Pembrolizumab and other immunotherapies in patients with extensive-stage small-cell lung cancer—are we entering a new era?
Editorial

Pembrolizumab and other immunotherapies in patients with extensive-stage small-cell lung cancer—are we entering a new era?

Jan Norum1,2

1Department of Clinical Medicine, Faculty of Health Science, UiT-The Arctic University of Norway, Tromsø, Norway; 2Department of Surgery, Finnmark Hospital Trust, Hammerfest, Norway

Correspondence to: Jan Norum, MD, PhD. Department of Surgery, Finnmark Hospital Trust, N-9600 Hammerfest, Norway. Email: jan.norum@uit.no.

Provenance: This is an invited Editorial commissioned by Section editor Dr. Wei Xu, MD (Division of Respiratory Disease, Department of Geriatrics, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China).

Comment on: Ott PA, Elez E, Hiret S, et al. Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 2017;35:3823-9.


Submitted Mar 30, 2018. Accepted for publication Apr 11, 2018.

doi: 10.21037/tcr.2018.04.12


Introduction

Small cell lung cancer (SCLC) is a very lethal and aggressive subtype of lung cancer, responsible for about 15% of all lung cancers (1). SCLC has a high somatic mutation burden and a strong association to tobacco use (2). In most countries, including Norway, a combination of cisplatin and etoposide has been employed as first line therapy for almost two decades (3-5). In cases of reduced kidney function, cisplatin has often been replaced by carboplatin. Four cycles have been the standard of care and prolonged therapy has not added any survival gain (6). Due to increased toxicity, the addition of granulocyte colony-stimulating factor (G-CSF) has not been recommended (7). Despite the fact that platinum containing regimens have shown high response rates (70–90%) (1,8-11), the prognosis of SCLC has been poor with a 2-year overall survival (OS) of only 5% (1,9,10).

Patients responding on a platinum based regimen (first line setting) and having a good performance status may be offered second line therapy (3,12). Whereas a platinum regimen may be re-implemented in late relapses (>3 months), a combination of adriamycin, vincristine and cyclophosphamide (ACO) has frequently been employed in early recurrence. Topotecan is another alternative and it is the present recommended second line therapy in United States, European Union, and Japan (13-15). Radiotherapy should always be kept in mind as an excellent supplement when palliation is needed.

Despite a response rate of up to 20% in second line therapy, the responses have been of short duration with very limited effect on OS. Consequently, there is an urgent need for new drugs/regimens providing better outcome. During the very last years, various new generation of immunotherapies have got significant attention and promising results have been achieved.


Pembrolizumab, an anti programmed death 1 (PD-1) immunotherapy, in SCLC

PD-1, an immune checkpoint receptor, is primarily expressed on activated T and B cells (1,16). Some tumors exploit the PD-1 pathway by constitutively expressing programmed death ligand 1 (PD-L1) or adaptively upregulating PD-L1 expression to evade immune attack and allowing growth. The PD-1 pathway is therefore a target for cancer immunotherapy. Pembrolizumab is a high-affinity humanized IgG highly selective monoclonal antibody against PD-1 that has shown important clinical activity in multiple tumor types (17). Especially, tumors with membranous PD-L1 expression on more than 50% of tumor cells have shown significant response to pembrolizumab therapy (18,19). Back in 2016, the KEYNOTE-010 study (1) was published and became in several countries a fundament for the implementation of this drug as standard therapy in advanced non-small cell lung cancer (NSCLC). SCLC is also a potential target for checkpoint immunotherapy as PD-L1, B7-H3 and B7-H4 are commonly present in this tumor. This suggests that immunotherapy agents alone or in combinations may be effective in a subset of these patients (20). However, until recently, no studies exploring pembrolizumab in extensive SCLC have been reported (15).

Ott and colleagues (15) got their work on pembrolizumab in extensive SCLC published in the Journal of Clinical Oncology in late 2017. Patients with a PD-L1 expression in ≥1% of tumor cells were available for the study. A total of 163 patients were screened for enrolment and 145 patients had available biopsy samples available for PD-L1 analysis. Forty-six patients (31.7%) tested positive, but 15 out of them did not meet the inclusion criteria and seven were excluded of various reasons. remaining 24 patients for the final analysis. Median age was 60.5 years (41–80 years). The primary endpoints were safety and efficacy, and the objective response rate (ORR) was the primary efficacy endpoint. Pembrolizumab was well tolerated. Only 2 patients (8%) experienced treatment related grade 3–5 adverse events (AEs). Arthralgia, asthenia and rash were the most common adverse effects. The ORR was 33% and one complete remission (CR) (4.2%) was achieved during a median follow-up of 9.8 months (range, 0.5–24 months). The median duration of response was 19.4 months. These figures were impressive as patients had undergone standard therapy (cisplatin and etoposide had been employed as first line therapy in all cases) and most of them (21 of 24 patients) had received two or more regimens prior to inclusion.


