Immune checkpoint inhibitors are a reality for the treatment of patients with NSCLC, and if approved for SCLC, would be a treatment breakthrough we have not seen for decades.
Immune checkpoint inhibitors are being utilized in thousands of lung cancer patients worldwide, and yielding unprecedented improvements in overall survival and quality of life. In lung cancer, biomarker testing is now an essential part of patient care, since overexpression of programmed death ligand 1 (PD-L1) as determined by a companion diagnostic test is required prior to initiating therapy with the immune checkpoint inhibitor pembrolizumab, approved in October 2015. In the current issue of ONCOLOGY, Drs. Marrone and Brahmer provide an excellent review of the current status of immune checkpoint inhibitors in both non–small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC). While the clinical efficacy of these drugs is undeniable, the dialogue has shifted to the dependability of PD-L1 as a biomarker, and the associated high cost of care.
In 2015, three randomized phase III trials,[2-4] one of which included only patients with PD-L1–positive tumors, found the immune checkpoint inhibitors nivolumab and pembrolizumab to have superior efficacy and less toxicity compared with second-line docetaxel chemotherapy in patients with NSCLC. Notable to each trial was an impressive improvement in overall survival, which is repeatedly referred to as the tail of the curve. In contrast, progression-free survival was marginally improved or worse for patients treated with checkpoint inhibition. For the first time, agents blocking a single pathway have shown significant benefit across multiple tumor types, with US Food and Drug Administration (FDA) approval in NSCLC, melanoma, and bladder and renal cell carcinoma. Now more than 1,000 immune checkpoint clinical trials are underway. The goal of these trials is to bring up the “tail of the curve”; to that end, many possible treatment avenues are being explored, including combinations of immunotherapy with radiation, chemotherapy, targeted therapy, and other checkpoint inhibitors. Some studies are also investigating checkpoint inhibitors as front-line therapy-an approach that may soon be considered viable, given the reported results of the phase I KEYNOTE-001 trial and the fact that the phase III KEYNOTE-024 trial met its primary and secondary endpoints of progression-free survival and overall survival when comparing first-line pembrolizumab with platinum-based chemotherapy in NSCLC patients with PD-L1 expression in ≥ 50% of tumor samples.
The efficacy results reported in the aforementioned trials lend undisputable support to the use of immune checkpoint inhibitors in the treatment of patients with NSCLC. However, clinicians treating these patients are demanding a biomarker test to use as an aid in selecting therapy. Despite the controversy over the accuracy of PD-L1 expression as an inclusive biomarker, it is required by both the FDA and European Union regulatory authorities for patient selection prior to initiating therapy with pembrolizumab. PD-L1 seems plausible biologically as a predictive biomarker, given that the goal of treatment is to block the programmed death 1 (PD-1)/PD-L1 interaction. Nevertheless, the fact that PD-L1 when positive is associated with an approximately 30% rate of response to checkpoint inhibitor therapy but when negative is associated with a 10% response indicates that its use as a biomarker requires further refinement. Indeed, several factors make the use of PD-L1 as a biomarker problematic, including tumor heterogeneity, changes in levels of PD-L1 expression with therapy, and assay variability.[8-10] Therefore, other avenues for predicting response are being explored, including chemokine gene expression signature, T-cell clonality, and mutation burden,[13,14] albeit at a higher cost.
As pointed out by Drs. Marrone and Brahmer in their review, the costs of treatment with these checkpoint inhibitor medications are substantial. The hope that development of multiple agents targeting the same signaling pathway (ie, PD-1 and PD-L1) would facilitate drug price competition has been a pipe dream. Given that the incidence of lung cancer is significantly higher than that of other tumor types for which treatment with these agents is approved, the burden on the healthcare system has led to FDA approval of checkpoint inhibitors for limited indications outside of the United States and European Union. A recent review by Tartari et al estimated the cost per patient of NSCLC treatment with a checkpoint inhibitor to be in the thousands of dollars, and the worldwide annual cost of nivolumab based on World Health Organization estimates of the global incidence of lung cancer is $1.7 billion, and $3.8 billion for pembrolizumab. A recent cost-based effectiveness evaluation was performed comparing nivolumab vs docetaxel in patients enrolled in the CheckMate 057 study in the Swiss healthcare system; it was determined that current pricing makes nivolumab not cost-effective in nonsquamous NSCLC compared with docetaxel, but that reduction in prices, dose, or treatment duration may improve the incremental cost-effectiveness ratio below a willingness-to-pay ratio. Another evaluation of the cost effectiveness of nivolumab compared with docetaxel and erlotinib was performed in the Canadian healthcare system; in this study, nivolumab was found to cost an additional $151,560 and $140,601 per quality-adjusted life-year gained when compared with treatment with docetaxel and erlotinib, respectively.
