Meeting News

First-line avelumab, axitinib benefit persists across advanced kidney cancer patient subgroups

Toni K. Choueiri, MD
Toni K. Choueiri

SAN FRANCISCO — The combination of avelumab and axitinib induced longer PFS and higher objective response rates than sunitinib among previously untreated patients with advanced renal cell carcinoma, according to results from the ongoing phase 3 JAVELIN Renal 101 trial presented at Genitourinary Cancers Symposium.

Results — published simultaneously in The New England Journal of Medicine — showed benefit with first-line avelumab (Bavencio; EMD Serono, Pfizer), a human anti-PD-L1 immunoglobulin G1 monoclonal antibody, and axitinib (Inlyta, Pfizer), a highly potent VEGF receptor tyrosine kinase inhibitor, across all prognostic risk groups and PD-L1 subgroups compared with sunitinib (Sutent, Pfizer).

“Patients receiving the drug combination also had a higher response rate — meaning their tumors shrank — than the sunitinib-only group,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, said in a press release. “This is certainly better than sunitinib — hopefully this will lead to FDA approval soon.”

Previous results from the JAVELIN Renal 101 trial — presented at European Society for Medical Oncology Congress last year — showed longer median PFS (13.8 months vs. 8.4 months; HR = 0.69; P = .0001) and higher ORR (51.4% vs. 25.7%) with the combination. Researchers observed a greater benefit among patients with PD-L1-positive tumors (median PFS, 13.8 months vs. 7.2 months; HR = 0.61; P < .001; ORR, 55.2% vs. 25.5%).

In the current analysis, Choueiri and colleagues report on prespecified patient subgroups.

The analysis included 886 treatment-naive patients with advanced renal cell carcinoma who researchers assigned 1:1 to receive 10 mg/kg IV avelumab every 2 weeks plus 5 mg twice-daily oral axitinib (n = 442; median age, 62 years; 72% men) or 50 mg oral sunitinib once daily for 4 weeks of a 6-week cycle (n = 444; median age, 61 years; 78% men). Sixty-three percent of patients had PD-L1-positive tumors, defined as expression on at least 1% of immune cells.

PFS and OS in patients with PD-L1-positive tumors and regardless of PD-L1 expression served as the primary and key secondary endpoints.

Among patients with poor International Metastatic RCC Database Consortium prognostic risk, median PFS was 6 months (95% CI, 3.6-8.7) with the combination and 2.9 months (95% CI, 2.7-5.5) with sunitinib (HR = 0.57; 95% CI, 0.37-0.88).

Researchers also observed a PFS benefit in the intermediate-risk group (13.8 months vs. 8.4 months; HR = 0.74; 95% CI, 0.57-0.95) and favorable-risk group (not estimable vs. 13.8 months; HR = 0.54; 95% CI, 0.32-0.9).

These findings appeared consistent when researchers evaluated Memorial Sloan Kettering Cancer Center risk groups.

“Interestingly, the analysis showed that all subgroups — favorable, intermediate and poor-risk patients — benefited from the combination treatment,” Choueiri said in the press release.

Key subgroups — including never and current/former smokers, BMI less than 25 mg/kg or 25 mg/kg and higher, PD-L1 positive, and prior nephrectomy — also demonstrated benefit with the combination. PD-L1-negative patients (HR = 0.8; 95% CI, 0.55-1.16) and patients who did not undergo prior nephrectomy (HR = 0.74; 95% CI, 0.48-1.16) demonstrated a trend toward benefit that did not reach statistical significance.

Fewer patients in the combination group received subsequent anticancer therapies (22.6% vs. 40.5%). The most frequent follow-up anticancer therapies included nivolumab in the sunitinib group (24.1%) and cabozantinib (Cometriq/Cabometyx, Exelixis) in the combination group (9.5%).

Researchers also evaluated PFS2, defined as the time from the date of randomization to discontinuation of next-line treatment after first objective disease progression, second objective disease progression after next-line treatment, or death from any cause.

