Pal Provides Perspective on Pivotal Trials in RCC and Prostate Cancer

Insights generated from several trials presented during the 2021 ASCO Annual Meeting in renal cell carcinoma illustrate the importance of evaluating checkpoint inhibitors in earlier stages of disease, quality of life, and long-term outcomes, and other data that point to 2 potential new standards of care in prostate cancer.

Sumanta K. Pal, MD

Sumanta K. Pal, MD

Insights generated from several trials presented during the 2021 ASCO Annual Meeting in renal cell carcinoma (RCC) illustrate the importance of evaluating checkpoint inhibitors in earlier stages of disease, quality of life, and long-term outcomes, and other data that point to 2 potential new standards of care in prostate cancer, explained Sumanta K. Pal, MD.

Pivotal Trials Demonstrate Mixed Findings in RCC

The first trial Pal highlighted was the phase 3 KEYNOTE-564 trial (NCT03142334), which evaluated pembrolizumab (Keytruda) vs placebo as adjuvant therapy in patients with high-risk localized or metastatic RCC. Eligible patients included those who had disease that had been resected within 12 weeks of randomization, an ECOG performance status of 0 to 1, and tissue sample for PD-L1 assessment.1

“If you had a patient who, for instance, had an isolated lung metastasis resected, that patient would be eligible provided they were within a year of surgery,” said Pal, a clinical professor in the Department of Medical Oncology and Therapeutics Research, co-director of the Kidney Cancer Program, and a medical oncologist at City of Hope, in a virtual presentation during the 2021 ASCO Direct HighlightsTM webcast in San Diego, a program developed by Physicians’ Education Resource® (PER®), LLC.

Patients were randomized to 200 mg of pembrolizumab every 3 weeks for 1 year or placebo in the same schedule for the same duration.

In the localized setting, high risk was defined as T4 disease with node positivity, T3N0 disease irrespective of grade, and T2 disease with a grade 4 tumor.

“It really is those individuals that have high risk [who were eligible for this trial],” said Pal. “You don’t want to be giving adjuvant therapy to patients who might have a very limited chance of recurrence from the get-go and might actually derive harm from the treatment.”

Baseline characteristics reflected a typical RCC trial population, said Pal. The majority of patients were male, a median age of 60 years, and had an ECOG performance status of 0.

Of note, only 5.8% of patients in each arm had M1 disease, 75.2% of patients in each arm were PD-L1 positive, and 11.1% of patients in each arm had sarcomatoid features.

Disease-free survival (DFS), which was the primary end point of the study, was significantly prolonged in the pembrolizumab arm vs the placebo arm. At a median follow-up of 24.1 months, the median DFS was not reached in either arm (HR, 0.68; 95% CI, 0.53-0.87; P = .0010). The 12-month DFS rate was 85.7% in the pembrolizumab arm vs 76.2% in the placebo arm. The 24-month DFS rates were 77.3% vs 68.1%, respectively.

“[We saw] an impressive benefit in DFS at this early juncture. The curves separate early, so it looks like we’re preventing a lot of those early recurrences. There is some merging of the curves towards the end, so it’s going to be interesting to see what happens as these data mature,” said Pal.

All patient subgroups derived benefit from pembrolizumab, particularly patients with M1 disease (HR, 0.29; 95% CI, 0.12-0.69) and those treated in the European Union (HR, 0.49; 95% CI, 0.32-0.74), added Pal.

The interim overall survival (OS), driven by approximately 5% of events in each arm, was not reached in either arm (HR, 0.54; 95% CI, 0.30-0.96; P = .0164). The 12-month OS rate was 98.6% in the pembrolizumab arm vs 98.0% in the placebo arm. The 24-month OS rates were 96.6% vs 93.5%, respectively.

Regarding safety, there was a modest rate of all-cause grade 3 to 5 adverse effects (AEs), at 32.4% in the pembrolizumab arm vs 17.7% in the placebo arm. All-cause AEs leading to treatment discontinuation occurred in 20.7% vs 2.0% of patients, respectively, which is “a bit higher than what you would expect in the context of metastatic disease,” said Pal.

Additionally, all-cause AEs led to 2 deaths in the pembrolizumab arm vs 1 death in the placebo arm.

The most common treatment-related AEs in the pembrolizumab arm included fatigue, pruritus, hypothyroidism, diarrhea, and rash vs fatigue, pruritus, diarrhea, arthralgia, and rash in the placebo arm.

“Grade 3 diarrhea and rash are issues we need to factor into the equation [as are] hypothyroidism and hyperthyroidism as [we’re] treating patients with [pembrolizumab],” said Pal.

Other immune-mediated AEs in the pembrolizumab arm included pneumonitis, adrenal insufficiency, and type 1 diabetes mellitus.

