Meeting NewsPerspective

Nivolumab plus ipilimumab outperforms sunitinib in certain kidney cancers

Bernard Escudier

MADRID — The immunotherapy combination of nivolumab plus ipilimumab improved objective response rate and prolonged PFS compared with sunitinib in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma, according to a phase 3 study presented at the European Society for Medical Oncology Congress.

“There is an unmet need for additional treatment options in the first-line setting that may provide a meaningful survival benefit including more durable, complete responses for patients with advanced renal cell carcinoma,” Bernard Escudier, MD, former chair of the genitourinary group of the Institut Gustave Roussy in Villejuif, France, said during his presentation. “These results for the combination of nivolumab [Opdivo, Bristol-Myers Squibb] and ipilimumab [Yervoy, Bristol-Myers Squibb] are very encouraging in patients with first-line metastatic renal cell carcinoma who have a very poor prognosis.”

The randomized, open-label CheckMate-214 study compared nivolumab and ipilimumab with sunitinib (Sutent, Pfizer) for the first-line treatment of 1,096 adults with measurable clear-cell metastatic renal cell carcinoma and a Karnofsky performance score of 70 or greater.

Patients in the combination arm (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four doses, followed by 3 mg/kg nivolumab every 2 weeks.

The 546 patients assigned sunitinib received 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.

ORR, PFS and OS served as co-primary endpoints. Researchers also evaluated efficacy according to baseline tumor PD-L1 expression.

Minimum follow-up was 17.5 months.

Among intermediate- and poor-risk patients — who comprised 425 patients assigned the combination and 422 assigned sunitinib — ORR was 41.6% for the nivolumab-ipilimumab combination compared with 26.5% for sunitinib (P < .0001). Additionally, 9.4% of patients assigned the combination achieved complete response compared with 1.2% of patients assigned sunitinib.

The median duration of response was not reached (95% CI, 21.82 to not reached) in the combination arm vs. 18.2 months (95% CI, 14.82 to not reached) with sunitinib.

Patients assigned the combination also demonstrated significantly longer median PFS (11.6 months vs. 8.4 months; HR = 0.82; P = .0331).

Notably, greater benefit occurred among intermediate- and poor-risk patients with PD-L1 levels of at least 1% at baseline in terms of ORR (58% vs. 22%) and median PFS (22.8 months vs. 5.9 months; HR = 0.48; 95% CI, 0.28-0.82).

In patients with favorable-risk disease, the combination did not improve ORR (29% vs. 52%; P = .0002) or PFS (15.3 months vs. 25.1 months; HR = 2.17; 95% CI, 1.46-3.22).

No significant difference occurred between arms for ORR or PFS in the overall composite of patients at any risk.

Researchers noted that PD-L1 expression of at least 1% at baseline was more common in intermediate- and poor-risk patients (combination, 26%; sunitinib, 29%) than among favorable-risk patients (combination, 11%; sunitinib, 12%).

Drug-related adverse events occurred in 93% of patients in the nivolumab-ipilimumab cohort and 97% of patients assigned sunitinib. Fifty-four percent of patients assigned the combination experienced a grade 3 to grade 4 adverse event, and 63% of the sunitinib arm experienced a grade 3 to grade 5 event.

Discontinuation due to toxicity occurred in 22% of patients assigned the combination and 12% assigned sunitinib.

Seven of 159 deaths (1%) in the combination arm were considered drug related, and four of 202 (1%) in the sunitinib arm were considered drug related.

“Patients reported better symptom control with nivolumab and ipilimumab compared with sunitinib,” Escudier said. “These results support the use of nivolumab and ipilimumab as a new first-line standard of care option for intermediate- and poor-risk patients with metastatic renal cell carcinoma.”– by Chuck Gormley

 

Reference:

Escudier B, et al. Abstract LBA5. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

 

Disclosures: Bristol-Myers Squibb and Ono Pharmaceutical Co. Ltd. funded this study. Escudier reports honoraria from Bristol-Myers Squibb, Bayer, Novartis, Pfizer, Exelixis and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

Bernard Escudier

MADRID — The immunotherapy combination of nivolumab plus ipilimumab improved objective response rate and prolonged PFS compared with sunitinib in intermediate- and poor-risk patients with previously untreated advanced or metastatic renal cell carcinoma, according to a phase 3 study presented at the European Society for Medical Oncology Congress.