“We wanted to investigate whether the benefit of treatment in first line had any impact on the benefit of subsequent-line therapies,” Choueiri said during his presentation. “In theory, a first-line treatment could change the biology of the disease, and therefore lead to substantially shorter benefit of second-line treatment. It is potentially an important endpoint for regulatory and reimbursement evaluation.”

Results showed longer median PFS2 with the combination than with sunitinib (not estimable vs. 18.4 months; HR = 0.56; 95% CI, 0.42-0.73).

“This suggests, at least, no negative impact of first-line treatment of the combination of avelumab and axitinib on subsequent benefit from second-line treatment,” Choueiri said.

ORR also was higher with the combination in all prognostic risk categories and patient subgroups.

After a minimum follow-up of 6 months, patients who received the combination showed a 4-month (95% CI, 2.9-5.1) longer mean duration of response than those who received sunitinib.

“Given the durable responses observed and the flat curve of the combination treatment, it’s reasonable to believe that there will be more improvement in mean duration of response vs. sunitinib with a longer follow-up time,” Choueiri said.

Any-grade treatment-related adverse events occurred in 95% of the combination group and 96% of the sunitinib group, with 4% of the combination group experiencing grade 3 to grade 4 events compared with 7% of the sunitinib group.

Any-grade diarrhea (54%), hypertension (48%) and fatigue (36%) were the most common treatment-related adverse events in the combination group.

Drug discontinuation due to an adverse event occurred among 4% of the combination group and 8% of the sunitinib group.

“The results support avelumab plus axitinib as a new first-line standard of care for all patients with advanced renal cell carcinoma,” Choueiri said.

Clinicians will need to choose between this combination; the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb), which became standard of care last year; and the combination of pembrolizumab (Keytruda, Merck) and axitinib, data from which also were presented at Genitourinary Cancers Symposium, Bernard Escudier, MD, of Gustave Roussy Cancer Campus in Villejuif, France, wrote in an editorial that accompanies the publication in NEJM.

“Comparisons between the pembrolizumab-plus-axitinib and the avelumab-plus-axitinib trials show that the rates of PFS and ORR were very similar, although there was a higher percentage of favorable-risk patients in the pembrolizumab trial,” Escudier wrote. “The difference in risk between the patients in the pembrolizumab trial and those in the avelumab trial is also reflected in the longer PFS among patients receiving sunitinib in the former trial than in the latter trial (11.1 months vs. 8.4 months). However, although the follow-up in the two trials was similar, patients in the pembrolizumab trial had a significantly longer OS than those in the avelumab trial; this might have been attributable to the long-term effect of PD-1 inhibition.”

Whether OS increases with avelumab with longer follow-up will be of interest, Escudier added.

“In contrast to these two current trials, the trial of nivolumab plus ipilimumab did not show a significant increase in PFS, although OS was significantly increased and, more importantly, the complete response rate among patients in that trial was high.” – by Alexandra Todak

References:

Choueiri TK, et al. Abstract 544. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Escudier B. N Engl J Med. 2019;doi:10.1056/NEJMe1900887.

Motzer RJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1816047.

Powles T, et al. Abstract 543. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: Choueiri reports grants, personal fees or nonfinancial support from Agensys, Alexion, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera, Cerulean, Clinical Care Options, Corvus, Eli Lilly, Esai, Exelixis, Foundation Medicine Inc., Genentech/Roche, GlaxoSmithKline, Harborside Press, Ipsen, Kidney Cancer Journal, L-path, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NEJM, Novartis, Peloton, Pfizer, Platform Q, Prometheus Labs, Takeda, Tracon, The Lancet Oncology and Up-to-Date. Please see the abstract and full study for all other authors’ relevant financial disclosures. Escudier reports grants or personal fees from Aveo, Bristol-Myers Squibb, EUSA, Ipsen, Novartis, Pfizer and Roche.

 

 

 

 

 

 

 

Toni K. Choueiri, MD
Toni K. Choueiri

SAN FRANCISCO — The combination of avelumab and axitinib induced longer PFS and higher objective response rates than sunitinib among previously untreated patients with advanced renal cell carcinoma, according to results from the ongoing phase 3 JAVELIN Renal 101 trial presented at Genitourinary Cancers Symposium.