Scientific and clinical relevance and beyond

The study of Ott et al. (15) is the first study of pembrolizumab in heavily pre-treated extensive stage SCLC. Looking at the primary endpoints, it revealed pembrolizumab a safe and tolerable drug with few serious AEs. This is in accordance with several other studies in various groups of patients (18,21). The finding is promising and should encourage researchers to run larger studies employing pembrolizumab in SCLC.

The ORR of 33% and a median duration of 19.4 months was remarkable. However, some selection criteria should be noticed when considering this finding. Patients selected for the study had a good performance status (ECOG 0 and 1). Furthermore, OS was not the primary endpoint of the study and only 24 patients were enrolled. The group consisted of patients with histologically confirmed SCLC or pulmonary neuroendocrine tumor. However, only one patient had the latter histology and consequently, the findings generally represents the SCLC histology.

Despite the results are impressive, they call for a larger study confirming the ORR, OS and the long lasting response. It is obvious that national health care services and insurers will not base their coverage of pembrolizumab therapy on a single study including only 24 patients. Looking at the median follow-up of 9.8 months, long-term survival data is still too immature to determine its overall impact on the prognosis of SCLC. Knowing the cost of pembrolizumab therapy and its possible budget impact (16), larger studies with efficacy (ORR and OS) as the primary endpoint will be requested. Furthermore, quality of life (QoL) instruments should be implemented, making it possible to clarify quality adjusted life years (QALYs) gained. Consequently, cost-effectiveness analysis should be implemented in future large-scale studies. If not included, transparency will be of utmost importance making details on survival gain available and a possibility for national health care services to indicate QALYs gained. Thus, making it possible to run health technology assessments (HTAs) to clarify whether pembrolizumab should be implemented into national guidelines/standards for the treatment of SCLC (16).

SCLC occurs almost exclusively among heavy smokers. Patients frequently asks their doctors what they can do to improve their own outcome. Various nutrition supplements and non-proven therapies are often on patients’ mind in this setting. However, recently it was shown that continuing tobacco smoking during pembrolizumab therapy (KEYNOTE-001) did significantly influence on treatment outcome (communication Hellmann MD, WCLC 2015). When progression free survival (PFS) vary by as much as 50%, depending on smoking status during therapy, it is obvious that patients may add significant life expectancy, simply by quitting smoking. However, this has to be confirmed and published in international medical journals with a peer review system. Consequently, SCLC patients’ smoking status should be monitored during immunotherapy in future large-scale studies. From a societal perspective, the spending of millions of dollars to improve and prolong lung cancer patients’ lives calls for a cooperation from the patients (stop smoking) to optimize their treatment outcome.

The study by Ott and colleagues (15) documented a long lasting response (median, 19.4 months) and one CR was achieved. In such a setting, long lasting therapies will introduce significant treatment costs to health care insurers and public hospital trusts. Consequently, when to stop therapy when a CR has been achieved, will also be an important issue in future studies.

Other immunotherapies have been tested in SCLC. Both other PD-1 monoclonal antibodies (in example nivolumab) and monoclonal antibodies that activate the immune system by targeting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) (in example ipilimumab) have been tested. The latter is a protein receptor that downregulates the immune system. One such major phase III trial included 1,132 and 954 patients received at least one dose of study therapy (NCT01450761) (22). In this study, ipilimumab (10 mg/kg every 3 weeks) versus placebo was tested in combination with standard first-line therapy in extensive stage SCLC. The median OS did not reveal any significant difference (11.0 and 10.9 months) between the two groups. The combined therapy increased toxicity, but did not prolong OS versus chemotherapy alone. The CheckMate 032 study (23) evaluated nivolumab monotherapy along with nivolumab in combination with ipilimumab in pre-treated patients suffering from extensive SCLC. They enrolled patients regardless of PD-L1 status. The ORR rates were 10% (nivolumab 3 mg/kg), 33% (nivolumab 1 mg/kg plus ipilimumab 1 mg/kg), 23% (nivolumab 1 mg/kg plus ipilimumab 3 mg/kg) and 19% (nivolumab 3 mg/kg plus ipilimumab 1 mg/kg), respectively. Combined therapy did also increase toxicity in this study. CheckMate 331 is an ongoing phase III study exploring nivolumab monotherapy for pre-treated advanced SCLC and CheckMate 451 is a phase III, randomized, double-blind study evaluating nivolumab monotherapy or in combination with ipilimumab versus placebo as maintenance therapy after platinum-based first-line chemotherapy in advanced SCLC (24). Primary endpoints include OS and PFS and the trial aims to recruit 810 patients.

