Kristi Rosa

While there are multiple frontline options in renal cell carcinoma (RCC), new data suggest that for patients with the rare non–clear cell histology, upfront immune checkpoint inhibitor therapy could improve overall survival (OS).

Findings shared during the 2021 Genitourinary Cancers Symposium showed that in a population of 1181 patients with non–clear cell metastatic RCC, the median OS was 28.6 months in patients receiving an immune checkpoint inhibitor–based regimen compared with 19.2 months and 12.6 month, respectively, in patients being treated with a VEGF inhibitor and an mTOR inhibitor.

The median time-to-treatment failure (TTF) in those who received an immunotherapy-based regimen was also longer at 6.9 months (95% CI, 2.8-14.0) versus 5.1 months with a VEGF inhibitor (95% CI, 4.6-5.7) and 3.9 months (95% CI, 3.0-5.1) with an mTOR inhibitor.

In the entire population of patients included in the analysis, the objective response rate (ORR) achieved in those who received an immunotherapy-based regimen was 25%; it was 17.8% in those who received VEGF targeted therapy and 5.8% in those who received mTOR-targeted treatment (

“Immune checkpoint inhibitor–based frontline therapy appears to be associated with improved OS compared to VEGF and mTOR targeted therapy in treatment-naïve metastatic non–clear cell RCC, even after adjustment for International Metastatic RCC Database Consortium [IMDC] risk, histology, and age,” lead study author Jeffrey Graham, MD, of the University of Manitoba, and colleagues, wrote in a poster on the data.

Immunotherapy options have induced impressive activity in patients with metastatic clear-cell RCC; as such, these options have become part of standard frontline treatment. Although non–clear cell RCC represents about 15% of all kidney cancers, findings supporting the efficacy of immune checkpoint inhibitors up front has remained largely limited.

To address this need, investigators launched a study to detail the real-world effectiveness of frontline approaches containing immune checkpoint inhibitors in patients with metastatic non–clear cell RCC.

To perform a retrospective analysis of the IMDC, investigators included all patients who had non–clear cell histology. Patients were categorized into 3 groups based on first-line treatment: single-agent VEGF therapy, single-agent or combination immunotherapy, and single-agent mTOR therapy. For the analysis, investigators looked at outcomes, such as ORR, TTF, and OS.

The median age of the entire patient population was 60.6 years, 65.4% were male, 76.4% had undergone nephrectomy, and 16.6% had sarcomatoid features. The most common histologic subtype across the groups was papillary disease (54.2%), and most patients fell into the intermediate IMDC risk group (55.1%). Across the groups, 25.1% of patients had liver metastases, 34.2% had bone metastases, and 3.6% had brain metastases.

Of the 1181 patients included in the analysis, 78.2% had received VEGF treatment (n = 924), which included sunitinib (Sutent; n = 632; 68.4%), pazopanib (Votrient; n = 171; 18.5%), sorafenib (Nexavar; n = 72; 7.8%), cabozantinib (Cabometyx; n = 12; 1.3%), or other (n = 37; 4%). Moreover, 15.8% had received mTOR inhibitors (n = 186) in the frontline setting, such as temsirolimus (Torisel; n = 141; 75.8%) or everolimus (Afinitor; n = 45; 24.2%).

The remaining 5.5% had received immune checkpoint inhibitor–based therapy (n = 65), which could include nivolumab (Opdivo) and ipilimumab (Yervoy; n = 20; 30.8%), atezolizumab (Tecentriq) plus bevacizumab (Avastin; n = 14; 21.5%), nivolumab (n = 13; 20.0%), pembrolizumab (Keytruda; n = 13; 20.0%), or other (n = 5; 7.7%).

Investigators performed a multivariable Cox regression analysis to adjust for imbalances in prespecified prognostic covariates, such as IMDC risk, histologic subtype, and age. Results revealed that the hazard ratio (HR) for OS between immune checkpoint inhibitor–based therapy and VEGF treatment was 0.58 (95% CI, 0.35-0.94; 

= .03), while it was 0.48 (95% CI, 0.29-0.80; 

= .005) for immunotherapy-based treatment versus mTOR therapy.

Additionally, the HR for TTF with immunotherapy-based treatment versus VEGF therapy was 0.72 (95% CI, 0.72; 95% CI, 0.51-1.0; 

= .06) and it was 0.54 (95% CI, 0.37-0.78; 

= .001) for immunotherapy-based treatment versus mTOR treatment.

When looking at ORR per histologic subgroup, those with papillary disease who received VEGF treatment experienced an ORR of 13.0% versus 3.7% with mTOR therapy and 31.6% with immunotherapy-based treatment (

= .002). In patients with the chromophobe subtype, the ORRs were 20.6% versus 13.6% versus 9.1% in those who received VEGF therapy, mTOR therapy, and an immunotherapy-based regimen, respectively (

= .527). Those with an unclassified disease subtype experienced ORRs of 15.2%, 0%, and 33.3%, respectively (

“The ORR of 25% in the entire population is consistent with the existing literature of immune checkpoint inhibitor therapy in non–clear cell RCC, with lower responses seen in the chromophobe subgroup and higher responses seen in the papillary subgroup,” the authors of the poster wrote. “The study population was predominantly papillary RCC, and the effectiveness of immune checkpoint inhibitor–based therapy in other less common histologic subtypes remains inconclusive.”

