ESMO 2022: New Combinations and Settings in RCC Show Mixed Results

James Larkin, MD

In recent years, several new treatment options have been introduced into the landscape for renal cell carcinoma (RCC), especially with immunotherapy-based doublet regimens in the first-line setting for patients with clear cell disease. Following these successes, investigators continue to explore new approaches for patients in a rapidly evolving field to continue to move the needle toward improved outcomes for patients with kidney cancer.

During the European Society for Medical Oncology (ESMO) Congress 2022, mixed results were seen across the RCC trials, even among several large phase 3 studies, that continue to challenge treatment selection in the adjuvant/neoadjuvant and frontline settings.

Following data revealed at the meeting, Toni Choueiri, MD, director of the Lank Center for Genitourinary Oncology, medical director for international strategic initiatives, and coleader of the Kidney Cancer Program at Dana-Farber Cancer Institute, Boston, Massachusetts, said in a presentation at the ESMO meeting that his approach for the first-line setting for patients with metastatic RCC has now adapted to defi ne immunotherapy plus VEGF inhibition as the preference for patients with favorable-risk disease. For those with intermediate-/poor-risk disease, he would use immunotherapy plus VEGF tyrosine kinase inhibitors (TKIs) in the case of rapid progression, but immunotherapy doublets are also benefi cial in the case of less rapid progression. Additionally, in those with sarcomatoid features, nivolumab (Opdivo) plus ipilimumab (Yervoy) should become the standard choice, according to Choueiri.

How data revealed at ESMO will continue to affect treatment choices in the clinic and future research remains to be seen.

New Immunotherapy Combinations

Among the anticipated presentations highlighted at ESMO included the phase 3 COSMIC-313 trial (NCT03937219), which looked at the triplet combination of cabozantinib (Cabometyx), nivolumab, and ipilimumab in patients with advanced RCC.

In the study, the median progression-free survival (PFS) for the triplet regimen was not reached (95% CI, 14.0-not evaluable [NE]) compared with 11.3 months with nivolumab and ipilimumab alone (HR, 0.73; 95% CI, 0.57-0.94; P = .013). At 12 months, the PFS rates were 57% with the triplet and 49% with the doublet.¹

The objective response rate (ORR) with added cabozantinib was 43% (95% CI, 37.2%-49.2%) compared with 36% (95% CI, 30.1%-41.8%) without, including complete responses (CRs) in 3% of patients in both arms. The median duration of response (DOR) was not reached in either arm.

Patients with intermediate-risk disease showed even greater benefi t from the addition of cabozantinib (HR, 0.37; 95% CI, 0.47-0.85) compared with those with poor-risk disease (HR, 1.04; 95% CI, 0.65-1.69).

Adverse events (AEs) were more common with the triplet regimen but were considered generally manageable and consistent with the known safety profi les of each agent. Grade 3/4 treatment-related AEs (TRAEs) occurred in 73% and 41% of patients in the cabozantinib and placebo arms, respectively. Each arm had 3 patients (1%) with grade 5 TRAEs and treatment discontinuations due to TRAEs were reported in 12% and 5% of patients, respectively.

Sumanta Kumar Pal, MD, FASCO

In an invited discussion of the presentation, Sumanta Kumar Pal, MD, FASCO, professor, Department of Medical Oncology & Therapeutics Research and co-director of the Kidney Cancer Program, City of Hope Comprehensive Cancer Center, Duarte, California, said the trial represented several firsts for the RCC field. It was the first phase 3 clinical trial to use a contemporary control arm and was the first to compare a triplet with a doublet, while also meeting its primary end point.

Putting the data into context compared with other data from the current landscape, Pal cautioned that there are no overall survival (OS) data available yet from COSMIC-313, and with the control arm differing from that of many other phase 3 trials in the field, it makes it harder to compare.

Additionally, although “the triplet did do what I hoped it would do, which is to reduce the rate of primary progressive disease,” Pal said in an interview with Targeted Therapies in Oncology™, he also pointed out that “there’s only a marginal increase in response rate vs control, and I think there are low CR rates in both arms, and I think the response rates that we saw in both arms, as well as the CR rates, fell short of what we in the RCC community had hoped for.” He suggested though, that this could be due to patients with more aggressive disease being enrolled in the triplet study.

The phase 3 PIVOT-09 trial (NCT03729245) looked at the combination of bempegaldesleukin, a pegylated IL-2 prodrug, and nivolumab in patients with advanced clear cell RCC in the fi rst-line setting compared with investigator’s choice of either sunitinib (Sutent) or cabozantinib (Cabometyx).

