Dr Zhonglin Hao Discusses Current Research, Clinical Practice in SCLC

Zhonglin Hao, MD, PhD, is a professor of medicine and co-leader of the Thoracic Oncology Program at the National Cancer Institute (NIH)-designated Markey Cancer Center, University of Kentucky. Hao is board-certified in hematology and oncology and is the lead author of a recent review article, “Current Strategies for Extensive Stage Small Cell Lung Cancer Beyond First-Line Therapy,” which discusses the array of approaches investigators are pursuing in ES-SCLC.¹ The American Journal of Managed Care^® discussed issues raised in the article as well as current trends in clinical practice.

AJMC®: When you see patients at the Markey Cancer Center who have relapsed small cell lung cancer (SCLC), have they typically been treated with chemotherapy, or are most receiving first-line immune checkpoint inhibitors at this point?

Hao: These patients have typically received immunochemotherapy upfront followed by a maintenance immune checkpoint inhibitor, such as atezolizumab or durvalumab, based on the current best evidence from the Impower 133 trial or the CASPIAN trial. Patients from community practice will have received 1 to 2 more lines of therapy usually. These include the newly approved lurbinectedin and/or irinotecan.

AJMC^®: One strategy discussed in relapsed SCLC is combining lurbinectedin with doxorubicin. Results from the ATLANTIS study showed the trial failed to meet its end point in overall survival but still showed some benefit, with less toxicity than the comparator arm. What are your thoughts on the future use of this combination?

Hao: ATLANTIS did not meet its primary overall survival (OS) objectives when lurbinectedin plus doxorubicin was compared with either cyclophosphamide + doxorubicin + vincristine, which we call it the CAV regimen, or topotecan. The OS curves were overlapping. Although this combination seemed less toxic than the control arm, it is not clear whether doxorubicin added anything, since the lurbinectedin alone arm was not included. When you compare ATLANTIS with the lurbinectedin registry trial, the overall response rate (ORR), median progression free survival (PFS) and median OS numbers are almost the same. I have not seen how many patients have received the CAV regimen versus topotecan in the control arm. We know that topotecan is also more toxic and less efficacious than the platinum etoposide retreatment from the French experience. Therefore, the future for this combination is not clear.

AJMC^®: In your opinion, of the 2 combinations being studied with lurbinectedin (irinotecan and paclitaxel), which offers the most promise? Do these combinations have pluses and minuses?

Hao: Single agent irinotecan and paclitaxel are both well tolerated and are frequently used in this setting. Combination treatment with lurbinectedin increased the overall response rate (ORR) significantly in both cases. However, it remains unclear whether the increased response rate means much in this population, since the combination could certainly increase toxicities. Past experiences seem to indicate limited value of conventional combination chemotherapy that seeks to kill indiscriminately. In my opinion, we need to explore novel targets instead of indulging in combining existing agents.

AJMC^®: You are studying the ATR kinase inhibitor berzosertib with topotecan in SCLC. Can you discuss the mechanism of this combination and which patient populations you believe may benefit?

Hao: Sure, small cell lung cancer cells replicate their DNA rapidly and the cell cycle machinery is under enormous replicative stress. ATR becomes more essential in this case. It ensures cancer cells have enough building blocks to complete DNA replication; damaged DNA is repaired before they proceed to cell division. It also stabilizes the replication fork, so they do not collapse while DNA is being repaired. Adding ATR inhibitor to DNA damaging agent like topotecan proved to be synergistic and the combination is synthetically lethal to cancer cells. So far, the combination seems benefit all patients regardless of platinum resistance status. Hence, this is a good approach especially for those cancer that are platinum resistant.

AJMC^®: You discussed the frustrating search for biomarkers in SCLC but noted that EZH2 [enhancer of zeste homolog 2] inhibition may offer a potential bright spot. What studies are planned in this area?

Hao: EZH2 is a histone methyltransferase. EZH2 inhibitor overcomes chemoresistance in preclinical studies. In addition, EZH2 is also part of an evolutionally conserved pathway that silences MHC class I antigen presentation and enables immune escape. So, a new phase I study is on the way from ETCTN combining EZH2 inhibitor with chemotherapy and immunotherapy, aimed at improving response to both chemotherapy and immunotherapy. Anish Thomas [MBBS, MD] of NIH is the [principal investigator] for this study. If the combination is tolerated well, the hope is that survival will be improved ultimately in relapsed patient population.

AJMC^®:Which patients will benefit if results from RESILIENT show benefits from liposomal irinotecan injection?

Hao: The RESILIENT phase 3 will inform us the role of liposomal irinotecan in small cell lung cancer patients progressed on or after patients receiving platinum plus etoposide at limited or extensive stage. Both platinum sensitive and resistant patients are included. They may receive immunotherapy as maintenance or as a sole second-line agent. However, these patients cannot receive prior topoisomerase I inhibitor.

AJMC^®:Given the known treatment challenges, side effects, and costs of CAR T-cell therapy, if these studies advance in SCLC, what steps would be needed to ensure representative participation of patients who have this condition?

Hao: Excellent question. Small cell lung cancer patients are heavy smokers invariably, they are in bad shape when the disease recurs. The disease progresses rapidly, and patients are disadvantaged socially and economically. My sense is that CAR-T cell therapy may not be for your average patients to ensure safety in the trial, at least initially. CAR-T cell therapy may be for those young patients, or with good performance and fewer comorbidities. And those patients whose disease progresses relatively slowly until we find it is safe to include the average patients seen in the practice.

Reference

Hao Z, Veedu JS. Current strategies for extensive-stage small cell lung cancer beyond first-line therapy. Clin Lung Cancer. Published online September 17, 2021. DOI:https://doi.org/10.1016/j.cllc.2021.09.003