The mentioned studies in SCLC indicate that pembrolizumab, nivolumab and ipilimumab are promising new immunotherapies in SCLC (25). In the near future, atezolizumab and durvalumab will probably be added to this list. Atezolizumab is a new checkpoint inhibitor that targets PD-L1. Compared to the mentioned PD-1 inhibitors, it interferes with the interaction between PD-L1 and the PD-1 as well as PD-L1 and B7-1, but does not interfere with the interaction between PD-L2 and PD-1 (2). This could have therapeutic implications when combination therapies are considered. Present data suggests that in SCLC combined PD-1 and CTLA-4 blockade (in example by combining nivolumab and ipilimumab) may produce a higher tumor response rate than PD-1 blockade alone. However, combined therapy is associated with an increased toxicity (22,23). Several large studies are ongoing and combination therapy has shown higher tumor response rates, but the significant ORR in the KEYNOTE-028 study (15), employing single drug pembrolizumab, is remarkable and should be considered carefully when future studies are planned and treatment guidelines are made.

Despite impressive effects of the new generation of immunotherapies, it should be kept in mind that the great majority of SCLC patients still do not respond to PD-1/PD-L1 inhibition. Consequently, a large and growing population have no benefit of these new therapies. In the study by Ott and colleagues (15), less than one-third (31.7%) tested positive for PD-L1 expression. This is half the frequency documented in the KEYNOTE-10 study in NSCLC (1). In NSCLC, the ORR has been shown varying with the cut off level of PD-L1 expressing cells (≥1%, ≥5% or ≥50%). This should also be explored in the SCLC setting. When national health services and public insurers are considering which group of patients should have these costly therapies covered, more details on response rates among various subgroups would be beneficial. Especially, when the cost per QALY is close or above frequently employed cut-off levels, such information may be crucial (16).

In summary, further evaluations are necessary to establish the role, order and optimal combination of immunotherapy in SCLC. Present studies are promising and we may be about to enter a new era for patients suffering from this highly malignant and deadly cancer. Checkpoint inhibitors, especially PD-1/PD-L1 inhibition therapy and CTLA-4 blockage, have shown notable activity in lung cancer and have been approved in the treatment of certain subgroups of patients with NSCLC. The introduction of these new drugs has revolutionized the treatment of NSCLC. Present data indicate that the time for immunotherapy in SCLC is about to come. Ott and co-workers’ study (15) indicates single drug pembrolizumab therapy a possible useful therapeutic approach for SCLC. However, it should be kept in mind that the great majority of patients are still not candidates for this new therapy.


Acknowledgements

The service offered by the library at the UiT-The Arctic University of North Norway in Tromsø was greatly appreciated.


Footnote

Conflicts of Interest: The author has no conflicts of interest to declare.


