The investigators and sponsors of the phase III REVEL trial should be congratulated and probably commiserated. In this large study, reported by Garon and colleagues in The Lancet and reviewed in this issue of The ASCO Post, 1,253 patients with advanced non–small cell lung cancer (NSCLC) were randomized to either the standard second-line chemotherapy of docetaxel or docetaxel in combination with ramucirumab—an antibody directed against VEGFR2.1
Study Details
REVEL was a well-conducted, impressive effort involving patients accrued from 26 countries across 6 continents over barely 2 years. The primary endpoint of improving median overall survival was met (10.5 vs 9.1 months, hazard ratio [HR] = 0.86, P = .023), as were the key secondary endpoints of improving both median progression-free survival (4.5 vs 3 months, HR = 0.76, P < .0001) and the objective response rate (23 vs 14%, P < .0001).
There was a minor increase in toxicity from the addition of ramucirumab, but the serious adverse event and treatment-related death rates were essentially identical between the two arms of the study. Yet, despite this being an exemplary, unequivocally positive phase III trial advancing overall survival from docetaxel monotherapy in the second-line NSCLC setting for the first time since docetaxel was licensed nearly 15 years ago, the reception to REVEL at the 2014 ASCO Annual Meeting was lukewarm. Why?
The ECOG 4599 Peak
To some extent, the development of antiangiogenics in NSCLC peaked with the ECOG 4599 study, which showed that bevacizumab (Avastin), an antibody directed against VEGF—the predominant ligand of VEGFR2—added significantly to standard first-line carboplatin and paclitaxel in nonsquamous, but otherwise unselected, advanced NSCLC. ECOG 4599 showed that bevacizumab improved both median progression-free survival (6.2 vs 4.5 months) and overall survival (12.3 vs 10.3 months).2
Since then, a first-line phase III combination study of bevacizumab with cisplatin and gemcitabine (AVAiL) showed prolonged progression-free survival but failed to show an overall survival advantage (the primary endpoint of the study). Further, a series of phase III studies adding in various small-molecule inhibitors of angiogenic kinases to different lines of chemotherapy have also all failed to show overall survival advantages.3-6
Challenges in Identifying Biomarkers
One of the problems in terms of advancing this field has been the lack of progress in identifying robust predictive biomarkers of benefit from antiangiogenics. Certainly, squamous histology was identified early on as a potential predictive marker of toxicity for bevacizumab; it is therefore noteworthy that, in contrast to the majority of bevacizumab studies, all lung cancer histologies were included in the REVEL study, with no suggestion of a differential effect by histology. However, it is uncertain whether this represents a true biologic differentiation between the two drugs or the difference in the vascular fragility (potentially of both tumor and host) in the lung cancer population present in a first-line study—as opposed to those who have survived first-line chemotherapy to enter a second-line study.
Indeed, since continuation of bevacizumab into the second-line setting after progression on an initial bevacizumab-containing regimen has now been proven to be beneficial in metastatic colorectal cancer, whether using ramucirumab would be any different than using or continuing bevacizumab in the second-line setting in NSCLC becomes a major question.7 Arguments in favor of VEGFR2 being a more effective target than VEGF note that trials of ramucirumab vs placebo (REGARD) and of paclitaxel plus or minus ramucirumab (RAINBOW) both showed that ramucirumab prolonged overall survival in second-line advanced gastric cancer, whereas a study of platinum/fluorouracil–based chemotherapy plus or minus bevacizumab in first-line advanced gastric cancer (AVAGAST) did not.8-10
Intriguingly, all of the chemotherapy combination trials positive for overall survival with either bevacizumab or ramucirumab in lung and gastric cancer have used taxane-based regimens. Consequently, whether REVEL and RAINBOW were better set for success than AVAGAST and AVAiL just because of their design has to be considered.
Ramucirumab: The Overall Benefit
A head-to-head comparison of a taxane combined with ramucirumab vs a taxane combined with bevacizumab in the bevacizumab-eligible population would be the most satisfying scientific way to address whether ramucirumab in REVEL represents a true new drug indication in NSCLC or just a new indication for an overall class. However, since the overall benefit compared to placebo is so modest in REVEL, it is hard to imagine that the size of any significant differential benefit between antiangiogenics would ever be clinically meaningful.
Even if the efficacy of ramucirumab in REVEL truly represents a new drug effect, when targeted therapy combined with accurate predictive biomarkers has generated amazing results in EGFR mutant and ALK-rearranged NSCLC, the reaction by those at the 2014 ASCO Annual Meeting may reflect the fact that progression-free survival and overall survival advantages of less than 2 months are just not exciting enough for thoracic oncologists anymore.
