Last year, Dr. Ticiana Leal, Director of the Thoracic Medical Oncology Program at Winship Cancer Institute of Emory University, recorded a continuing medical education (CME)/nursing continuing professional development (NCPD)–accredited activity titled Harnessing Immunotherapy-Based Strategies for Advanced Non–Small Cell Lung Cancer (NSCLC). With numerous developments in the field occurring since recording the activity, including new FDA approvals and clinical trial results, Dr. Leal sat down with Oncology Data Advisor to provide an update on the rapidly evolving field of NSCLC immunotherapy.  

Dr. Leal: The field of thoracic oncology is moving quite rapidly. Even since we last recorded our podcast and video about advances in immunotherapy for non–small cell lung cancer, we've had new approvals of therapies in the frontline setting for patients with advanced non–small cell lung cancer.

For example, we now have approval of a regimen called the POSEIDON regimen. This is the combination of chemotherapy and immunotherapy with the programmed death ligand 1 (PD-L1) inhibitor called durvalumab in combination with the cytotoxic T-lymphocyte–associated antigen 4 (CTLA-4) inhibitor tremelimumab in patients with advanced non–small cell lung cancer whose tumors do not harbor any epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) alteration. This is another strategy in the frontline setting using a CTLA-4 inhibitor for patients with advanced non–small cell lung cancer.

We've also had approval of another agent in combination with chemotherapy, cemiplimab. Cemiplimab, a PD-L1 inhibitor, was previously approved as monotherapy, and now we have approval of cemiplimab in combination with platinum-based chemotherapy for advanced non–small cell lung cancer in the frontline setting.

Based on our last presentation, I had discussed the excitement around tiragolumab, an anti–

T-cell immunoglobulin and ITIM domain (TIGIT) antibody used in the frontline in combination with atezolizumab. We had some really promising data based on the CITYSCAPE, which was a phase 2 trial demonstrating some promising results in patients with PD-L1–high expression. Since then, we've had readout of one of the coprimary end points of the SKYSCRAPER-01 trial, which demonstrated that the combination of tiragolumab with atezolizumab in patients with high PD-L1 tumor expression did not meet the coprimary end point of progression-free survival. However, we're still waiting on the readout of overall survival, and tiragolumab, the anti-TIGIT inhibitor, is still in development for advanced non–small cell lung cancer.

Lastly, another interesting development has occurred. We talked about some promising strategies in the second line looking at how to overcome immunotherapy resistance for patients with advanced non–small cell lung cancer, and we talked about the vascular endothelial growth factor (VEGF) pathway as a potential interesting pathway to target in combination with immunotherapy.

We saw the results of a study presented at the American Society of Clinical Oncology (ASCO) 2022 and published in the Journal of Clinical Oncology, investigating the combination of pembrolizumab with ramucirumab, hitting VEGF as a target to overcome resistance to immunotherapy (IO). This was a positive study in a randomized phase 2 setting demonstrating improved overall survival, and it is a really promising strategy that is moving forward in phase 3 now. Talking about future trials, PRAGMATICA is the next step to confirm these results. PRAGMATICA is a study investigating the combination of pembrolizumab/ramucirumab in the second-line setting, looking at patients who have had prior immunotherapy.

Oncology Data Advisor: Awesome, that was such a comprehensive update to the trials that were talked about in the activity. You touched upon some of the ongoing trials; what are the developments that you're most looking forward to in this coming year?

Dr. Leal: Definitely, there are a lot of ongoing trials. The second-line and beyond space is a very rich field of active investigation, including novel immunotherapy agents as well as adding other agents. There's a lot of interest in seeing the readouts of some of the studies that are looking at poly-ADP ribose polymerase (PARP) inhibitors in combination with immunotherapy. In our presentation, we talked about the SAPPHIRE study, which is a randomized phase 3 trial combining sitravatinib with nivolumab versus docetaxel in previously treated patients. That randomized phase 3 study has completed accrual, and we're waiting for the readout.

Certainly, there's a lot of interest in continuing to improve on the outcomes with ADCs, or antibody-drug conjugates. That's a rich field of active investigation. These agents are not only being investigated in the second line and beyond, but they are also being investigated in the frontline in combination with immunotherapy.

In addition, we're also combining immunotherapy with targeted agents. We're seeing results of studies combining, for example, immunotherapy with Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors. There's a lot of interest in continuing to build upon the success of both immunotherapy as well as targeted therapy. There are multiple ongoing studies that would be too numerous to tell you about, but those are some of the interesting strategies that I'm looking forward to seeing read out in 2023 and beyond.

Oncology Data Advisor: Awesome. Are you currently involved in any clinical trials or research that you'd like to highlight?

