Lung cancer is the most common, lethal, and costly cancer worldwide, accounting for at least 1.8 million new cases per year (12.9% of the total).1 Over the past decade, there has been a major shift in the treatment of non–small cell lung cancer (NSCLC), especially in adenocarcinoma, accompanied by a better understanding of cancer pathways and identification of highly effective targeted therapies (targeting EGFR mutations and ALK translocations). This has led to significant improvements in patient outcomes with minimal toxicity.
Progress in squamous cell carcinoma of the lungs has lagged behind. Although molecular alterations have been described, effective targeted therapies have not yet been developed, and platinum-based chemotherapy remains standard as initial therapy in advanced squamous cell carcinoma. However, the recent approval of nivolumab (Opdivo) and pembrolizumab (Keytruda) as second-line therapy in advanced lung carcinoma including squamous cell carcinoma has led to renewed hope for better outcomes in this disease.2
SQUIRE Trial
The SQUIRE trial, published in The Lancet Oncology earlier this year by Thatcher et al3 and reviewed in this issue of The ASCO Post, is a phase III, multicenter, open-label, randomized trial examining the impact of adding necitumumab, a second-generation anti-EGFR antibody, to first-line gemcitabine/cisplatin in advanced squamous cell lung carcinoma patients. Between 2010 and 2012, the trial randomly assigned 1,093 patients and demonstrated improved overall survival with the addition of necitumumab to chemotherapy, with a 1.6-month median increase from 9.9 months to 11.5 months (hazard ratio [HR] = 0.84, P = .01).
The addition of necitumumab to chemotherapy did not meaningfully improve progression-free survival—despite a statistically significant difference (median = 5.7 vs 5.5 months, HR = 0.86, P = .02)—or response rate (31.2% vs 28.8%). Higher tumor EGFR expression (immunohistochemistry H score ≥ 200) did not significantly predict better progression-free survival or overall survival, although there was a trend toward better survival with necitumumab in this subgroup (HR = 0.75, 95% confidence interval [CI] = 0.60–0.94, interaction P value = .235). Half of the study patients had tumor assessment of EGFR copy number by fluorescence in situ hybridization (FISH); those with a high copy number or amplification had a trend toward progression-free survival and overall survival benefit (median overall survival = 12.6 vs 9.2 months, HR = 0.70, 95% CI = 0.52–0.96, interaction P value = .066).4 More toxicity was seen in the necitumumab arm—in particular, hypomagnesemia, rash, venous and arterial thromboembolic events, and infusion reactions.
Monoclonal antibodies targeting EGFR are not new to lung cancer. The INSPIRE trial,5 similar to SQUIRE, evaluated necitumumab plus pemetrexed (Alimta)/cisplatin vs pemetrexed/cisplatin alone in advanced nonsquamous lung cancer patients. After accrual of 633 patients, this study closed due to an excess of thrombotic events in the necitumumab arm. Survival was similar in both arms, but toxicity was significantly higher with necitumumab, including severe rash, hypomagnesemia, and venous thromboembolic events. High EGFR expression (H score ≥ 200) was neither predictive of necitumumab benefit nor prognostic in INSPIRE.
Addition of Cetuximab
Multiple studies have also been conducted with cetuximab, a first-generation anti-EGFR antibody, in combination with first-line chemotherapy in NSCLC, with results ranging from negative to modestly positive. FLEX6 is the best-known phase III trial of this combination, with a median 1.2-month overall survival benefit with cetuximab in an unselected advanced NSCLC population (median = 11.3 vs 10.1 months with chemotherapy alone, HR = 0.87, P = .04). No improvement in progression-free survival was seen, and toxicity was worse in the cetuximab arm (rash, diarrhea, and febrile neutropenia). In the subgroup of patients with squamous carcinoma (25%), outcomes were similar (median survival gain of 1.3 months, 10.2 vs 8.9 months, HR = 0.80, 95% CI = 0.69–1.0).