The combination failed to improve outcomes over VEGF TKIs, as assessed by the coprimary end points of ORR and OS in the intermediate-/ poor-risk patient population.²

ORR with the combination was 23.0%, including CRs in 2.0% of patients, and was 30.6% with TKIs, including CRs in 2.7%. Specifically, the ORR with sunitinib was 27.9% and 38.2% with cabozantinib. The clinical benefi t rate was 64.8% with the doublet regimen and 78.7% with the single-agent TKIs. The median DOR, however, was greater with bempegaldesleukin and nivolumab at 16.4 months (95% CI, 10.5-22.7) vs 13.2 months (95% CI, 10.6-18.6).

Despite early improvements in OS rates with the immunotherapy regimen (6 months, 91.3% vs 85.3%, respectively; 12 months, 78.9% vs 71.9%), the Kaplan-Meier curves eventually crossed and the median OS was 29.0 months (95% CI, 25.6-NE) with bempegaldesleukin and nivolumab compared with NE (95% CI, 25.6-NE) with the TKI arm (HR, 0.82; 95% CI, 0.61-1.10; P = .1915). Subgroup analysis for OS showed that patients with poor-risk disease (HR, 0.65; 95% CI, 0.41-1.04) and positive PD-L1 expression (HR, 0.43; 95% CI, 0.22-0.81) showed greater benefit from the combination regimen, and improvement was also seen when the combination was compared with sunitinib alone (HR, 0.76; 95% CI, 0.55-1.04).

Of note, patients in the immunotherapy arm experienced fewer grade 3/4 TRAEs than those in the TKI arm (25.8% vs 56.5%, respectively).

ESMO discussant Laurence Albiges, MD, PhD, vice chair of the Department of Cancer Medicine at Gustave Roussy Institute in France, suggested that earlier supportive data for the rationale of the study were perhaps not strong enough compared with the current treatment landscape. In the phase 1/2 PIVOT02 trial (NCT02983045) for the combination, the ORR was 34.7% in the overall cohort (n = 49) and 25.0% in patients with intermediate-/poor-risk disease.^3,4 She noted that this was not improved over responses seen with nivolumab monotherapy.³

New Targeted Regimen

The ongoing phase 2 LITESPARK-003 trial (NCT03634540) is exploring belzutifan (Welireg), a hypoxia-inducible factor 2α (HIF2α) inhibitor, in combination with cabozantinib in patients with advanced or metastatic clear cell RCC. Cohort 1 of the study looked at treatment-naïve patients and cohort 2 looked at patients with prior immunotherapy treatment and up to 2 prior regimens for locally advanced or metastatic disease. The regimen showed promising activity in both cohorts and was well tolerated.^5,6

In the treatment-naïve cohort, the ORR was 57%, with CRs in 6% of patients, and the disease control rate (DCR) was 94%. In patients with intermediate-/poor-risk disease specifically, the ORR was 50% and the DCR was 100%. Those with favorable-risk disease had an ORR of 62%, and the DCR was 90%. The overall median DOR was 28.6 months.⁵

The median PFS was 30.3 months, and median OS was not reached.

In the previously treated cohort, the ORR was 31%, with ORRs of 27% and 32% in the favorable and intermediate-/poor-risk patient populations, respectively. The median DOR was 18.6 months. Median PFS was 13.8 months, and median OS was 24.1 months.⁶

The data have led us to preliminarily conclude that dual targeting of HIF-2α and VEGF pathways may be an effective treatment strategy in advanced clear cell RCC,” presenter Jaime R. Merchan, MD, director, Phase I Program, University of Miami Sylvester Comprehensive Cancer Center, Florida, said.

New Disease Settings for Immunotherapy in RCC

Several anticipated phase 3 studies for neoadjuvant/adjuvant immunotherapy in RCC failed to demonstrate improvements in outcomes, causing a stir and a great deal of questions about why these studies did not meet end points.

“I would propose that the emerging bodies of evidence do cause some pause in the overall role of adjuvant immunotherapy for RCC, but I still think it represents the standard clinical practice for the time being,” Pal said.

In the open-label, randomized, phase 3 PROSPER RCC trial (ECOG-ACRIN EA8143; NCT03055013), neoadjuvant nivolumab was explored prior to nephrectomy followed by adjuvant nivolumab and was compared with surgery alone in patients with high-risk RCC. Patients in the investigational arm received 1 dose of nivolumab followed by partial or radical nephrectomy and 9 doses of nivolumab.⁷

The trial, which had a primary end point of recurrence-free survival (RFS), was stopped for ineffi cacy at the first interim analysis when it was made clear that there was no benefit in RFS with neoadjuvant and adjuvant therapy compared with surgery alone (HR, 0.97; 95% CI, 0.74-1.28; 1-sided P = .43).