In fact, Maurice Pérol, MD, of the Léon-Bérard Cancer Centre, Lyon, France, the presenter of REVEL at the ASCO Annual Meeting, made the point that the very absence of a predictive biomarker for ramucirumab might be an advantage, emphasizing its value in those lung cancer patients without an actionable genetic abnormality. Yet, patients with EGFR mutations, ALK rearrangements, or other actionable markers would almost certainly have been contained within the REVEL dataset. Therefore, unfortunately, this logic doesn’t hold up. In the absence of information on specific drivers, it is not possible to even say that driver-negative patients are deriving the same degree of benefit (vs a greater or lesser degree of benefit) compared to the overall unselected population within the trial.
Consider the Cost
Perhaps, in the era of economic meltdowns and health-care restructuring, the study’s tentative reception simply reflects anticipatory “sticker shock” from what those extra few weeks are likely to cost. In REVEL, ramucirumab was given at 10 mg/kg every 21 days. In April of 2014, following its licensing by the U.S. Food and Drug Administration for second-line advanced gastric cancer, ramucirumab at 8 mg/kg every 14 days, was priced at $7,140 per infusion, approximately 20% more than bevacizumab costs.11,12 While breakthroughs should certainly be heralded and everyone has to pay the bills somehow, it is hard not to fantasize about a world where ramucirumab in NSCLC was launched as not just another marginally effective anti-angiogenic, but also as the cheapest one in its class by far—bringing a little incremental benefit more comfortably within reach of everyone and every health system. In that world, the results of REVEL really would have made us sit up and take notice. ■
Disclosure: Dr. Camidge reported no potential conflicts of interest.
References
1. Garon EB, Ciuleanu T-E, 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.
2. Sandler A, Gray R, Perry MC, et al: Paclitaxel–carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 355:2542-2550, 2006.
3. Reck M, von Pawel J, Zatloukal P, et al: BO17704 Study Group. Overall survival with cisplatin–gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: Results from a randomized phase III trial (AVAiL). Ann Oncol 21:1804-1809, 2010.
4. Herbst RS, Sun Y, Eberhardt WE, et al: Vandetanib plus docetaxel versus docetaxel as second-line treatment for patients with advanced non-small-cell lung cancer (ZODIAC): A double-blind, randomized, phase 3 trial. Lancet Oncol 11:619-626, 2010.
5. Paz-Ares LG, Biesma B, Heigener D, et al: Phase III, randomized, double-blind, placebo-controlled trial of gemcitabine/cisplatin alone or with sorafenib for the first-line treatment of advanced, nonsquamous non-small-cell lung cancer. J Clin Oncol 30:3084-3092, 2012.
6. Scagliotti G, Vynnychenko I, Ichinose Y, et al: An international, randomized, placebo-controlled, double-blind phase III study of motesanib plus carboplatin/paclitaxel in patients with advanced nonsquamous non-small cell lung cancer. J Clin Oncol 30:2829-2836, 2011.
7. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomised phase 3 trial. Lancet Oncol 14:29-37, 2013.
8. Fuchs CS, Tomasek J, Yong CJ, et al: Ramucirumab monotherapy for previously treated advanced gastric or gastro-oesophageal junction adenocarcinoma (REGARD). Lancet 383:31-39, 2014.
9. Wilke H, Van Cutsem E, Oh SC, et al: RAINBOW: A global, phase III, randomized, double-blind study of ramucirumab plus paclitaxel versus placebo plus paclitaxel in the treatment of metastatic gastroesophageal junction and gastric adenocarcinoma following disease progression on first-line platinum- and fluoropyrimidine-containing combination therapy. J Clin Oncol 32 (suppl 3): Abstract LBA7, 2014.
10. Ohtsu A, Shah MA, Van Cutsem E, et al: Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer. J Clin Oncol 29:3968-3976, 2011.
11. The cost of cancer breakthroughs. Economist. June 4, 2014. Available at www.businessinsider.com/the-cost-of-cancer-breakthroughs-2014-6.
12. Díaz-Rubio E, Pietrantonio F, de Braud F: Continuing single-agent bevacizumab as maintenance therapy after induction XELOX (or FOLFOX) plus bevacizumab in first-line treatment of metastatic colorectal cancer. Oncologist 17:1426-1428, 2012.
Dr. Camidge is Associate Director for Clinical Research, University of Colorado Cancer Center, Denver.