In exploratory analyses, high EGFR protein expression (H score ≥ 200) was associated with cetuximab benefit (median survival = 12.0 vs 9.6 months, HR = 0.73, P = .011), whereas no benefit was seen in those with low EGFR expression (interaction P value = .044).7 The benefit appeared even greater in squamous cell carcinoma patients with high EGFR expression (HR = 0.62, 95% CI = 0.43–0.88, 1-year survival of 44% vs 25%). However, those with FISH-positive tumors (ie, EGFR gene amplification or high polysomy) did not derive preferential benefit.8
The phase III BMS-099 study, similar in design to FLEX, did not achieve its primary endpoint of increasing progression-free survival, nor did it show increased overall survival, and biomarker studies were negative.9 A meta-analysis of FLEX, BMS-099, and two smaller trials suggested a minor overall survival gain with cetuximab (median = 10.3 vs 9.4 months, HR = 0.88, P = .009), and a better progression-free survival (median = 4.7 vs 4.5 months, HR = 0.90, P = .045) and response rate (32% vs 24%, odds ratio = 1.46, P < .001).10 Exploratory analysis suggested greater survival benefit in squamous cell lung carcinoma patients, with a hazard ratio of 0.77 (95% CI = 0.64–0.93).
These marginal benefits were not sufficient to convince the medical community that adding anti-EGFR therapy to first-line platinum doublet therapy should be a new standard but raised questions about its utility in subgroups such as squamous cell carcinoma and EGFR-positive tumors. A recent report of the SWOG S0819 study confirmed a lack of benefit from adding cetuximab to first-line therapy in unselected NSCLC patients, with exploratory analyses suggesting greater effect in squamous cell lung carcinoma with FISH-positive tumors (HR = 0.56, 95% CI = 0.37–0.84, P = .006).11
Meaningful Gains
Defining clinically meaningful outcomes has become a challenge in oncology, particularly with the evolution of targeted therapies and immune checkpoint inhibitors yielding major improvements in outcomes for selected patient populations. Ellis et al12 recently published the perspective of the ASCO Cancer Research Committee, highlighting the importance of raising the bar for oncology clinical trial outcomes in order to achieve meaningful gains in patient care. A relative improvement in median survival of at least 20% was defined as the minimum necessary to define a clinically meaningful improvement in outcome. For squamous cell carcinoma of the lungs, a minimum improvement of 2.5 to 3 months in median survival was recommended, corresponding to a survival hazard ratio of ≤ 0.80.
Unfortunately, the trend in lung cancer has been the reverse, with a decreasing magnitude of survival gain seen in positive lung cancer trials over time (3.9 months in 1980–1990, 2.5 months in 2001–2010; P = .11).13 Investigators appear progressively less stringent in deeming treatments of value even when the statistically significant advantage achieved is no longer clinically relevant.
Despite this, progress in lung cancer therapy has been a rising tide, with novel targeted therapies and immunotherapy leading to dramatic and durable responses, better quality of life, and even improved survival in selected cases, often with less toxicity than standard chemotherapy. For example, nivolumab as second-line therapy in squamous cell lung carcinoma yielded an absolute median survival improvement of 3.2 months (9.2 vs 6.0 months, HR = 0.59, P < .01), a doubling of response rate (20% vs 9%), and a markedly longer duration of response (median not reached vs 8 months with chemotherapy), with significantly less toxicity and better quality of life compared with docetaxel.2
Remaining Questions
Given all the recent progress in lung cancer, should we embrace necitumumab plus platinum-based chemotherapy as the new first-line standard of care for advanced squamous cell lung carcinoma? Does it meet the high bar set by ASCO? Does it yield the dramatic, durable responses of EGFR or ALK tyrosine kinase inhibitors or programmed cell death protein (PD-1) checkpoint inhibitors? Does it yield less toxicity than the current standard and improve quality of life? The answer to these last three questions is no.
And what about financial toxicity? Goldstein and colleagues have recommended pricing in the range of US$500 to US$1,300 per cycle of necitumumab to achieve reasonable cost-effectiveness in today’s economic climate.14 Will necitumumab’s future cost further outweigh its benefit for our patients?