“There is an unmet need for additional treatment options in the first-line setting that may provide a meaningful survival benefit including more durable, complete responses for patients with advanced renal cell carcinoma,” Bernard Escudier, MD, former chair of the genitourinary group of the Institut Gustave Roussy in Villejuif, France, said during his presentation. “These results for the combination of nivolumab [Opdivo, Bristol-Myers Squibb] and ipilimumab [Yervoy, Bristol-Myers Squibb] are very encouraging in patients with first-line metastatic renal cell carcinoma who have a very poor prognosis.”

The randomized, open-label CheckMate-214 study compared nivolumab and ipilimumab with sunitinib (Sutent, Pfizer) for the first-line treatment of 1,096 adults with measurable clear-cell metastatic renal cell carcinoma and a Karnofsky performance score of 70 or greater.

Patients in the combination arm (n = 550) received 3 mg/kg nivolumab plus 1 mg/kg ipilimumab every 3 weeks for four doses, followed by 3 mg/kg nivolumab every 2 weeks.

The 546 patients assigned sunitinib received 50 mg once daily for 4 weeks and 2 weeks off in 6-week cycles.

ORR, PFS and OS served as co-primary endpoints. Researchers also evaluated efficacy according to baseline tumor PD-L1 expression.

Minimum follow-up was 17.5 months.

Among intermediate- and poor-risk patients — who comprised 425 patients assigned the combination and 422 assigned sunitinib — ORR was 41.6% for the nivolumab-ipilimumab combination compared with 26.5% for sunitinib (P < .0001). Additionally, 9.4% of patients assigned the combination achieved complete response compared with 1.2% of patients assigned sunitinib.

The median duration of response was not reached (95% CI, 21.82 to not reached) in the combination arm vs. 18.2 months (95% CI, 14.82 to not reached) with sunitinib.

Patients assigned the combination also demonstrated significantly longer median PFS (11.6 months vs. 8.4 months; HR = 0.82; P = .0331).

Notably, greater benefit occurred among intermediate- and poor-risk patients with PD-L1 levels of at least 1% at baseline in terms of ORR (58% vs. 22%) and median PFS (22.8 months vs. 5.9 months; HR = 0.48; 95% CI, 0.28-0.82).

In patients with favorable-risk disease, the combination did not improve ORR (29% vs. 52%; P = .0002) or PFS (15.3 months vs. 25.1 months; HR = 2.17; 95% CI, 1.46-3.22).

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No significant difference occurred between arms for ORR or PFS in the overall composite of patients at any risk.

Researchers noted that PD-L1 expression of at least 1% at baseline was more common in intermediate- and poor-risk patients (combination, 26%; sunitinib, 29%) than among favorable-risk patients (combination, 11%; sunitinib, 12%).

Drug-related adverse events occurred in 93% of patients in the nivolumab-ipilimumab cohort and 97% of patients assigned sunitinib. Fifty-four percent of patients assigned the combination experienced a grade 3 to grade 4 adverse event, and 63% of the sunitinib arm experienced a grade 3 to grade 5 event.

Discontinuation due to toxicity occurred in 22% of patients assigned the combination and 12% assigned sunitinib.

Seven of 159 deaths (1%) in the combination arm were considered drug related, and four of 202 (1%) in the sunitinib arm were considered drug related.

“Patients reported better symptom control with nivolumab and ipilimumab compared with sunitinib,” Escudier said. “These results support the use of nivolumab and ipilimumab as a new first-line standard of care option for intermediate- and poor-risk patients with metastatic renal cell carcinoma.”– by Chuck Gormley

 

Reference:

Escudier B, et al. Abstract LBA5. Presented at: European Society for Medical Oncology Congress; Sept. 8-12, 2017; Madrid.