References

  1. Pesch B, Kendzia B, Gustavsson P, et al. Cigarette smoking and lung cancer. Relative risk estimates for the major histological types from a pooled analysis of case control studies. Int J cancer 2012;131:1210-9. [Crossref] [PubMed]
  2. Somasundaram A, Burns TF. The next generation of immunotherapy: keeping lung cancer in check. J Hematol Oncol 2017;10:87. [Crossref] [PubMed]
  3. Früh M, De Ruysscher D, Popat S, et al. Small-cell lung cancer (SCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2013;24 Suppl 6:vi99-105. [Crossref] [PubMed]
  4. Mascaux C, Paesmans M, Berghmans T, et al. A systematic review of the role of etoposide and cisplatin in the chemotherapy of small cell lung cancer with methodology assessment and meta-analysis. Lung Cancer 2000;30:23-36. [Crossref] [PubMed]
  5. Pujol JL, Carestia L, Daurès JP. Is there a case for cisplatin in the treatment of small-cell lung cancer? A meta-analysis of randomized trials of a cisplatin-containing regimen versus a regimen without this alkylating agent. Br J cancer 2000;83:8-15. [Crossref] [PubMed]
  6. Sculier JP, Berghmans T, Castaigne C, et al. Maintenance chemotherapy for small cell lung cancer: a critical review of the literature. Lung cancer 1998;19:141-51. [Crossref] [PubMed]
  7. Bunn PA Jr, Crowley J, Kelly K, et al. Chemotherapy with or without granulocyte-macrophage colony stimulating factor in the treatment of limited-stage small-cell lung cancer: a prospective phase III randomized study of the Southwest Oncology Group. J Clin Oncol 1995;13:1632-41. [Crossref] [PubMed]
  8. Amarasena IU, Chatterjee S, Walters JA, et al. Platinum versus non-platinum chemotherapy regimens for small cell lung cancer. Cochrane Database Syst Rev 2015;8:CD006849. [PubMed]
  9. Alvarado-Luna G, Morales-Espinosa D. Treatment for small cell lung cancer, where are we now?-a review. Transl Lung Cancer Res 2016;5:26-38. [PubMed]
  10. Hurwitz JL, McCoy F, Scullin P, et al. New advances in the second-line treatment of small-cell lung cancer. Oncologist 2009;14:986-94. [Crossref] [PubMed]
  11. Rossi A, Di Maio M, Chiodini P, et al. Carboplatin or cisplatin-based chemotherapy in first-line treatment of small-cell lung cancer. The COCIS-meta-analysis of individual patient data. J Clin Oncol 2012;30:1692-8. [Crossref] [PubMed]
  12. Rudin CM, Ismaila N, Hann CL, et al. Treatment of small-cell lung cancer: American Society of Clinical Oncology endorsement of the American College of Chest Physicians guieline. J Clin Oncol 2015;33:4106-11. [Crossref] [PubMed]
  13. O’Brien ME, Ciuleanu TE, Tsekov H, et al. Phase III trial comparing supportive care alone with supportive care with oral topotecan in patients with relapsed small-cell lung cancer. J Clin Oncol 2006;24:5441-7. [Crossref] [PubMed]
  14. von Pawel J, Gatzemeier U, Pujol JL, et al. Phase ii comparator study of oral versus intravenous topotecan in patients with chemosensitive small-cell lung cancer. J Clin Oncol 2001;19:1743-9. [Crossref]
  15. Ott PA, Elez E, Hiret S, et al. Pembrolizumab in Patients With Extensive-Stage Small-Cell Lung Cancer: Results From the Phase Ib KEYNOTE-028 Study. J Clin Oncol 2017;35:3823-9. [Crossref] [PubMed]
  16. Norum J, Antonsen MA, Tollåli T, et al. Pembrolizumab as second line therapy in non-small cell lung cancer in northern Norway: budget impact and expected gain – a model-based analysis. ESMO Open 2017;2:e000222. [Crossref] [PubMed]
  17. Sharma P, Allison JP. The future of immune checkpoint therapy. Science 2015;348:56-61. [Crossref] [PubMed]
  18. 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. [Crossref] [PubMed]
  19. Carbognin L, Pilotto S, Milella M, et al. Differential activity of Nivolumab, Pembrolizumab and MPDL3280A according to the tumor expression of Programmed Death-Ligand-1 (PD-L1): sensitivity analysis of trials in melanoma, lung and genitourinary cancers. PLoS One 2015;10:e0130142. [Crossref] [PubMed]
  20. Schalper KA, Carvajal-Hausdorf DE, McLaughlin JF, et al. Objective measurement and significance of PD-L1, B7-H3, B7-H4 and TILs in small cell lung cancer (SCLC). ASCO Meeting Abstracts 2016;34:8566.
  21. Garon EB, Naiyer AR, Rina H, et al. Pembrolizumab for the treatment of non-small-cell lung cancer. N Engl J Med 2015;372:2018-28. [Crossref] [PubMed]
  22. Reck M, Luft A, Szczesna A, et al. Phase III randomized trial of ipilimumab plus etoposide and platinum versus placebo plus etoposide and platinum in extensive-stage small-cell lung cancer. J Clin Oncol 2016;34:3740-8. [Crossref] [PubMed]
  23. Antonia SJ, Lopez-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]
  24. Ready N, Owonikoko TK, Postmus PE, et al. CheckMate 451: a randomized, double-blind, phase III trial of nivolumab (nivo), nivo plus ipilimumab (ipi), or placebo as maintenance therapy in patients (pts) with extensive-stage disease small cell lung cancer (ED-SCLC) after first-line platinum-based doublet chemotherapy (PT-DC). ASCO Meeting Abstracts 2016;34:TPS8579.
  25. Tanvetyanon T, Gray JE, Antonia SJ. PD-1 checkpoint blockade alone or combined PD-1 and CTLA-4 blockade as immunotherapy for lung cancer? Expert Opin Biol Ther 2017;17:305-12. [Crossref] [PubMed]
Cite this article as: Norum J. Pembrolizumab and other immunotherapies in patients with extensive-stage small-cell lung cancer—are we entering a new era? Transl Cancer Res 2018;7(Suppl 5):S553-S557. doi: 10.21037/tcr.2018.04.12