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Survival Benefit With Nivolumab Still Seen at 5 Years in Melanoma, RCC, and NSCLC

Lisa Astor
Published Online:4:00 PM, Wed July 31, 2019
Suzanne L. Topalian, MD
Suzanne L. Topalian, MD
Nivolumab (Opdivo) demonstrated long-term survival benefit in heavily pretreated patients with advanced melanoma, renal cell carcinoma (RCC), and non–small cell lung cancer (NSCLC), according to an analysis of 5-year results from the CA209-003 trial. The analysis also identified favorable and adverse factors associated with survival that could inform future use of nivolumab. 

Patients with melanoma treated with nivolumab had an objective response rate (ORR) of 31.8% (95% CI, 23.1%-41.5%), 29.4% (95% CI, 15.1%-47.5%) with RCC, and 17.1% (95% CI, 11.0%-24.7%) with NSCLC. 

“The results of this study suggest that survival benefits reported in the more limited follow-up of recent nivolumab randomized clinical trials may persist for prolonged periods in some patients, extending to at least 5 years,” the study authors, led by Suzanne L. Topalian, MD, wrote in their report published recently in JAMA Oncology. “The estimated 5-year survival rates…exceed survival rates expected from conventional second-line or third-line therapies available for patients at the time that this trial was conducted.”

The multicenter, dose-escalation/dose-expansion phase I trial was the first multidose trial of a PD-1/PD-L1 antagonist. It enrolled patients with advanced cancer into one of 5 dose-expansion cohorts: melanoma, RCC, NSCLC, colorectal cancer (CRC), or castration-resistant prostate cancer (CRPC). 

Patients received intravenous nivolumab at varying doses every 2 weeks in 8-week cycles for up to 96 weeks or until the development of progressive disease, complete response, unacceptable toxicity, or the withdrawal of consent. 

A total of 270 heavily pretreated patients with advanced disease were included in the melanoma, RCC, and NSCLC cohorts. In the melanoma cohort, patients received doses of 0.1, 0.3, 1.0, 3.0, or 10.0 mg/kg of nivolumab; in the RCC cohort, patients received either 1.0 or 10.0 mg/kg doses; and in the NSCLC cohort, patients received 1.0, 3.0, or 10.0 mg/kg doses.

In the melanoma cohort (n = 107), 67.3% of patients were male and the median age was 61 years (range, 29-85). Among those with RCC (n = 34), 76.5% of patients were male and the median age was 58 years (range, 35-74). In the NSCLC cohort (n = 129), 61.2% of patients were male and the median age was 65 years (range, 38-85). Overall, 40.4% of patients between the 3 cohorts had received ≥3 prior treatment regimens. 

Two patients in the melanoma cohort (1.9%), 1 in the RCC cohort (2.9%), and none in the NSCLC cohort achieved complete responses. The disease control rates were 53.3%, 70.6%, and 41.9% in the melanoma, RCC, and NSCLC cohorts, respectively. 

The responses were durable across the 3 tumor types with a median response duration of 22.9 months (95% CI, 16.7-31.8) among those with melanoma, 12.9 months (95% CI, 8.4–not estimable [NE]) with RCC, and 19.1 months (95% CI, 8.7-NE) with NSCLC. 

After a minimum follow-up of 58.3 months for the melanoma and NSCLC cohorts and 63.9 months for the RCC cohort, the median overall survival (OS) was 20.3 months (95% CI, 12.5-37.9) in the group of patients with melanoma, 22.4 months (95% CI, 12.5-48.6) in the group with RCC, and 9.9 months (95% CI, 7.8-12.4) in those with NSCLC. 

The rate of OS at 3 years was 42.3% in the melanoma cohort, 40.1% in the RCC cohort, and 18.4% in the NSCLC cohort. At 5 years, the rates of OS were 34.2%, 27.7%, and 15.6% in the melanoma, RCC, and NSCLC cohorts, respectively. Among those with squamous NSCLC, the 5-year OS rate was 16% and the 5-year rate was 15% in patients with nonsquamous NSCLC. 

Most patients treated beyond progression, which was defined as receiving nivolumab for ≥4 weeks after evidence of disease progression, did not achieve an objective response. Of 43 patients treated beyond progression, 23 patients were evaluable after progression. Four of these patients demonstrated a reduction in tumor burden of ≥30%, 4 had a reduction of <30%, and 13 had a reduction of <20%. 

“The CA209-003 study was, to our knowledge, the first trial of any anti–PD-1/PD-L1 drug to use treatment beyond progression,” Topalian et al noted in their report.

Treatment-related adverse events (TRAEs) were experienced by 77.8% of patients, and grade ≥3 TRAEs were experienced by 19.6%. Three treatment-related deaths were reported, all among patients with NSCLC. 

Analyses of Factors Associated With OS
Patients were assessed by univariate and multivariate analyses for factors associated with long-term survival. 

“The current report provides preliminary evidence for early surrogate markers of long-term clinical benefit. Such markers may be valuable on a per-patient basis and in designing the conduct and assessment of future trials of anti–PD-1 drugs,” the study authors wrote. 

By univariate analysis, an ECOG performance status of 0 versus ≥1 was associated with increased 5-year OS (HR, 0.53; 95% CI, 0.40-0.71). On the other hand, decreased survival was associated with the presence of bone (HR, 1.58; 95% CI, 1.13-2.20), liver (HR, 1.78; 95% CI, 1.31-2.41), or visceral metastases (HR, 1.78; 95% CI, 1.13-2.79). 

By multivariate analysis, the baseline presence of liver (odds ratio [OR], 0.31; 95% CI, 0.12-0.83; P= .02) or bone metastases (OR, 0.31; 95% CI, 0.10-0.93; P= .04) were both independently associated with a decreased likelihood of survival at 5 years. A larger baseline tumor burden was also negatively associated with survival at 5 years (<.02). An ECOG performance status of 0 was favorable associated with an increased likelihood of 5-year survival by multivariate analysis compared with a status of ≥1 (OR, 2.74; 95% CI, 1.43-5.27; = .003). 

Across analyses, the presence or absence of brain or lymph node metastases did not negatively affect long-term survival in the 3 cohorts. However, patients with untreated brain metastases were excluded from entering the trial. The number of prior treatment regimens (>2 vs ≤2) also did not have a statistically significant effect on long-term survival. 

A significant association was found between ORR and 5-year OS rate. Of the 55 patients alive at 5 years between the 3 cohorts, 74.5% of these patients had achieved a response versus just 11.6% of those who were dead at 5 years (OR, 22.3; 95% CI, 10.7-46.5; P<.001). 

Patients who experienced TRAEs of any grade showed longer OS compared with those who did not (median 19.8 vs 5.8), and patients who experienced grade ≥3 TRAEs had a median OS of 20.3 months (<.001). A similar association was also found between TRAEs and ORR. 

Higher mean baseline absolute lymphocyte counts (ALCs) were also observed among patients who responded to treatment with nivolumab compared with those who did not (1480 vs 1300 cells/μL; = .04). Patients who were still alive at 5 years also demonstrated higher mean baseline ALCs (1546 vs 1290 cells/μL; = .01). 
Topalian SL, Hodi FS, Brahmer JR, et al. Five-year survival and correlates among patients with advanced melanoma, renal cell carcinoma, or non–small cell lung cancer treated with nivolumab [published online July 25, 2019]. JAMA Oncol. doi: 10.1001/jamaoncol.2019.2187. 

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