“The overall take home message from the Virtual ASCO Annual Meeting this year is that chemoimmunotherapy is effective and beneficial for patients with SCLC,” says Taofeek Owonikoko, MD, PhD, MSCR, who was a session discussant in chemoimmunotherapy at ASCO 2020. Dr. Owonikoko is a Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine.

Programmed death ligand 1 (PD-L1) interacts with PD-1 to inhibit T-cells and the immune system. This pathway is often hijacked by tumors, and antibodies to PD-1 and PD-L1 have therefore been investigated for SCLC treatment. Clinical trials that have tested the combination of chemotherapy and immunotherapy for the treatment of SCLC have not shown notable differences in the efficacy of PD-1 compared with PD-L1 antibodies when combined with chemotherapy.

The efficacy of the anti-PD-1 drug, pembrolizumab, in combination with chemotherapy for the treatment of SCLC was investigated in the KEYNOTE-604 clinical trial.2

“In my opinion, this trial, although negative for its primary endpoint by statistical design, was important. The relative impact that was seen, terms of progression-free survival (PFS) and overall survival (OS), was in the same ballpark as what we saw with the anti-PD-L1 durvalumab and atezolizumab trials combined with chemotherapy, published in the Lancet and the New England Journal of Medicine, respectively,” says Dr. Owonikoko.3,4  “More importantly, the ECOG-ACRIN EA5161 trial was presented this yearand showed both PFS and OS advantage with nivolumab combined with chemotherapy. 5,6 As a result, I do not think the data we have supports a claim that anti-PD-L1 drugs are better than or act differently to anti-PD-1 drugs. Could there be unique differences between anti-PD-L1 and anti-PD-1 drugs? Possibly, however I don’t think we can claim that such unique differences are significant enough to impact the efficacy of each in SCLC.

While chemoimmunotherapy does not help every patient, the positive impact seen in the subset of patients is evident, even in a clinical trial design that does not select patients based on specific biomarkers. According to Dr. Owonikoko, going forward, it is important to determine which SCLC patients benefit from chemoimmunotherapy in order to optimize its benefits. This is the key question in the field right now. “It is going to be hard, but I don’t think it is impossible to define these patients. Many different groups around the world are looking at biomarkers, or exposure to previous therapies in the subset of patients who relapse, or looking at PD-L1 expression and tumor mutational burden,” Dr. Owonikoko notes. “These avenues have shown promise in research but have not held up well when applied to patients being treated in the frontline with chemoimmunotherapy.”

Small cell lung cancer treatment is not effective in all patients

A major obstacle facing the field right now, Dr. Owonikoko explains, is that there is still a large proportion of SCLC lung cancer patients that are not treated; 30% of newly diagnosed cases never receive any treatment. That subset of patients has a significant impact on overall prognosis for this disease when compared with population-based theories. “Another major obstacle is that, although frontline treatment can be effective, the efficacy may not be durable. And once this frontline treatment fails, the treatment options for managing the disease dwindles very quickly,” he says. “Chemotherapy is only effective for a vanishingly small subset of patients, if it even works at all. Furthermore, the duration of that efficacy is such that after maybe one or two restaging scans, the efficacy has worn off and you need to start looking for new ways of managing their disease.

Future perspectives in small cell lung cancer phenotyping and treatment

One of the most promising ideas going forward is the emergence of SCLC stratification in different phenotypes of SCLC. “We have to stop treating SCLC as one uniform disease and recognize that there are likely biologically unique subsets that may or may not respond to different interventions, be it chemotherapy, immunotherapy, or a combination of the two,” says Dr. Owonikoko. “Of course, the first thing that needs to be done is to phenotypically define the distinct subsets in SCLC. These subsets are not necessarily distinguishable by the typical somatic mutations like we have seen in other tumor types, but by more dominant transcriptional activation pathways.”

The early work to tease apart the subset phenotypes would require RNA sequencing, to generate hypotheses, and then prospectively validate the subtypes. RNA sequencing may be impractical as a tool to identify patients for unique treatment approaches given the technical sophistication and time it requires to interpret the data. Therefore, in order to operationalize it, the correlation with protein expression must first be examined, and then traditional immunohistochemistry for patient selection should be trusted.