Results — published simultaneously in The New England Journal of Medicine — showed benefit with first-line avelumab (Bavencio; EMD Serono, Pfizer), a human anti-PD-L1 immunoglobulin G1 monoclonal antibody, and axitinib (Inlyta, Pfizer), a highly potent VEGF receptor tyrosine kinase inhibitor, across all prognostic risk groups and PD-L1 subgroups compared with sunitinib (Sutent, Pfizer).

“Patients receiving the drug combination also had a higher response rate — meaning their tumors shrank — than the sunitinib-only group,” Toni K. Choueiri, MD, director of the Lank Center for Genitourinary Oncology and of the Kidney Cancer Center at Dana-Farber Cancer Institute, said in a press release. “This is certainly better than sunitinib — hopefully this will lead to FDA approval soon.”

Previous results from the JAVELIN Renal 101 trial — presented at European Society for Medical Oncology Congress last year — showed longer median PFS (13.8 months vs. 8.4 months; HR = 0.69; P = .0001) and higher ORR (51.4% vs. 25.7%) with the combination. Researchers observed a greater benefit among patients with PD-L1-positive tumors (median PFS, 13.8 months vs. 7.2 months; HR = 0.61; P < .001; ORR, 55.2% vs. 25.5%).

In the current analysis, Choueiri and colleagues report on prespecified patient subgroups.

The analysis included 886 treatment-naive patients with advanced renal cell carcinoma who researchers assigned 1:1 to receive 10 mg/kg IV avelumab every 2 weeks plus 5 mg twice-daily oral axitinib (n = 442; median age, 62 years; 72% men) or 50 mg oral sunitinib once daily for 4 weeks of a 6-week cycle (n = 444; median age, 61 years; 78% men). Sixty-three percent of patients had PD-L1-positive tumors, defined as expression on at least 1% of immune cells.

PFS and OS in patients with PD-L1-positive tumors and regardless of PD-L1 expression served as the primary and key secondary endpoints.

Among patients with poor International Metastatic RCC Database Consortium prognostic risk, median PFS was 6 months (95% CI, 3.6-8.7) with the combination and 2.9 months (95% CI, 2.7-5.5) with sunitinib (HR = 0.57; 95% CI, 0.37-0.88).

Researchers also observed a PFS benefit in the intermediate-risk group (13.8 months vs. 8.4 months; HR = 0.74; 95% CI, 0.57-0.95) and favorable-risk group (not estimable vs. 13.8 months; HR = 0.54; 95% CI, 0.32-0.9).

PAGE BREAK

These findings appeared consistent when researchers evaluated Memorial Sloan Kettering Cancer Center risk groups.

“Interestingly, the analysis showed that all subgroups — favorable, intermediate and poor-risk patients — benefited from the combination treatment,” Choueiri said in the press release.

Key subgroups — including never and current/former smokers, BMI less than 25 mg/kg or 25 mg/kg and higher, PD-L1 positive, and prior nephrectomy — also demonstrated benefit with the combination. PD-L1-negative patients (HR = 0.8; 95% CI, 0.55-1.16) and patients who did not undergo prior nephrectomy (HR = 0.74; 95% CI, 0.48-1.16) demonstrated a trend toward benefit that did not reach statistical significance.

Fewer patients in the combination group received subsequent anticancer therapies (22.6% vs. 40.5%). The most frequent follow-up anticancer therapies included nivolumab in the sunitinib group (24.1%) and cabozantinib (Cometriq/Cabometyx, Exelixis) in the combination group (9.5%).

Researchers also evaluated PFS2, defined as the time from the date of randomization to discontinuation of next-line treatment after first objective disease progression, second objective disease progression after next-line treatment, or death from any cause.

“We wanted to investigate whether the benefit of treatment in first line had any impact on the benefit of subsequent-line therapies,” Choueiri said during his presentation. “In theory, a first-line treatment could change the biology of the disease, and therefore lead to substantially shorter benefit of second-line treatment. It is potentially an important endpoint for regulatory and reimbursement evaluation.”