Stopping short of giving a definitive answer as to whether adjuvant pembrolizumab will become a standard of care in this setting if approved, Pal said, “I’m encouraged by what I see. The DFS end point was met, and the OS data are trending in the right direction. However, few OS events have occurred thus far, and we’re awaiting results from multiple other trials, such as IMmotion010 [NCT03024996] with adjuvant atezolizumab [Tecentriq].”

Shifting to the advanced setting, Pal highlighted the health-related quality of life (HRQOL) data from the phase 3 CLEAR trial (NCT02811861), which evaluated lenvatinib (Lenvima) plus pembrolizumab or everolimus (Afinitor) vs sunitinib (Sutent) in patients with treatment-naïve advanced RCC.2

Notably, in the lenvatinib/pembrolizumab arm, lenvatinib was given at a dose of 20 mg, which exceeds an already difficult-to-tolerate approved dose of 18 mg in the second-line setting, said Pal.

“This [study] has drawn a lot of attention because of some of the data that we have seen early on,” said Pal.

Primary results demonstrated an objective response rate (ORR) of 71.0% in the lenvatinib/pembrolizumab arm and a complete response rate of 16.1%, 53.5% in the lenvatinib/everolimus arm, and 36.1% in the sunitinib arm. The median progression-free survival (PFS) was 23.9 months, 14.7 months, and 9.2 months, respectively. The median OS was not reached in all 3 arms but favored the lenvatinib/pembrolizumab arm (HR, 0.66).

“As far as response rates go, there are a lot of ‘oohs and aahs’ around the 70% response rate and 16% complete response rate, but keep in mind this study had the highest preponderance of patients with favorable-risk disease [and] fewer patients with de novo metastatic disease, which may have influenced outcomes,” said Pal.

Moreover, the HRQOL data did not indicate that lenvatinib/pembrolizumab performed significantly better than sunitinib unlike the combination of nivolumab (Opdivo) and ipilimumab (Yervoy) as well as cabozantinib (Cabometyx) and nivolumab, which have shown progressive improvements in QOL compared with sunitinib, said Pal.

“I would probably balk at using this regimen in the frontline setting for most patients,” said Pal.

Also presented at the meeting were updated results of the phase 3 KEYNOTE-426 trial (NCT02853331), which evaluated the combination of axitinib (Inlyta) and pembrolizumab in patients with newly diagnosed advanced RCC.3

Primary OS results for the combination had shown a hazard ratio of 0.53, leading people to believe that pembrolizumab plus axitinib should become the standard frontline treatment for patients with advanced RCC, explained Pal.

However, additional follow-up showed reduced OS benefit with the combination (HR, 0.73; 95% CI, 0.60-0.88; P < .001), now “perhaps looking the least attractive among the various combination regimens that we have in the frontline setting now,” said Pal.

Another combination, cabozantinib plus nivolumab, which has become a preferred frontline regimen for patients with advanced clear cell RCC is also under study in a phase 2 trial (NCT03635892) for patients with non–clear cell RCC.4

In the study, patients with advanced or metastatic non–clear cell RCC who had received up to 1 prior line of therapy received 40 mg of oral cabozantinib daily plus 240 mg of intravenous nivolumab every 2 weeks or 480 mg every 4 weeks.

Across patients with papillary RCC, unclassified RCC, and translocation-associated RCC, the ORR was 47.5% (95% CI, 31.5%-63.9%), the median PFS was 12.5 months (95% CI, 6.3-15.9), and the median OS was 28.0 months (95% CI, 16.3-not evaluable).

“I was quite impressed by these data. Right now, I would suggest that the standard of care [in papillary RCC] is still cabozantinib, but I think we’re going to be looking long and hard at building on this data set [with trials such as PAPMET2 (NCT02761057)],” said Pal.

Newfound Standards in Metastatic Prostate Cancer

Turning to prostate cancer, Pal first provided insight into the phase 3 PEACE-1 trial (NCT01957436), which randomized patients to 1 of 4 arms: standard of care (SOC), SOC plus abiraterone acetate (Zytiga), SOC plus radiotherapy, or SOC plus abiraterone and radiotherapy. SOC consisted of androgen deprivation therapy and docetaxel.5

Eligible patients included those with de novo metastatic castration-sensitive prostate cancer. Patients had to have at least 1 metastatic lesion on bone scan and/or CT scan.

Regarding baseline characteristics, the median time from diagnosis to treatment was about 2 months, the median prostate-specific antigen level was about 12 ng/mL, and approximately 60% of patients received docetaxel following a protocol amendment.