 

Disclosures: Bristol-Myers Squibb and Ono Pharmaceutical Co. Ltd. funded this study. Escudier reports honoraria from Bristol-Myers Squibb, Bayer, Novartis, Pfizer, Exelixis and Roche. Please see the abstract for a list of all other researchers’ relevant financial disclosures.

    Perspective

    Are we seeing a great change in paradigm in the first-line treatment of metastatic renal cell carcinoma? Vascular endothelial growth factor (VEGF) has been recognized as one of the major drivers of clear-cell metastatic renal cell carcinoma and, more than a decade ago, VEGF inhibitors were established as the new standard of care in metastatic renal cell carcinoma. European Society for Medical Oncology treatment guidelines recommend VEGF inhibitors in first-line treatment for patients with favorable or intermediate risk. These agents received approval based on PFS and ORR, and not on OS. OS would have confounded data — for instance, see the final OS analysis of sunitinib vs. interferon alpha by Motzer and colleagues; the CALGB 90206  trial on bevacizumab (Avastin, Genentech) plus interferon vs. interferon monotherapy by Rini and colleagues; bevacizumab with interferon alpha-2a vs. placebo and interferon alpha-2a in the AVOREN trial; and pazopanib (Votrient, Novartis) vs. placebo phase 3 data from Sternberg and colleagues — because patients could either cross over or have access to a VEGF inhibitor after treatment failure.  

    Comparative phase 2 or phase 3 trials between established agents, such as sunitinib or pazopanib, had primary endpoints of noninferiority PFS or patient’s preference, but not superiority in terms of PFS or OS. So far, sunitinib has never been defeated by any other agent in a randomized phase 3 superiority trial. This suggests sunitinib is ideal and, I must say, CheckMate-214 was a very brave comparative trial. This study showed a statistically significant and clear benefit in response rates and OS with nivolumab and ipilimumab; although PFS was not statistically significant, the PFS improvement with ipilimumab and nivolumab vs. sunitinib can be regarded as clinically meaningful. Therefore, this combination indeed can be considered a new standard of care in this patient population. In addition, there were some quite remarkable aspects of this study. The response rates were among the highest ever reported in this patient population, and the complete response rate (9% vs. 1%) was the highest I’ve ever seen.

    Does this imply that VEGF inhibitors are no longer the primary choice in the first-line treatment of metastatic renal cell carcinoma? What could prompt us to perceive nivolumab and ipilimumab as a new standard of care rather than the standard of care? When seeing these results, I ask myself if it is about the timing of first-line nivolumab and ipilimumab, or about nivolumab plus ipilimumab in general. Is the population addressed for the primary endpoints a clear-cut population? Are there other strategies for intermediate- and poor-risk patients that we may be tempted to use instead of nivolumab and ipilimumab? Should we always consider a VEGF receptor tyrosine kinase inhibitor in favorable-risk patients, or is nivolumab-ipilimumab an option? How relevant are the results showing the association of PD-L1 expression and outcome?

    Firstly, without any doubt, the combination of nivolumab and ipilimumab is highly efficacious. In the CheckMate-214 study, patients had access to this highly efficacious combination only if assigned to it. Patients in the sunitinib arm never had access to nivolumab and ipilimumab throughout their entire course of disease. How would they have performed if they would have been given the chance to cross over after sunitinib failure? Crossover is a well-known confounder of OS, but so could be the lack of crossover. Can the OS be confounded in this trial because sunitinib patients never had access to nivolumab and ipilimumab?

    There also is rationale for both prior and deferred TKI treatment. The benefits of receiving a TKI first is that several treatments, including sunitinib, modulate the tumor microenvironment by reducing regulatory T cells, improving tumor-infiltrating lymphocyte expansion and reducing the intratumoral content of myeloid-derived suppressor cells. A TKI first may also optimize outcome from immuno-oncology treatment, and this is enough to rationalize trials combining immuno-oncology and TKIs. Conversely, starting a TKI first could induce a hypoxic microenvironment with the occurrence of resistance and epithelial-to-mesenchymal transition. Antiangiogenic therapy also elicits increased local invasion and distant metastases.