More AEs were observed in the nivolumab arm compared with the surgery-alone arm (treatment-related AEs, 78% vs 27%, respectively). However, this was considered consistent with the known safety profile of nivolumab from other clinical trials. Fourteen percent of patients discontinued treatment because of any AE in the nivolumab arm.

James Larkin, MD, the lead of the Uncommon Cancers Theme at The Royal Marsden, Biomedical Research Centre, The Institute of Cancer Research in London, United Kingdom, noted in a presentation regarding perioperative strategies in high-risk RCC that the PROSPER RCC trial unfortunately does not have an adjuvant-only arm for more accurate comparison.

Perioperative Strategies

Use of nivolumab and ipilimumab as adjuvant therapy for patients with localized, resected RCC was explored in part A of the phase 3 CheckMate 914 trial (NCT03138512). Disease-free survival (DFS) by blinded independent central review was the primary end point of the study.⁸

The adjuvant combination regimen did not show a signifi cant benefi t over placebo; median DFS with nivolumab and ipilimumab was not reached compared with 50.7 months with placebo, with an HR of 0.92 (95% CI, 0.71-1.19; P = .5347). At 24 months, the DFS rate was 76.4% with adjuvant therapy vs 74.0% with placebo.

Investigator assessment of DFS showed similar 24-month rates, at 77.1% and 74.1%, respectively. Larkin noted that these data were a surprise to him.

Some subgroups did demonstrate greater benefi t for the adjuvant regimen, especially for those with sarcomatoid features (HR, 0.29; 95% CI, 0.09-0.91). However, this was demonstrated in a small subset of patients (n = 40 total between both arms).

Additionally, many more patients discontinued treatment from the investigational arm vs the placebo arm (43% vs 11%, respectively), including because of AEs (33% vs 1%).

Part B of the study is ongoing and will explore the use of adjuvant nivolumab monotherapy. “I think this comparison of [part] A vs [part] B in due course will be important, and I hope, illuminating.”

IMmotion010 was a double-blind phase 3 trial (NCT03024996) that investigated the use of adjuvant atezolizumab (Tecentriq) compared with placebo in patients with resected intermediate- to high-risk RCC and clear cell and/or sarcomatoid components. The primary end point was investigator-assessed DFS in the intention-to-treat population.^9,10

The median DFS was 57.2 months (95% CI, 44.6-NE) with atezolizumab compared with 49.5 months (95% CI, 47.4-NE) with placebo, but the difference was not considered statistically signifi cant (HR, 0.93; 95% CI, 0.75-1.15; P = .50). At 2 years, the DFS rates were 67% with atezolizumab and 65% with placebo.

Patients with higher PD-L1 expression (tumor-infiltrating immune cells 2/3) did demonstrate greater benefi t from adjuvant therapy with the median DFS with atezolizumab NE compared with 49.5 months with placebo (HR, 0.57; 95% CI, 0.29-1.15).

OS also showed no significant benefit for atezolizumab (HR, 0.97; 95% CI, 0.67-1.42).

Larkin pointed out in his presentation that atezolizumab does not have the same track record in metastatic RCC as the PD-1 inhibitors.

Putting Neoadjuvant Trials Into Context

“None of these 3 trials seemed to result in an efficacy benefit, so I guess the question is: What does that mean?” Larkin said. “The main point that I want to make is that [these] trials are not homogeneous.”

He suggested that a true understanding of the curative benefit of neoadjuvant and adjuvant therapy is difficult to answer and would require a nonfeasible clinical trial.

Comparatively, Larkin pointed to another phase 3 trial of adjuvant immunotherapy in RCC, which he called “solid.” The KEYNOTE-564 trial (NCT03142334) of adjuvant pembrolizumab (Keytruda), which was not presented at ESMO, did show a DFS benefit amounting to a 37% reduction in risk of disease progression over placebo. The median DFS was not reached in either treatment arm.¹¹

Evidence from this trial supported the November 2021 FDA approval of adjuvant pembrolizumab in patients with intermediate-/high-risk RCC following resection.¹²

Patients with M1 with no evidence of disease showed significant benefit in a subgroup analysis with an HR of 0.28 (95% CI, 0.12-0.66), although this was a small subset.¹¹ Larkin also noted that the population with M1 with no evidence of disease was not included in CheckMate 914.

Although OS data from KEYNOTE-564 are not completely mature, there was a signal of benefit with an HR of 0.52 (95% CI, 0.31-0.86).

When comparing KEYNOTE-564 and CheckMate 914 specifi cally, Larkin noted that both nivolumab and pembrolizumab have clear activity in advanced disease and are approved for use in these settings, “and I think it’s unlikely there’s any significant difference between these 2 drugs.”

