hypertension (54.3%), hypothy- roidism (44.9%), and decreased appetite (35.5%).

Additional Agents Provide Options

In another phase 3 trial, KEYNOTE-426 (NCT02853331), the safety and efficacy of pembrolizumab plus another TKI, axitinib (Inlyta), were compared with those of sunitinib in patients with treatment-naïve locally advanced or metastatic clear cell RCC. Findings from the 5-year analysis of KEYNOTE-426 presented during ASCO 2023 demonstrated that at a median follow-up of 67.2 months (range, 60.0-75.0), the median PFS was 15.7 months (95% CI, 13.6-20.2) in the combination arm (n = 432) compared with 11.1 months (95% CI, 8.9-12.5) in the sunitinib arm (n = 429; HR, 0.69; 95% CI, 0.59-0.81). The ORR was 60.6% with an 11.6% complete response (CR) rate compared with an ORR of 39.6% with a 4.0% CR rate, respectively. The median OS was 47.2 months (95% CI, 43.6-54.8) vs 40.8 months (95% CI, 34.3-47.5) in the respective arms (HR, 0.84; 95% CI, 0.71-0.99). When stratified by International Metastatic RCC Database Consortium risk score, patients with intermediate- and poor-risk disease (HR, 0.76; 95% CI, 0.62-0.93) appeared to derive more benefit than those with favorable risk (HR, 1.10; 95% CI, 0.79-1.54); (TABLE 2).⁴

“We have many options at this indication,” Bruno R. Bastos, MD, said. “These data just corroborate that those regimens are effective regimens that can be used up front—the combination of VEGF TKIs and immunotherapies. It gives us more confidence that we are providing good care to our patients. However, this OS may make us think about perhaps the second- and third- line therapies that are coming along.”

Table 2

“I divide it up between favorable risk, intermediate [risk], and...poor [risk],” Eric Jonasch, MD, added. “Within the intermediate- and poor[- risk category], [this comprises] those who have threatening disease vs non-threatening disease. [In] the favorable[-risk subgroup], I’ll typically use axitinib plus pembrolizumab. In the intermediate- and poor[-risk patients], if they have non-threatening disease, I’ll use ipilimumab [Yervoy] plus nivolumab [Opdivo], and then I’ll use either cabozantinib [Cabometyx] plus nivolumab or lenvatinib plus pembrolizumab in those who have life-threatening disease.”

Additionally, triplet regimens are showing promise in the frontline treatment of patients with advanced clear cell RCC. Findings from the phase 3 COSMIC-313 trial (NCT03937219) showed that patients who received cabozantinib in addition to nivolumab and ipilimumab (n = 276) did not reach the median PFS (95% CI, 14.0-not reached [NR]) vs a median PFS of 11.3 months (95% CI, 7.7-18.2) among patients who received placebo in place of cabozantinib (n = 274). The 12-month PFS rates were 57% (95% CI, 50%-63%) compared with 49% (95% CI, 42%-55%), respectively (HR, 0.73; 95% CI, 0.57-0.94; P = .01). However, findings from the prespecified subgroup analysis suggested that patients with poor-risk disease did not benefit from the addition of cabozantinib (HR, 1.04; 95% CI, 0.65-1.69).5

Safety findings showed that all patients in the investigational (n = 426) and control (n = 424) arms experienced an any-grade AE. The most common any-grade AEs in the experimental arm were diarrhea (50%) and increased alanine aminotransferase (49%) and aspartate amino-transferase (46%) levels.

Moreover, in the phase 3 MK-6482-012 trial (NCT04736706) investigators are planning to compare the safety and efficacy of the combination of pembrolizumab plus hypoxia-inducible factor 2α (HIF-2α) inhibitor belzutifan (Welireg) and lenvatinib or pembrolizumab/quavonlimab plus lenvatinib with those of pembrolizumab plus lenvatinib. The trial is currently recruiting patients with clear cell RCC who have not previously received systemic therapy for their disease. The coprimary end points are PFS and OS. Secondary end points include ORR, duration of response, and safety.⁶

Beyond Frontline Therapies

Novel combinations are also being examined in the second-line setting. In the phase 1/2 LITESPARK-024 trial (NCT05468697), investigators are evaluating belzutifan with or without the CDK4/6 inhibitor palbociclib (Ibrance).

