There is ample evidence to suggest that older adults with a good performance status (0 or 1) with advanced non–small cell lung cancer (NSCLC) should be treated with combination chemotherapy akin to younger patients.1,2 However, older adults comprise a heterogeneous group that has been underrepresented in clinical trials, forcing oncologists to extrapolate findings derived in younger, healthier patients to older patients with multiple chronic conditions and compromised physiologic reserve.
The Invisible Majority
A search of the clinicaltrials.gov website for the terms “NSCLC” and “elderly” revealed 11 trials with an actively recruiting status. Only five of those trials are phase III studies, with the others being observational/single-arm phase II or phase I trials. Of the five phase III trials, four are European (two evaluating the role of single-agent vs cisplatin combination chemotherapy and two others evaluating the role of pemetrexed [Alimta] maintenance vs surveillance). The single, U.S.-based phase III interventional trial is evaluating two schedules of nab-paclitaxel (Abraxane) and carboplatin in older patients. Similarly, a search for “NSCLC” and “ECOG PS2” (commonly encountered in the elderly) revealed a single phase II clinical trial currently open to enrollment in the United States.
In a disease wherein the elderly comprise over half of the patients, it is worrisome that there is such little ongoing investigation for this “invisible majority.” A counter explanation offered repeatedly by funding agencies, cooperative groups, and investigators alike is that elderly patients should be included in ongoing, age-unspecified clinical trials. However, it is well known that only the fit elderly meet the eligibility for age-unspecified clinical trials, and hence those results (efficacy and toxicity) may not be applicable to the vulnerable elderly. It has been demonstrated that elderly-specific trials have a higher median age of participants, a greater proportion of octogenarians, and fewer adverse events than age-unspecified trials.3
Immune Checkpoint Inhibitors
On the other hand, there is much to rejoice for thoracic medical oncologists and patients, given the advent of immune checkpoint inhibition for NSCLC and unraveling of oncogenic drivers in adenocarcinoma.
Immune checkpoint inhibitors target proteins that regulate the immune system, including CTLA-4 (cytotoxic T-lymphocyte–associated antigen) and the PD-1 (programmed cell death protein 1) pathway, to enhance the response of the immune system to tumor cells. Recent approval of nivolumab (Opdivo) and pembrolizumab (Keytruda), both PD-1–blocking antibodies, after failure of platinum-based combination chemotherapy has generated a great deal of excitement and hope in patients with advanced NSCLC. These agents have demonstrated durable clinical responses and improved overall survival in some patients with NSCLC, irrespective of histology.
In a trial limited to patients with squamous cell histology, of the 272 patients randomized to receive nivolumab or docetaxel, 44% and 11% of patients were aged ≥ 65 and ≥ 75 years, respectively. The median overall survival was 9.2 months vs 6 months (hazard ratio [HR] for death, 0.59; 95% confidence interval [CI], 0.44–0.79; P < .001) favoring nivolumab.4 In a similar study, albeit limited to nonsquamous cell histology (n = 582), of the patients (performance status of 0 or 1) randomized to receive nivolumab or docetaxel, 42% and 7% were aged ≥ 65 and ≥ 75 years, respectively. The median overall survival was 12.2 months vs 9.4 months (HR, 0.73; 95% CI, 0.59–0.89; P = .002) favoring nivolumab.5
In both these trials, a consistent treatment effect favoring nivolumab was observed in most prespecified subgroups, except in the group of patients ≥ 75 years, possibly attributable to small sample size and type 1 error for multiple comparisons. Similarly, pembrolizumab demonstrated improved overall survival in previously treated patients with advanced NSCLC.6 Among patients (with ≥ 50% of tumor cells expressing PD-L1), overall survival was significantly longer with pembrolizumab (2 mg/kg) than with docetaxel (median 14.9 months vs 8.2 months; HR, 0.54; 95% CI, 0.38–0.77; P = .0002).