The results yielded from the analysis must be confirmed in prospective, randomized clinical trials, the authors concluded.

1. Graham J, Wells C, Dudani S, et al. Effectiveness of first-line immune checkpoint inhibitors (ICI) in advanced non-clear cell renal cell carcinoma. 

. 2021;39(suppl 6):316. doi:10.1200/JCO.2021.39.6_suppl.316

Articles

Determining the optimal treatment approach for patients with non–clear cell renal cell carcinoma has long been an unmet medical need in the field. 

Study suggests immunotherapy may be optimal frontline choice in non–clear cell RCC

The antibody-drug conjugate (ADC) sacituzumab govitecan-hziy (Trodelvy) induced an overall response rate (ORR) of 27% in heavily pretreated patients with metastatic urothelial carcinoma following the failure of both platinum-based chemotherapy and checkpoint inhibition, according to the final data from cohort 1 of the phase 2 TROPHY-U-01 trial presented during the 2020 ESMO Congress.

There were 31 responders, including 6 (5%) complete responses (CRs) and 25 (22%) partial responses (PRs). The median response duration with the ADC was 5.9 months. 

"The final results from TROPHY-U-01 cohort 1 confirmed the interim findings and the results from the prior phase 1 study, and showed that sacituzumab govitecan is generally well tolerated and has significant anticancer activity in heavily pretreated [patients with] metastatic urothelial cancer who have progressed on both platinum-based chemotherapy and checkpoint inhibitors,” Yohann Loriot, MD, PhD, lead author of the study and a medical oncologist at the Institut de Cancèrologie Gustave Roussy, in Villejuif, France, said in a presentation during the congress.

The open-label, global phase 2 TROPHY-U-01 trial evaluated sacituzumab govitecan in 3 cohorts: patients with metastatic urothelial carcinoma who progressed on platinum-based chemotherapy and checkpoint inhibition (cohort 1); those who were ineligible for platinum-based chemotherapy and progressed following checkpoint inhibition (cohort 2); and those who never received checkpoint inhibitors but had progressed on platinum-based therapy (cohort 3).

The findings shared at ESMO were from cohort 1, which patients received 10 mg/kg of the ADC on days 1 and 8, every 21 days and continued treatment until loss of clinical benefit or intolerable toxicity. The primary end point of this analysis was ORR per central review.

Among the evaluated patients, the median age was 66 years, with 23% of patients 75 years of age or older and 78% male. Moreover, the majority of patients were white, at 74%. Twenty-eight percent of patients had an ECOG performance status of 0, while 72% had a status of 1. Overall, 62% of patients had visceral metastases; 40% had lung metastases, 28% had liver metastases, and 12% had other.

The median number of prior anticancer regimens received was 3. “Therefore, this is a heavily pretreated patient population, and sacituzumab govitecan was the fourth line of therapy,” noted Loriot.

Sixteen (14%) of 113 evaluable patients continued to receive treatment with sacituzumab govitecan at the time of the analysis. The majority of patients who discontinued treatment did so because of disease progression (66%; n = 75). Only 7% (n = 8) of patients discontinued the ADC because of toxicity. Three percent of patients (n = 3) discontinued because of withdrawn consent and 3% (n = 3) died. The median time on treatment was 3.7 months, according to Loriot, and the maximum time on treatment is 16 months thus far. Fifty-percent of patients (n = 56) are in follow-up for survival.

The median time to onset of response was 1.6 months. The ORR, median DOR, and median time to response reported were consistent with investigator assessments.

“There was a reduction in target lesion size in three-quarters of patients,” noted Loriot. Moreover, 27 of 31 responders were alive with 8 of these patients still experiencing a response and receiving the treatment at the time of the data cutoff.

Regarding safety, diarrhea was the most commonly experienced treatment-related adverse effect, occurring in two-thirds of patients (all grade, 65%); this is consistent with what has been reported in prior studies with the ADC. However, most of these effects were grade 1/2, noted Loriot.

Grade 3 diarrhea occurred in 9% of patients, with only 1% experiencing grade 4. Forty-six percent of patients experienced neutropenia, with 22% having a grade 3 effect and 12% reporting a grade 4 effect. “However, neutropenia was manageable with dose reductions and granulocyte colony-stimulating factor; it was reversible,” said Loriot. “Thirty-percent of patients received GCSF either as primary prophylaxis or in response to neutropenia.”

Moreover, 1 treatment-related death was reported, with a patient presenting with sepsis due to febrile neutropenia.

The phase 3 TROPiCs-04 trial (NCT04527991) is being launched to confirm these promising phase 2 results.

“Sacituzumab govitecan received fast track designation [from the FDA] for this indication and may have the potential to change practice in this setting,” Loriot concluded.

1. Loriot Y, Balar AV, Petrylak DP, et al. Final results from TROPHY-U-01 cohort 1: a phase 2 open-label study of sacituzumab govitecan (SG) in patients with metastatic urothelial cancer (mUC) and disease progression after platinum (PLT)-based regimens and checkpoint inhibitors. Presented at: 2020 ESMO Virtual Congress; September 19-21, 2020; Virtual. Abstract LBA24.

Pivotal phase 3 trial launched to confirm promising results in metastatic urothelial carcinoma.

Kristi Rosa

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Study suggests immunotherapy may be optimal frontline choice in non–clear cell RCC

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