Debating the Merits of New Therapeutic Stars in NSCLC

Suresh S. Ramalingam, MD

Immunotherapies (immune checkpoint inhibitors) and targeted therapies (tyrosine kinase inhibitors [TKIs] that target specific mutations in one or more oncogenic drivers) represent two of the most researched types of therapy under investigation for the treatment of non— small cell lung cancer (NSCLC).

But which of these two types of therapy—both of which certainly offer bold new opportunities for disease control over cytotoxic therapies—do oncologists think has been, overall, the greater contributor to NSCLC treatment?

On the Immunotherapy Side

This was the topic of a session at the Debates and Didactics in Hematology and Oncology Conference, held in Sea Island, Georgia, July 22-26. OncologyLive caught up with the two presenters on the topic to weigh in on this timely debate.Presenting the argument for immunotherapy was Suresh S. Ramalingam, MD, who is nationally recognized for his research in developing individualized therapies for patients with small cell and NSCLC. Ramalingam serves as co-leader for the Discovery & Developmental Therapeutics Program and director of the Medical Oncology and Lung Cancer Programs at Winship Cancer Institute, and professor of hematology and medical oncology at Emory University School of Medicine.

In his presentation, Ramalingam acknowledged the robust response rates seen with targeted therapies in patients with a driver mutation, but noted that resistance inevitably develops and leaves limited options for patients with acquired resistance. With that backdrop, he then described the durable responses seen in up to 25% of patients with immunotherapy, and the marked superiority of immunotherapy to chemotherapy in the salvage setting, as seen in the CheckMate and other studies.

On the Targeted Therapies Side

He also emphasized the long-term survival that has been observed with combination therapies in other cancers, such as melanoma, and that targeted therapies (with or without combination) have thus far not resulted in cure for patients with NSCLC.Presenting the argument for targeted therapies was Fadlo R. Khuri, MD, a world-renowned lung cancer and head and neck cancer expert. Khuri serves as deputy director of Winship Cancer Institute and editor-in-chief of the journal Cancer. He is also professor and chairman of the Department of Hematology and Medical Oncology, and executive associate dean of research at Emory University School of Medicine.

The Presenters Weigh In

During his presentation, Khuri noted that targeted therapies represent an opportunity to hone in on drivers of so-called oncogene-addicted cancers, and pointed to the high response rates and durable benefits associated with these therapies. He also emphasized the reliability and availability of biomarkers and genomic testing with targeted agents, and medicine’s growing understanding of potential resistance mechanisms (eg, T790M in acquired resistance to EGFR TKIs). He also believes that targeted therapies offer a better cost/ benefit ratio and fewer toxicities than immunotherapies, particularly compared with combined cytotoxic T-lymphocyte-associated protein 4 (CTLA—4)/ programmed cell death–1 (PD-1) blockade.Q: Which, in your opinion, has made the greater contribution to NSCLC treatment, targeted therapies or immunotherapy?

Ramalingam: Targeted therapies against driver mutations in advanced NSCLC patients have resulted in robust response rates and improvements in survival. However, resistance is inevitable, and the fact remains that targeted therapies have not helped improve cure rates in lung cancer. Immunotherapy provides the hope that longterm survival is achievable in a subset of patients. We hope that cures can be achieved with novel treatment approaches that include immunotherapy.

Khuri: Targeted therapies have contributed more to date, but immunotherapy stands to [make] the bigger, longer-term contribution, as it presents the possibility of long-term cure for a fraction of patients with metastatic disease. However, to date, targeted therapies have made a bigger impact, because, for the fraction of patients with lung cancer who have driver mutations (generally, nonsmokers), durable response and prolongation of survival [have been observed with] therapies targeted to EGFR, ALK, RAF, ROS, RET, and HER2.

Q: What are some of the key data from your presentation that you feel support this conclusion?

Ramalingam: The CheckMate studies randomized patients with advanced NSCLC to nivolumab or docetaxel in the salvage therapy setting. These two studies enrolled patients with squamous and nonsquamous histology, respectively. Both trials demonstrated improvement in overall survival for nivolumab, with a better toxicity profile over docetaxel. In the nonsquamous study, programmed cell death ligand 1 (PD-L1) expression in the tumor was predictive of improved progression-free survival [PFS] and overall survival with nivolumab.

Fadlo R. Khuri, MD

Fadlo R. Khuri, MD

The importance of biomarker-based selection was also demonstrated in the KEYNOTE study with pembrolizumab. Patients with advanced NSCLC with high tumor expression of PD-L1 achieved a higher response rate and prolonged PFS with pembrolizumab monotherapy. In these studies, the duration of response is significantly longer than that with chemotherapy and targeted therapy. With nivolumab, the median duration of response was approximately 17 months. These promising data provide us with the optimism that immunotherapy can make a greater impact in the treatment of NSCLC.

Khuri: A number of data show that targeted therapies are more specific, have reliable biomarkers of response, and that treatment with them results in much higher response rates than immunotherapy and longer median PFSs. However, lung cancer is generally a disease of smokers, and in these individuals immunotherapy seems more potent, and again provides a chance for a cure. Also, the cost of immunotherapy seems higher than targeted therapies.

Q: Which therapy, if either, do you think won the debate at the conference?

Ramalingam: In a disease that had relatively few treatment options until 10 years ago, both targeted therapies and immunotherapy are valuable tools to improve patient outcome. For patients with targetable mutations such as EGFR and ALK, targeted therapy remains the standard of care. However, the enthusiasm for immunotherapy is very high among physicians and patients, given the promising efficacy and durability of benefits, despite the fact that we are still in the early days of development of these novel agents.

Khuri: Immunotherapy won hands down. It is more impactful in most lung cancer patients, smokers in particular, and it offers the elusive possibility of long-term, disease-free survival, including cure, something targeted therapies have not yet shown. I was happy to lose to my friend and colleague, Suresh Ramalingam, MD.