Immune checkpoint inhibitors are a reality for the treatment of patients with NSCLC, and if approved for SCLC, would be a treatment breakthrough we have not seen for decades. We now need to find tangible biomarkers to inform patient selection for treatment, understand the optimal duration of therapy, optimize the management of toxicities, and find ways to align the factors that could maximize patient and societal benefit from these exciting new therapies.
Financial Disclosure:Dr. Horn is compensated for her service on the advisory boards of AbbVie, Genentech, and Lilly; and holds uncompensated positions on the advisory boards of Boehringer Ingelheim and Bristol-Myers Squibb. She is also a consultant to Bayer (compensated) and Xcovery (uncompensated). Dr. Beckermann has no significant financial interest in or other relationship with the manufacturer of any product or provider of any service mentioned in this article.
1. Marrone KA, Brahmer JR. Using immune checkpoint inhibitors in lung cancer. Oncology (Williston Park). 2016;30:713-21.
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. 2015;373:123-35.
3. Borghaei H, Paz-Ares L, Horn L, et al. Nivolumab versus docetaxel in advanced nonsquamous non-small-cell lung cancer. N Engl J Med. 2015;373:1627-39.
4. Herbst RS, Baas P, Kim DW, et al. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016;387:1540-50.
5. Garon EB, Rizvi NA, Hui R, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med. 2015;372:2018-28.
6. Merck & Co, Inc. Merck’s pembrolizumab demonstrates superior progression-free and overall survival compared to chemotherapy as first-line treatment in patients with advanced non-small cell lung cancer [news release]. Kirkland, Quebec, Canada. June 16, 2016. http://www.merck.ca/Assets/en/pdf/Merck%20Canada%20-%20News%20Release%2006%2016%2016%20-%20Topline%20Results%20from%20KEYNOTE-024%20-%20EN.pdf. Accessed July 13, 2016.
7. Fehrenbacher L, Spira A, Ballinger M, et al. Atezolizumab versus docetaxel for patients with previously treated non-small-cell lung cancer (POPLAR): a multicentre, open-label, phase 2 randomised controlled trial. Lancet. 2016;387:1837-46.
8. Kondo A, Yamashita T, Tamura H, et al. Interferon-gamma and tumor necrosis factor-alpha induce an immunoinhibitory molecule, B7-H1, via nuclear factor-kappaB activation in blasts in myelodysplastic syndromes. Blood. 2010;116:1124-31.
9. Akbay EA, Koyama S, Carretero J, et al. Activation of the PD-1 pathway contributes to immune escape in EGFR-driven lung tumors. Cancer Discov. 2013;3:1355-63.
10. McLaughlin J, Han G, Schalper KA, et al. Quantitative assessment of the heterogeneity of PD-L1 expression in non-small-cell lung cancer. JAMA Oncol. 2016;2:46-54.
11. Messina JL, Fenstermacher DA, Eschrich S, et al. 12-Chemokine gene signature identifies lymph node-like structures in melanoma: potential for patient selection for immunotherapy? Sci Rep. 2012;2:765.
12. McGranahan N, Furness AJ, Rosenthal R, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463-9.
13. Campesato LF, Barroso-Sousa R, Jimenez L, et al. Comprehensive cancer-gene panels can be used to estimate mutational load and predict clinical benefit to PD-1 blockade in clinical practice. Oncotarget. 2015;6:34221-7.
14. Rizvi NA, Hellmann MD, Snyder A, et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124-8.
15. Tartari F, Santoni M, Burattini L, et al. Economic sustainability of anti-PD-1 agents nivolumab and pembrolizumab in cancer patients: recent insights and future challenges. Cancer Treat Rev. 2016;48:20-4.
16. Matter-Walstra K, Schwenkglenks M, Aebi S, et al. A cost-effectiveness analysis of nivolumab versus docetaxel for advanced non-squamous non-small cell lung cancer including PD-L1 testing. J Thorac Oncol. 2016 Jun 13. [Epub ahead of print]
17. Goeree R, Villeneuve J, Goeree J, et al. Economic evaluation of nivolumab for the treatment of second-line advanced squamous NSCLC in Canada: a comparison of modeling approaches to estimate and extrapolate survival outcomes. J Med Econ. 2016;19:630-44.