Results showed longer median PFS2 with the combination than with sunitinib (not estimable vs. 18.4 months; HR = 0.56; 95% CI, 0.42-0.73).

“This suggests, at least, no negative impact of first-line treatment of the combination of avelumab and axitinib on subsequent benefit from second-line treatment,” Choueiri said.

ORR also was higher with the combination in all prognostic risk categories and patient subgroups.

After a minimum follow-up of 6 months, patients who received the combination showed a 4-month (95% CI, 2.9-5.1) longer mean duration of response than those who received sunitinib.

“Given the durable responses observed and the flat curve of the combination treatment, it’s reasonable to believe that there will be more improvement in mean duration of response vs. sunitinib with a longer follow-up time,” Choueiri said.

Any-grade treatment-related adverse events occurred in 95% of the combination group and 96% of the sunitinib group, with 4% of the combination group experiencing grade 3 to grade 4 events compared with 7% of the sunitinib group.

PAGE BREAK

Any-grade diarrhea (54%), hypertension (48%) and fatigue (36%) were the most common treatment-related adverse events in the combination group.

Drug discontinuation due to an adverse event occurred among 4% of the combination group and 8% of the sunitinib group.

“The results support avelumab plus axitinib as a new first-line standard of care for all patients with advanced renal cell carcinoma,” Choueiri said.

Clinicians will need to choose between this combination; the combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb), which became standard of care last year; and the combination of pembrolizumab (Keytruda, Merck) and axitinib, data from which also were presented at Genitourinary Cancers Symposium, Bernard Escudier, MD, of Gustave Roussy Cancer Campus in Villejuif, France, wrote in an editorial that accompanies the publication in NEJM.

“Comparisons between the pembrolizumab-plus-axitinib and the avelumab-plus-axitinib trials show that the rates of PFS and ORR were very similar, although there was a higher percentage of favorable-risk patients in the pembrolizumab trial,” Escudier wrote. “The difference in risk between the patients in the pembrolizumab trial and those in the avelumab trial is also reflected in the longer PFS among patients receiving sunitinib in the former trial than in the latter trial (11.1 months vs. 8.4 months). However, although the follow-up in the two trials was similar, patients in the pembrolizumab trial had a significantly longer OS than those in the avelumab trial; this might have been attributable to the long-term effect of PD-1 inhibition.”

Whether OS increases with avelumab with longer follow-up will be of interest, Escudier added.

“In contrast to these two current trials, the trial of nivolumab plus ipilimumab did not show a significant increase in PFS, although OS was significantly increased and, more importantly, the complete response rate among patients in that trial was high.” – by Alexandra Todak

References:

Choueiri TK, et al. Abstract 544. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Escudier B. N Engl J Med. 2019;doi:10.1056/NEJMe1900887.

Motzer RJ, et al. N Engl J Med. 2019;doi:10.1056/NEJMoa1816047.

Powles T, et al. Abstract 543. Presented at: Genitourinary Cancers Symposium; Feb. 14-16, 2019; San Francisco.

Disclosures: Choueiri reports grants, personal fees or nonfinancial support from Agensys, Alexion, Alligent, Analysis Group, AstraZeneca, Bayer, Bristol-Myers Squibb, Calithera, Cerulean, Clinical Care Options, Corvus, Eli Lilly, Esai, Exelixis, Foundation Medicine Inc., Genentech/Roche, GlaxoSmithKline, Harborside Press, Ipsen, Kidney Cancer Journal, L-path, Merck, Michael J. Hennessy Associates, Navinata Healthcare, NEJM, Novartis, Peloton, Pfizer, Platform Q, Prometheus Labs, Takeda, Tracon, The Lancet Oncology and Up-to-Date. Please see the abstract and full study for all other authors’ relevant financial disclosures. Escudier reports grants or personal fees from Aveo, Bristol-Myers Squibb, EUSA, Ipsen, Novartis, Pfizer and Roche.

 

 

 

 

 

 

 

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