Both necitumumab and cetuximab give rise to remaining questions about the magnitude and value of their benefit in lung cancer, the role of biomarker selection, and incremental toxicities, including cost. Perhaps it is time to swim with the tide and await the results of phase III trials of first-line PD-1 checkpoint inhibitors before determining the best place for necitumumab in squamous cell lung carcinoma. ■
Disclosure: Drs. Fares, Araujo, and Leighl reported no potential conflicts of interest.
References
1. Ferlay J, Soerjomataram I, Dikshit R, et al: Cancer incidence and mortality worldwide: Sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136:E359-E386, 2015.
2. Brahmer J, Reckamp KL, Baas P, et al: Nivolumab versus docetaxel in advanced squamous-cell non–small-cell lung cancer. N Engl J Med 373:123-135, 2015.
3. Thatcher N, Hirsch FR, Luft AV, et al: Necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone as first-line therapy in patients with stage IV squamous non-small-cell lung cancer (SQUIRE): An open-label, randomised, controlled phase 3 trial. Lancet Oncol 16:763-774, 2015.
4. Hirsch FR, Boyle TA, Thatcher N, et al: EGFR IHC and FISH correlative analyses (SQUIRE trial): Necitumumab + gemcitabine-cisplatin vs. gemcitabine-cisplatin in 1st-line squamous NSCLC. World Conference on Lung Cancer. Abstract ORAL32.05. Presented September 9, 2015.
5. Paz Ares L, Mezger J, Ciuleanu TE, et al: Necitumumab plus pemetrexed and cisplatin as first-line therapy in patients with stage IV non-squamous non-small-cell lung cancer (INSPIRE): An open-label, randomized, controlled phase 3 study. Lancet Oncol 16:328-337, 2012.
6. Pirker R, Pereira JR, Szczesna A, et al: Cetuximab plus chemotherapy in patients with advanced non-small-cell lung cancer (FLEX): An open-label randomised phase III trial. Lancet 373:1525-1531, 2009.
7. Pirker R, Pereira JR, von Pawel J, et al: EGFR expression as a predictor of survival for first-line chemotherapy plus cetuximab in patients with advanced non-small-cell lung cancer: Analysis of data from the phase 3 FLEX study. Lancet Oncol 13:33-42, 2012.
8. O’Byrne KJ, Gatzemeier U, Bondarenko I, et al: Molecular biomarkers in non-small-cell lung cancer: A retrospective analysis of data from the phase 3 FLEX study. Lancet Oncol 12:795-805, 2011.
9. Lynch TJ, Patel T, Dreisbach L, et al: Cetuximab and first-line taxane/carboplatin chemotherapy in advanced non-small-cell lung cancer: Results of the randomized multicenter phase III trial BMS099. J Clin Oncol 28:911-917, 2010.
10. Pujol JL, Pirker R, Lynch TJ, et al: Meta-analysis of individual patient data from randomized trials of chemotherapy plus cetuximab as first-line treatment for advanced non-small cell lung cancer. Lung Cancer 83:211-218, 2014.
11. Herbst R, Redman M, Kin ES, et al: A randomized phase III study comparing carboplatin/paclitaxel or carboplatin/paclitaxel/bevacizumab with or without concurrent cetuximab in patients with advanced non-small cell lung cancer (NSCLC): SWOG S0819. World Conference on Lung Cancer. Abstract PLEN04.01. September 9, 2015.
12. Ellis LM, Bernstein DS, Voest EE, et al: American Society of Clinical Oncology perspective: Raising the bar for clinical trials by defining clinically meaningful outcomes. J Clin Oncol 32:1277-1280, 2014.
13. Sacher AG, Le LW, Leighl NB: Shifting patterns in the interpretation of phase III clinical trial outcomes in advanced non-small-cell lung cancer: The bar is dropping. J Clin Oncol 32:1407-1411, 2014.
14. Goldstein DA, Chen Q, Ayer T, et al: Necitumumab in metastatic squamous cell lung cancer: Establishing a value-based cost. JAMA Oncol. August 27, 2015 (early release online).