These agents appear well tolerated, with grade 3/4 adverse events in 7% to 13% of patients, but do have some unique adverse events, such as endocrinopathies, pneumonitis, interstitial lung disease, and colitis. Details of adverse events by age have not been reported thus far. Although there is modest representation of older adults (performance status of 0 or1) on the pivotal trials, further assessment in the elderly, specifically those with a borderline performance status and high comorbid burden representative of the average clinical trial–ineligible patient, is urgently warranted.
A Closer Look at Mutations
Mutation-positive NSCLC: Targeting oncogenic drivers has been an area of intense study over the past decade. The proportion of patients with adenocarcinoma of the lungs with “actionable drivers” is growing. Contrary to the broad appeal of checkpoint inhibition, mutation-positive NSCLC offers a model for specific target inhibition. In a recent report from the Lung Cancer Mutation Consortium, actionable drivers were detected in 64% of lung adenocarcinomas. Those encountered with greatest frequency included KRAS (25%), EGFR (21%), ALK rearrangements (8%); ERBB2 (formerly HER2; 3%), and BRAF (2%).7 These mutations were largely mutually exclusive, with more than one mutation detected in only 3% of patients studied. The specific agents available against common drivers include:
- EGFR mutations: Erlotinib, afatinib (Gilotrif) and gefitinib; osimertinib (Tagrisso) was recently approved in the treatment of patients with metastatic EGFR T790M mutation–positive NSCLC.
- ALK mutations: Crizotinib (Xalkori), ceritinib (Zykadia), and alectinib (Alecensa)
- ROS-1 mutations: Crizotinib was granted priority review by the U.S. Food and Drug Administration (FDA) in December 2015.
- BRAF V600E mutation: Dabrafenib (Tafinlar) and trametinib (Mekinist) combination therapy was granted Breakthrough Therapy designation by the FDA and is under review.
Although information specific to the elderly is not available for each agent, generally there is no evidence that these agents are more harmful or less active in elderly patients.1 Thus, elderly patients should be treated on the basis of functional status and comorbid disease burden, with the recognition that the elderly may tolerate common adverse effects such as cutaneous toxicity and diarrhea poorly compared with younger patients.
Differences in Benefit by Age
There are some examples whereby targeted agents did not demonstrate the same benefit among elderly as in younger patients. For instance, in an age-based subset analysis of patients aged 70 or older (n = 224) of the Eastern Cooperative Oncology Group (ECOG) 4599 trial, addition of bevacizumab (Avastin) to paclitaxel and carboplatin was associated with no improvement in overall survival (11.3 months vs 12.1 months; P = .4) contrary to the entire trial population, which revealed improvement in overall survival with bevacizumab (12.3 vs 10.3 months; P = .003).
Furthermore, grade 3 to 5 toxicities occurred in 87% of elderly patients with the addition of bevacizumab vs 61% without (P < .001). Elderly patients had a higher incidence of grade 3–5 neutropenia, bleeding, and proteinuria in the bevacizumab arm compared with younger patients.8 Similarly, in a phase III study of second-line therapy in patients (n = 1,253) with stage IV NSCLC, the addition of ramucirumab (Cyramza; a monoclonal antibody to the vascular endothelial growth factor receptor) to docetaxel improved overall survival in patients < 65 years (11.3 vs 8.9 months; P < .001) but not in patients ≥ 65 years (9.2 vs 9.3 months; P = .393).9
ASCO Statement
ASCO has recently issued a bold statement with the goal of improving the evidence base for treating older adults with cancer.10 The principles include better use of the existing research infrastructure, with enhanced research designs to improve the inclusion of older adults on clinical trials; a higher bar set in terms of publication policies by journals to include detailed information regarding age and comorbidity of trial participants; and potential authorization of the FDA to require results in older adults prior to the drug-approval process. Given the magnitude of mortality and the high proportion of elderly, as well as the availability of novel agents with improved toxicity profiles, NSCLC should serve as a poster child for application of these principles. ■
Disclosure: Dr. Gajra reported no potential conflicts of interest.
References
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9. Garon EB, Ciuleanu TE, Arrieta O, et al: Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL). Lancet 384:665-673, 2014.
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