“There are currently quite a few studies that are being eagerly awaited, especially in limited-stage SCLC. Lots of the research has been conducted in extensive stage disease, but 30% of patients do not fall into this category. There are at least two major trials ongoing in limited stage disease: a national US study (NRG Oncology LU005), the STIMULI trial in Europe which is looking more at a post-chemotherapy maintenance strategy, and the ADRIATIC trial looking at the durvalumab and tremelimumab strategy both as concurrent and consolidation treatment,” says Dr. Owonikoko. 7–9. “With limited stage disease we begin with the same treatment regime that we have been using for the past 25 years of chemotherapy and radiation. Whether adding immunotherapy to that regime will result in better outcomes is what we are eagerly waiting to find out.”

 

Taofeek Owonikoko, MD, PhD, MSCR, Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine, is a board-certified Medical Oncologist and Vice Chair for Faculty Development in the Department of Hematology and Medical Oncology at Emory University School of Medicine. Dr. Owonikoko specializes in the treatment of lung cancer, thyroid cancer, translational research, and early phase drug development in cancers of the aerodigestive tract. He has published over 130 peer reviewed manuscripts in high impact journals and, since 2008, has been designated a Distinguished Cancer Scholar by the Georgia Cancer Coalition.

 

References:

  1. Li Q, Yuan D, Ma C, et al. A new hope: the immunotherapy in small cell lung cancer. Neoplasma. 2016;63(03):342-350. doi:10.4149/302_151001N511
  2. Merck Sharp & Dohme Corp. A Phase 3 Randomized, Double-Blind, Placebo-Controlled Trial of Pembrolizumab (MK-3475/SCH900475) in Combination With Etoposide/Platinum (Cisplatin or Carboplatin) for the First-Line Treatment of Subjects With Extensive Stage Small Cell Lung Cancer (KEYNOTE-604). clinicaltrials.gov; 2020. Accessed July 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03066778
  3. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab plus platinum–etoposide versus platinum–etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. The Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6
  4. Horn L, Mansfield AS, Szczęsna A, et al. First-Line Atezolizumab plus Chemotherapy in Extensive-Stage Small-Cell Lung Cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064
  5. Leal T, Wang Y, Dowlati A, et al. Randomized phase II clinical trial of cisplatin/carboplatin and etoposide (CE) alone or in combination with nivolumab as frontline therapy for extensive-stage small cell lung cancer (ES-SCLC): ECOG-ACRIN EA5161. J Clin Oncol. 2020;38(15_suppl):9000-9000. doi:10.1200/JCO.2020.38.15_suppl.9000
  6. National Cancer Institute (NCI). Randomized Phase II Clinical Trial of Cisplatin/Carboplatin and Etoposide (CE) Alone or in Combination With Nivolumab as Frontline Therapy for Extensive Stage Small Cell Lung Cancer (ED-SCLC). clinicaltrials.gov; 2020. Accessed July 4, 2020. https://clinicaltrials.gov/ct2/show/NCT03382561
  7. Small Cell Lung Carcinoma Trial With Nivolumab and IpiliMUmab in LImited Disease – Full Text View – ClinicalTrials.gov. Accessed July 4, 2020. https://clinicaltrials.gov/ct2/show/NCT02046733
  8. Chemoradiation With or Without Atezolizumab in Treating Patients With Limited Stage Small Cell Lung Cancer – Full Text View – ClinicalTrials.gov. Accessed July 4, 2020. https://clinicaltrials.gov/ct2/show/NCT03811002
  9. AstraZeneca. A Phase III, Randomized, Double-Blind, Placebo-Controlled, Multi-Center, International Study of Durvalumab or Durvalumab and Tremelimumab as Consolidation Treatment for Patients With Limited Stage Small Cell Lung Cancer Who Have Not Progressed Following Concurrent Chemoradiation Therapy (ADRIATIC). clinicaltrials.gov; 2020. Accessed July 1, 2020. https://clinicaltrials.gov/ct2/show/NCT03703297

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