From the Journals

Study outlines survival factors with nivolumab

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A good start, but better combinations needed

Although the existence of a subset of patients experiencing long-term survival certainly substantiates the role of PD-1/ PD-L1 checkpoint blockade in cancer immunotherapy, it is noteworthy to consider that these agents as monotherapy have not yielded sufficient activity and efficacy to replace standard-of-care therapy in the first line of therapy in advanced solid tumors, with the exception of NSCLC expressing high levels of PD-L1 and melanoma; emerging results also restrict monotherapy to stringently defined subsets of patients with gastric, esophageal, head and neck, and bladder cancers. Baseline predictive biomarkers have demonstrated distinct shortcomings, the first being their poor discriminatory ability and low negative predictive value. The clinician keen on securing the best possible outcome for his patients is thus left with the necessity for indiscriminate administration of PD-1/PD-L1 checkpoint inhibitors.

Unsurprisingly, the field of combination therapies using PD-1/PD-L1 checkpoint blockade as a backbone has been growing exponentially; a recent review shows more than 2,250 immunotherapy trials, 1,716 of which are investigating PD-1/ PD-L1 checkpoint inhibitors with more than 240 combination partners. Analysis of the pipeline also reveals a 67% increase in the number of active agents, amounting to more than 3,300, between September 2017 and September 2018. A noteworthy development is a 113% increase in cell therapies, and an increase of agents targeting neoantigens identified through bioinformatics analysis of an individual patient’s tumor, suggesting a shift toward increased personalization of immunotherapy. The observation that clinical development of immunotherapy agents has outstripped our understanding of the cancer-immune interactions advocates for renewed collective efforts in standardizing immune monitoring methods in clinical trials to identify immune evasion pathways that are dominant and to build novel trial designs able to efficiently enhance matching of patients with therapy.

Stefan Zimmermann, MD, and Solange Peters, MD, PhD, are from the Centre Hospitalier Universitaire Vaudois in Lausanne,Switzerland. Their remarks are excerpted and adapted from an editorial accompanying the study (JAMA Oncol. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2186). Dr. Zimmerman disclosed fees for advisory roles, travel grants, and clinical research support from Bristol-Myers Squibb and others. Dr. Peters disclosed fees for advisory board participation and/or lectures from Bristol-Myers Squibb and others.



Predictors of long-term survival of patients with advanced melanoma, renal cell carcinoma (RCC), non–small cell lung cancer (NSCLC), and other malignancies treated with nivolumab include the absence of liver or bone metastases, excellent baseline performance status, and the presence of grade 3 or greater treatment-related adverse events, investigators have found.

A secondary analysis of the phase 1 CA209-003 trial with expansion cohorts showed that, among 270 heavily pretreated patients with melanoma, RCC, and NSCLC who received single-agent nivolumab (Opdivo) during this trial, those with liver or bone metastases had a 69% higher risk for death within 5 years.

In contrast, patients with Eastern Cooperative Oncology Group (ECOG) performance status of 0 had a nearly threefold higher chance for survival, compared with patients with less favorable performance status scores, reported Suzanne L. Topalian, MD, from the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore and colleagues.

“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,” they wrote in JAMA Oncology.

In the CA209-003 trial, investigators enrolled patients 18 years or older with documented evidence of advanced melanoma, RCC, NSCLC, castration-resistant prostate cancer, or colorectal cancer. To be eligible, patients needed to have received 1-5 previous systemic therapies for advanced or recurrent cancer, measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.0, and an ECOG performance status of 0-2. The current survival analysis included data on 107 patients with melanoma, 34 with RCC, and 129 with NSCLC.

Estimated 5-year overall survival rates were 34.2% for patients with melanoma, 27.7% for patients with RCC, and 15.6% for patients with NSCLC. A multivariable analysis controlling for age, sex, performance status, metastatic disease, and number of prior therapies showed that the presence of either liver or bone metastases was associated with an odds ratio for 5-year survival of 0.31 (P = .02 and .04, respectively).

One factor favorably associated with survival included ECOG performance status 0 (OR, 2.74; P = .003). The investigators also found that treatment-related adverse events (AEs) were associated with longer overall survival, with a median of 19.8 months for patients with any grade of treatment-related event and 20.3 months for patients with grade 3 or greater events, compared with a median of 5.8 months for patients with no treatment-related events (P less than .001 for each comparison based on hazard ratios).

“Of note, patients in our study who developed treatment-related AEs, regardless of whether the AEs were deemed to have an immune-mediated causality, had significantly higher ORRs [overall response rates] and prolonged 5-year OS. These findings are reminiscent of some reports of anti–CTLA-4 therapy and align with other studies of anti–PD-1 therapies, “ Dr. Topalian and associates wrote.

The study and the secondary analysis were supported by Bristol-Myers Squibb. Dr. Topalian disclosed grants and travel reimbursements from Bristol-Myers Squibb and consulting fees with other entities. Multiple co-authors reported similar relationships. Four of the co-authors are Bristol-Myers Squibb employees.

SOURCE: Topalian SL et al. JAMA Oncology. 2019 Jul 25. doi: 10.1001/jamaoncol.2019.2187.

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