He suggested that the high rate of toxicity in CheckMate 914 could have been driven by ipilimumab. “We can justify more toxicity in principle, but only if there is a clear upside. I think the bottom line here is that we need to be able to select patients better for treatment, so who really needs anti–CTLA-4 in addition to anti–PD-1, and unfortunately in kidney cancer today in 2022, we still do not have any clinically usable molecular markers for treatment selection,” Larkin concluded.

Non–Clear Cell RCC

Following the success of the combination of pembrolizumab and lenvatinib (Lenvima) in clear cell RCC, the combination was explored in the frontline setting in patients with locally advanced or metastatic non– clear cell RCC in the single-arm phase 2 KEYNOTE-B61 trial (NCT04704219).¹³

The ORR in the study was 47.6% (95% CI, 36.4%-58.9%), including CRs in 3.7% of patients. The DCR was 79.3% (95% CI, 68.9%-87.4%). The median DOR was not yet reached. PFS and OS rates at 6 months were 72.3% (95% CI, 60.7%-81.0%) and 87.8% (95% CI, 78.5%-93.2%), respectively

Patients with positive PD-L1 expression showed more of a benefi t than those with negative expression (ORR, 54.5% vs 27.3%, respectively), but responses were seen regardless of risk status (ORR, 56.3% with favorable risk vs 42% with intermediate/poor risk).

“Given the encouraging ORR and DCR, lenvatinib plus pembrolizumab may represent a potential frontline treatment option for nccRCC,” Albiges, the lead investigator, said during the presentation of the data.

_REFERENCES:

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_{2. Tannir N, Formiga MN, Agarwal N, et al. Bempegaldesleukin (BEMPEG) plus nivolumab (NIVO) compared to the investigator’s choice of sunitinib or cabozantinib in previously untreated advanced renal cell carcinoma (RCC): results from a phase III randomized study (PIVOT-09). Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{3. Albiges L. Invited discussant LBA68 and LBA73. Presented at: European Society for Medical Oncology Congress 2022; September 9-13, 2022; Paris, France.}

_{4. Tannir NM, Cho DC, Diab A, et al. Bempegaldesleukin plus nivolumab in first-line renal cell carcinoma: results from the PIVOT-02 study. J Immunother Cancer. 2022;10:e004419. doi:10.1136/jitc-2021-004419}

_{5. Choueiri TK, Bauer T, Merchan J, et al. Phase II study of belzutifan plus cabozantinib as fi rst-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}

_{6. McDermott DF, Choueiri TK, Tykodi SS, et al. Phase II study of belzutifan plus cabozantinib for previously treated advanced renal cell carcinoma (RCC): update from cohort 2 of LITESPARK-003. Ann Oncol. 2022;33(suppl 7):S660-S680. doi:10.1016/annonc/annonc1072}

_{7. Allaf M, Kim SE, Harshman LC, et al. Phase III randomized study comparing perioperative nivolumab (nivo) versus observation in patients (Pts) with renal cell carcinoma (RCC) undergoing nephrectomy (PROSPER, ECOG-ACRIN EA8143), a National Clinical Trials Network trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{8. Motzer RJ, Russo P, Gruenwald V, et al. Adjuvant nivolumab plus ipilimumab (NIVO+IPI) vs placebo (PBO) for localized renal cell carcinoma (RCC) at high risk of relapse after nephrectomy: results from the randomized, phase 3 CheckMate 914 trial. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{9. Bex A, Uzzo R, Karam JA, et al. IMmotion010: effi cacy and safety from the phase III study of atezolizumab (atezo) vs placebo (pbo) as adjuvant therapy in patients with renal cell carcinoma (RCC) at increased risk of recurrence after resection. Ann Oncol. 2022;33(suppl 7):S808-S869. doi:10.1016/annonc/annonc1089}

_{10. Pal SK, Uzzo R, Karam JA, et al. Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial. Lancet. 2022;400(10358):1103- 1116. doi:10.1016/S0140-6736(22)01658-0}

_{11. Choueiri TK, Tomczak P, Park SH, et al; KEYNOTE-564 Investigators. Adjuvant pembrolizumab after nephrectomy in renal-cell carcinoma. N Engl J Med. 2021;385(8):683-694. doi:10.1056/NEJMoa2106391}

_{12. FDA approves pembrolizumab for adjuvant treatment of renal cell carcinoma. FDA. November 17, 2021. Accessed October 6, 2022. https://bit.ly/3rxoVyh 13. Albiges L, Gurney HP, Atduev V, et al. Phase II KEYNOTE-B61 study of pembrolizumab (Pembro) + lenvatinib (Lenva) as first-line treatment for non-clear cell renal cell carcinoma (nccRCC). Ann Oncol. 2022;33(suppl_7):S660-S680. doi:10.1016/annonc/annonc1072}