    Secondly, is a clear-cut population addressed for the primary endpoints? Current guidelines recommend treatment based on different populations, and this would mean favorable or intermediate vs. poor risk. The CheckMate-214 trial combined intermediate- and poor-risk patients and evaluated favorable-risk patients separately. The favorable-risk patients did better on sunitinib, whereas the intermediate-risk patients did better on nivolumab and ipilimumab. In the patients with synchronously diagnosed primary tumor and metastasis, the primary tumor may have been there undetected for years; in such a case, the disease biology could be closer to favorable than intermediate.         

    Third, are there strategies for intermediate- to poor-risk patients other than nivolumab-ipilimumab? CABOSUN, a randomized phase 2 trial in intermediate- and poor-risk patients, demonstrated a PFS and ORR benefit from cabozantinib (Cometriq/Cabometyx, Exelixis) vs. sunitinib, but the trial was not designed to test for differences in OS. However, more patients had bone metastases in that trial (cabozantinib, 37%; sunitinib, 36%) than patients in this trial assigned nivolumab and ipilimumab (21%). Also, the patient population had mostly poor ECOG scores.

    Fourth, should we always consider VEGF receptor TKI in favorable-risk populations? Favorable-risk patients did much better on sunitinib than nivolumab and ipilimumab. It could be a matter of PD-L1 expression — in the favorable group, only 11% had PD-L1 greater than 1%, whereas more than twice as many expressed PD-L1 in the intermediate to poor population. In an analysis by Choueiri and colleagues, PD-L1 expression was shown to be associated with shorter OS in patients undergoing TKI therapy.

    That leads to our final and fifth question: Should we choose nivolumab-ipilimumab rather than sunitinib based on PD-L1 status? An exploratory endpoint of the study revealed that PD-L1-positive patients derived particular benefits from nivolumab-ipilimumab. But, considering the majority of the study patients were PD-L1-negative, should this be perceived as hypothesis generating, as the role of PD-L1 as a predictive marker remains unclear? Individual immune phenotype may identify appropriate treatment for each individual patient. Addressing the disease biology of patients by whole transcriptome profiling has been shown to identify patients who will derive benefit from sunitinib, or atezolizumab (Tecentriq, Genentech) or a combination of atezolizumab and bevacizumab (Avastin, Genentech).

    In conclusion, the nivolumab and ipilimumab combination induces a high rate of objective response, and the quality of this response is highlighted by the rate of complete remissions, the duration of response and its translation into OS benefit.

    This first-line treatment is a new standard of care with a potentially massive impact, but we don’t have a final picture yet. Once we can properly address the biology of a patient’s individual tumor, we may pick out the best individual treatment among various first-line options like sunitinib, nivolumab plus ipilimumab, immunotherapy plus a TKI, or an anti-VEGF monoclonal antibody. The current data are encouraging news for those conducting phase 3 trials with immunotherapy-VEGF inhibitor combination vs. sunitinib.

    References:

    Choueiri TK, et al. Clin Cancer Res. 2015;doi:10.1158/1078-0432.CCR-14-1993.

    Escudier B, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.7849.

    Motzer RJ, et al. J Clin Oncol. 2009; doi:10.1200/JCO.2008.20.1293.

    Rini BI, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2009.26.5561.

    Sternberg CN, et al. Eur J Cancer. 2013;doi:10.1016/j.ejca.2012.12.010.

    • Manuela Schmidinger , MD
    • Medical University of Vienna, Austria

    Disclosures: Schmidinger reports honoraria for lectures from or advisory board roles with Astellas, AstraZeneca, Bristol-Myers Squibb, Eisai, Exelixis, Ipsen, Novartis, Pfizer and Roche.

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