Is the door open to further investigation with antiangiogenesis in SCLC?

We thank Dr. Goto for his Editorial (1) on GOIRC-AIFA FARM6PMFJM study, the first randomized phase III trial evaluating the survival impact of bevacizumab combined to standard cisplatin-etoposide respect cisplatin-etoposide alone as first-line therapy of extended disease small cell lung cancer (SCLC) (2).

Our Italian multicenter trial shows that the addiction of bevacizumab to platinum-etoposide is practicable, well tolerated and able to lead a small statistically significant benefit in progression-free survival (PFS), but not in overall survival (OS), the primary end-point, respect to standard chemotherapy alone.

Two hundred and four patients were randomized to receive a combination of either cisplatin or carboplatin and etoposide for a maximum of 6 cycles or the same regimen with bevacizumab (7.5 mg/kg). Patients randomized to experimental arm continued bevacizumab alone as maintenance therapy until disease progression or for a maximum of 18 courses. The results showed a non-significant improvement in OS, with a median of 8.9 months in the chemotherapy arm compared with 9.8 months in the bevacizumab arm (HR: 0.78; 95% CI, 0.58 to 1.06; P=0.113); median PFS was 5.7 vs. 6.7 months, in favor to bevacizumab treatment (HR: 0.7; 95% CI, 0.54 to 0.97; P=0.030).

The survival results obtained in this trial are consistent with those of prior studies performed using anti-angiogenic agents in SCLC (3,4). For example, these data are similar to those obtained in the SALUTE phase II trial, that randomized 102 patients to the same regimens; this study met its primary end-point of improvement in PFS (from 4.4 to 5.5 months; HR: 0.53; 95% CI, 0.32 to 0.86), but similarly no statistically significant benefit in OS was observed (3).

As underlined by Dr. Goto (1) and also in editorial of Neal and Wakelee in the Journal of Clinical Oncology (5), the planned survival improvement was ambitious (1-year survival rate from 40% to 58%, corresponding to a median OS from 9 to 15 months) and the relative small sample size does not allow to demonstrate a possible smaller survival benefit. This optimistic goal was chosen, when planning this study, taking into account the feasibility in term of accrual of a non-profit study in this disease and that the government funding body (AIFA) would have considered for practice-changing in SCLC only a clinically significant survival improvement, given the toxicity and cost of bevacizumab.

When primary objective of this trial was planned, had the bar been raised too high? Higher than established by ASCO Perspective for example in squamous cell lung cancer (improvement in OS of 2.5–3 months with a HR of 0.77–0.80) (6), but the only reasonable considering costs, sustainability and feasibility of a non-profit trial in our country and, anyway, plausible accounting the results achieved with bevacizumab in other tumor types (7). In this context, the absence of predictive factors of anti-angiogenic agents is also a significant limiting factor.

Considering the reported OS HR of 0.78, the doubt remains as to whether a larger trial with a more modest, but clinically relevant, end-point (i.e., of a 3-month improvement) might have been met. This consideration, as also cited by Goto, is relevant also keeping in mind the survival benefit obtained with bevacizumab combined with carboplatin-paclitaxel in advanced NSCLC (from 10.3 to 12.3 months, with an HR of 0.79) (8). Moreover, it is interesting to speculate, considering the statistically significant OS benefit in patients who received bevacizumab maintenance according a landmark analysis, whether using bevacizumab also after progression combined with later therapy lines could have yielded additional benefit.

Also Goto underlines these findings and, therefore, another disappointing result, but how good is it? This trial is negative, but the PFS improvement observed, as in others performed with similar drugs, justify, in our opinion, further studies with new anti-angiogenic drugs in SCLC, in particular in the maintenance strategy. The possibility to maintain open the door to further investigation with anti-angiogenesis in SCLC is also related to recent results with immunotherapy in pre-treated SCLC patients (9) and the strong rational to combined anti-angiogenic agents and immunotherapy (10). In fact, a trial of combined immunotherapy, chemotherapy and anti-angiogenic treatment as first-line strategy is under consideration within the GOIRC cooperative group for advanced SCLC.

Acknowledgements

The study GOIRC-AIFA FARM6PMFJM was funded by the Agenzia Italiana del Farmaco (AIFA) and Bevacizumab was provided free of charge by Roche (Italy).

Footnote

Conflicts of Interest: The authors have no conflicts of interest to declare.

References

1. Goto Y. Another disappointing result, but how good is it? J Thorac Dis 2017;9:1426-8. [Crossref] [PubMed]
2. Tiseo M, Boni L, Ambrosio F, et al. Italian, Multicenter, Phase III, Randomized Study of Cisplatin Plus Etoposide With or Without Bevacizumab as First-Line Treatment in Extensive-Disease Small-Cell Lung Cancer: The GOIRC-AIFA FARM6PMFJM Trial. J Clin Oncol 2017;35:1281-7. [Crossref] [PubMed]
3. Spigel DR, Townley PM, Waterhouse DM, et al. Randomized phase II study of bevacizumab in combination with chemotherapy in previously untreated extensive-stage small-cell lung cancer: results from the SALUTE trial. J Clin Oncol 2011;29:2215-22. [Crossref] [PubMed]
4. Ready NE, Pang HH, Gu L, et al. Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance). J Clin Oncol 2015;33:1660-5. [Crossref] [PubMed]
5. Neal JW, Wakelee HA. Elusive Target of Angiogenesis in Small-Cell Lung Cancer. J Clin Oncol 2017;35:1269-71. [Crossref] [PubMed]
6. 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 2014;32:1277-80. [Crossref] [PubMed]
7. Hurwitz H, Fehrenbacher L, Novotny W, et al. Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 2004;350:2335-42. [Crossref] [PubMed]
8. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med 2006;355:2542-50. [Crossref] [PubMed]
9. Antonia SJ, López-Martin JA, Bendell J, et al. Nivolumab alone and nivolumab plus ipilimumab in recurrent small-cell lung cancer (CheckMate 032): a multicentre, open-label, phase 1/2 trial. Lancet Oncol 2016;17:883-95. [Crossref] [PubMed]
10. Manegold C, Dingemans AC, Gray JE, et al. The Potential of Combined Immunotherapy and Antiangiogenesis for the Synergistic Treatment of Advanced NSCLC. J Thorac Oncol 2017;12:194-207. [Crossref] [PubMed]