In a preclinical study, the effects of CDK4/6 inhibition were synergistic with HIF-2α inhibition, providing the clinical rationale for the trial. The open-label, randomized study is currently recruiting patients.⁷

Regarding triplets, the phase 3 CONTACT-03 trial (NCT04338269) was
the first randomized phase 3 trial to examine the effect of adding an immune checkpoint inhibitor to a control arm. Updated findings presented at ASCO 2023 showed that patients with metastatic clear cell RCC who progressed on or after immune checkpoint inhibitor treatment did not experience a benefit with this approach.⁸

Patients who received atezolizumab (Tecentriq) plus cabozantinib (n=263) experienced a median PFS of 10.6 months (95% CI, 9.8-12.3) compared with 10.8 months (95% CI, 10.0-12.5) among patients who were treated with cabozantinib monotherapy (n = 259; HR, 1.03; 95% CI, 0.83-1.28; P = .7844). Additionally, the median OS was 25.7 months (95% CI, 21.5-NE) vs NE (95% CI, 21.1-NE), respectively (HR, 0.94; 95% CI, 0.70- 1.27; P = .6902).⁸

“Unfortunately, [CONTACT-03] was a nega- tive trial,” Rini commented. “Not surprisingly, there was an excess of toxicity in the combination arm. There was a difference [in excess of] 10% in high-grade AEs and serious AEs between the combination arm and the monotherapy arm, with 3 deaths due to toxicity in the combination arm. So, not only was it not as efficacious, but it was also more toxic.”

Elizabeth Plimack, MD, MS, argued that she “wouldn’t throw out this entire approach for all patients based on this study. If we looked at patients who responded and then progressed or patients who had a gap or a stronger combination, we might do better.” However, she acknowledged that this approach should not be used in clinical practice until more data proving its benefit are available.

Despite the disappointing findings from CONTACT-03, findings from the phase 1/2 KEYMAKER-U03B/ MK-3475-03B trial (NCT04626518), also presented during ASCO 2023, displayed more favorable data for patients with clear cell RCC. Results showed that the combination of belzutifan and lenvatinib showed promising antitumor activity in patients with clear cell RCC who experienced disease progression on or after treatment with PD-1/L1 inhibitors and VEGF TKIs. Efficacy-evaluable patients (n = 32) experienced a median PFS of 11.2 months (95% CI, 4.2-NR), with a 6-month PFS rate of 55%. Among 24 patients who underwent at least 2 postbaseline scans, the ORR was 50% (95% CI, 29%-71%); all responses were partial.⁹

The combination of belzutifan and lenvatinib is now under further eval- uation in the phase 3 LITESPARK-011 study (NCT04586231).

The Evolving Landscape

Non–clear cell RCC comprises a group of subtypes that differ genetically and biologically from each other and are extremely rare. There is no current standard of care for these rare forms of non–clear cell RCC and the prognosis for these patients is generally poor.¹⁰ However, during ASCO 2023, promising findings were presented from a pair of phase 2 clinical trials in this population.

Updated findings from the phase 2 KEYNOTE-B61 trial (NCT04704219) revealed that lenvatinib plus pembrolizumab showed antitumor activity in patients with treatment- naïve non–clear cell RCC; the ORR was 49% (95% CI, 41%-57%), with a 6% CR rate, in the efficacy-evaluable population (n = 158). Moreover, the median PFS was 17.9 months (95% CI, 14.0-NR) and the median OS was NR (95% CI, NR-NR). The 1-year PFS and OS rates were 63% (95% CI, 54%-70%) and 82% (95% CI, 75%-88%), respectively.¹¹

To date, KEYNOTE-B61 is the largest prospective trial evaluating an immune checkpoint inhibitor combination in non–clear cell RCC. Investigators concluded that the findings presented at the 2023 ASCO Annual Meeting supported the use of pembrolizumab plus lenvatinib as a frontline treatment option for patients with non–clear cell RCC, irrespective of histology. Patients with papillary (n = 93), chromophobe (n = 29), unclassified (n = 21), translocation (n = 6), and other (n = 9) histologies experi- enced ORRs of 54.0%, 28.0%, 52.0%, 67.0%, and 56.0%, respectively.

Additionally, investigators also presented findings from a phase 2 trial (NCT03635892) that evaluated the combination of cabozantinib plus nivolumab in patients with metastatic non–clear cell RCC. At a median follow-up of 34 months (range, 20-51), the median OS was 28 months (95% CI, 23-43) and the median PFS was 13 months (95% CI, 7-16) among 40 efficacy-evaluable patients. Additionally, the 18- and 36-month OS rates were 70% (95% CI, 53%-82%) and 44% (95% CI, 28%-60%), respectively.¹²

Findings from both studies indicated that the safety profiles of the 2 combinations were in-line with their previously observed AE profiles. In KEYNOTE-B61, most patients experienced an AE (94.3%), with hypertension (57.0%), diarrhea (43.7%), and hypothyroidism (36.7%) being the most common. In the latter phase 2 study, the most common any-grade AEs were fatigue (70%), palmar-plantar erythrodysesthesia syndrome (68%), and diarrhea (63%).

“If we take a step back from all these data, it’s kind of amazing how many [patients] are living beyond 5 years,” Plimack said in conclusion. “We could not have imagined this when we started these studies. I’m excited to see [where this research goes] and as we cross-compare and decide which [approach] is better, [we have to acknowledge] they’re all really great compared with where we were before.”

References

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