The median radiographic PFS (rPFS) was 4.5 months (95% CI, 3.5–not evaluable [NE]) in the SOC plus abiraterone arm (n = 583) vs 2.2 months (95% CI, 2.0-2.6) in the SOC arm (n = 589), translating to a 46% reduction in the risk of progression or death (HR, 0.54; 95% CI, 0.46-0.64; P < .0001).

In solely looking at patients who had received docetaxel, an even more marked difference in rPFS was reported, at 4.5 months (95% CI, 3.1-NE) vs 2.0 months (95% CI, 1.8-2.3), respectively (HR, 0.50; 95% CI, 0.40-0.62; P < .0001).

“On the basis of this rPFS benefit, should I potentially be offering my patients in clinical practice docetaxel plus abiraterone? I don’t think it’s unheard of to do that,” said Pal.

Moreover, the addition of abiraterone to SOC prolonged the time to castration resistance by at least 1.5 years in both populations.

The final study Pal discussed, the phase 3 VISION trial (NCT03511664) evaluated 177Lu-PSMA-617 (LuPSMA), a targeted radioligand therapy, plus standard of care vs SOC alone in patients with progressive PSMA-positive metastatic castration-resistant prostate cancer (mCRPC).6

Eligible patients had received at least 1 androgen receptor inhibitors and 1 or 2 taxane regimens.

The findings showed that at a median follow-up of 20.9 months, the median OS was 15.3 months in the LuPSMA arm vs 11.3 months in the SOC alone arm, translating to a 38% reduction in the risk of death (HR, 0.62; 95% CI, 0.52-0.74; P < .001).

Adding the targeted radioligand therapy also led to a median rPFS of 8.7 vs 3.4 months, respectively (HR, 0.40; 99.2% CI, 0.29-0.57; one-sided P < .001).

There was also a statistically significant benefit favoring the LuPSMA arm for the key secondary endpoints of ORR, disease control rate, and time to first symptomatic skeletal event.

In terms of safety, no unexpected or concerning safety signals were reported with LuPSMA, although Pal advised careful monitoring of patient’s blood counts given the high rate of grade 3 to 5 anemia in the trial.

On June 17, 2021, the FDA granted a breakthrough therapy designation to LuPSMA for the treatment of patients with mCRPC based on findings from the VISION trial.7 If approved, LuPSMA would become the first PSMA theranostic approved in prostate cancer.

“Lutetium really has raised the bar and probably represents the new standard in this setting,” concluded Pal.


  1. Choueiri TK, Tomczak P, Park SH, et al. Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. J Clin Oncol. 2021;39(suppl 15):LBA5. doi:10.1200/JCO.2021.39.15_suppl.LBA5
  2. Motzer RJ, Porta C, Alekseev B, et al. Health-related quality-of-life (HRQoL) analysis from the phase 3 CLEAR trial of lenvatinib (LEN) plus pembrolizumab (PEMBRO) or everolimus (EVE) versus sunitinib (SUN) for patients (pts) with advanced renal cell carcinoma (aRCC). J Clin Oncol. 2021;39(suppl 15):4502. doi:10.1200/JCO.2021.39.15_suppl.4502
  3. Plimack ER, Powles T, Bedke J, et al. Outcomes for patients in the pembrolizumab+axitinib arm with advanced renal cell carcinoma (RCC) who completed two years of treatment in the phase III KEYNOTE-426 study. J Clin Oncol. 2021;39(suppl 15):327. doi:10.1200/JCO.2021.39.15_suppl.327
  4. Lee CH, Voss MH, Carlo MI, et al. Nivolumab plus cabozantinib in patients with non-clear cell renal cell carcinoma: Results of a phase 2 trial. J Clin Oncol. 2021;39(suppl 15):4509. doi:10.1200/JCO.2021.39.15_suppl.4509
  5. Fizazi K, Maldonado X, Foulon S, et al. A phase 3 trial with a 2x2 factorial design of abiraterone acetate plus prednisone and/or local radiotherapy in men with de novo metastatic castration-sensitive prostate cancer (mCSPC): First results of PEACE-1. J Clin Oncol. 2021;39(suppl 15):5000. doi:10.1200/JCO.2021.39.15_suppl.5000
  6. Morris MJ, De Bono JS, Chi KM, et al. Phase III study of lutetium-177-PSMA-617 in patients with metastatic castration-resistant prostate cancer (VISION). J Clin Oncol. 2021;39(suppl 15):LBA4. doi:10.1200/JCO.2021.39.15_suppl.LBA4
  7. Novartis receives FDA breakthrough designation for investigational 177Lu-PSMA-617 in patients with metastatic castration-resistant prostate cancer (mCRPC). News release. Novartis. June 16, 2021. Accessed July 26, 2021.
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