Dr. Leal: Definitely. Doing research and clinical care are really what drive me to do what I do every day. Some of the efforts that I'm working on with our multidisciplinary team at Emory include investigating frontline trials looking at ADCs and the combination of ADCs. We have the TROPION study, which is now moving forward in the phase 3 setting. Datopotamab deruxtecan (dato-DXd) is a really interesting agent that is moving forward as a trophoblast cell-surface antigen 2 (TROP2) ADC in the frontline setting. We also have some investigator-initiated trials looking at combining immunotherapy, for example, with interleukin 2 (IL-2), looking at some biomarker end points.

In addition, we have a study in the second-line and beyond setting looking at the combination of pembrolizumab, ramucirumab, and docetaxel. This is a single-arm phase 2 study that we're conducting at Emory. I also conduct phase 2 and phase 3 studies in small cell lung cancer. Currently, we have some interesting studies in that space as well, which we didn't talk about in our presentation, but there's a lot of interest in combining immune checkpoint inhibitors with other agents to overcome resistance in small cell lung cancer. We also have another agent called lurbinectedin, which is approved in small cell. We have an investigator-initiated trial combining lurbinectedin with radiation, and there are a lot of interesting efforts that are ongoing.

I did conduct a study while I was at the University of Wisconsin, a randomized phase 3 study investigating tumor-treating fields, which are delivered using a device. These are electric fields that interfere with mitosis and lead to immunogenic cell death as well. This is a randomized phase 3 study called the LUNAR study that randomized patients to tumor-treating fields in combination with immunotherapy or docetaxel versus the standard of care. This study has recently had a press release demonstrating that it met the primary end point of overall survival, so we'll be talking more about this at future meetings and are excited to present these results.

Oncology Data Advisor: Great, those will all be so exciting to see. My last question is, do you have any strategies for balancing the efficacy of all these novel immunotherapies with their potential toxicities?

Dr. Leal: One of the ongoing challenges of treating patients with advanced non–small cell lung cancer continues to be biomarker selection. I think PD-L1 is our main biomarker. We do need better biomarkers to really tease out, "Should we be using monotherapy? Should we be using combination strategies?" We're now looking at studies trying to really hone in on the impact of, for example, serine/threonine kinase 11 (STK11), Kelch-like ECH-associated protein 1 (KEAP1), and co-mutations in immunotherapy resistance.

One important way to balance out toxicities and benefits is identifying which patient needs combination strategies, using biomarker selection. I think future trials should continue to look at that, because monotherapy, for sure, is certainly very well-tolerated and is associated with excellent quality of life and efficacy. We can really hone in, beyond PD-L1, which patients are most likely to derive benefit versus who really needs the combination strategy of a quadruplet regimen such as what we saw in CheckMate 9LA or now POSEIDON or Empower150. In these trials, you're combining four drugs for a patient with advanced non–small cell lung cancer who may have multiple comorbidities and is struggling with symptoms from their disease. So, I think biomarkers are definitely a big one.

The other thing I think is very important is monitoring. While patients are receiving frontline therapy with immunotherapy or immunotherapy combinations, it's really important to educate the patient and their family members in terms of the potential for side effects and immune-related adverse events that they can occur at any time, even after you discontinue therapy. Educating patients on when to call, not to wait, and to have check-in methods with the patient to make sure that we're recognizing these immune-related adverse events early is really important and crucial in allowing patients to continue on their therapies if they're benefiting from them, avoiding escalation of these side effects to more severe side effects.

The third key point, I think, is working as a multidisciplinary team and getting specialists in early to give their opinions and to help manage some of these immune-related adverse events—working with pulmonology for pneumonitis, working with gastrointestinal (GI) specialists for colitis, working with dermatology for skin toxicities, and so on. Getting involved early and involving in the management of our patients when they develop these immune-related adverse events, I think, are really important.

Oncology Data Advisor: That's really great advice, and this was such a comprehensive update. Thank you so much for sharing all these exciting advances today.

About Dr. Leal

Ticiana Leal, MD, is the Director of the Thoracic Medical Oncology Program and an Associate Professor in the Department of Hematology and Medical Oncology at Emory University School of Medicine and Winship Cancer Institute. She specializes in the treatment of patients with lung cancer, mesothelioma, and thymic malignancies. Dr. Leal's research centers around clinical trials investigating chemotherapy and immunotherapy agents for lung cancer. She has authored or coauthored numerous peer-reviewed articles, posters, and book chapters.

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Transcript edited for clarity. Any views expressed above are the speaker's own and do not necessarily reflect those of Oncology Data Advisor.