Acquired Resistance Remains Key Challenge in Oncogene-Driven NSCLC

Balazs Halmos, MD, MS

Targeted agents have revolutionized the treatment of patients with oncogene-driven non—small cell lung cancer (NSCLC), but they have brought forth new challenges for researchers, such as acquired resistance, said Balazs Halmos, MD, MS.

Ongoing research efforts continue to explore novel treatments and tools for combatting acquired resistance, noted Halmos. For example, the FDA approved lorlatinib (Lorbrena) in November 2018 for the treatment of patients with ALK-positive metastatic non—small cell lung cancer (NSCLC) who have progressed on 1 or more ALK TKIs.

Lorlatinib is specifically approved for patients who have progressed on crizotinib (Xalkori) and at least 1 other ALK inhibitor for metastatic disease; alectinib (Alecensa) as the first ALK inhibitor therapy for metastatic disease; or ceritinib (Zykadia) as the first ALK inhibitor therapy for metastatic disease.

The approval was based on data from the nonrandomized, multicohort phase II B7461001 study of patients with ALK-positive metastatic NSCLC who were previously treated with at least one 1 ALK TKI. Results showed that the overall response rate with lorlatinib was 48%, including a complete response rate of 4% and a partial response rate of 44%.

OncLive: What would you like to emphasize about selecting therapy for patients with oncogene-driven NSCLC?

In an interview with OncLive ahead of the 2018 New York Lung Cancers Symposium, Halmos, director of thoracic oncology and clinical cancer genomics at Albert Einstein Cancer Center and Montefiore Medical Center, discussed overcoming acquired resistance and other next steps needed to advance the oncogene-driven NSCLC paradigm.Halmos: Acquired resistance is a key issue where we now have great understanding of some of the molecular events. We have developed multiple generations of targeted agents to try to overcome that resistance. Identifying these mutations is a key issue. We need clinical advances to make it useful and more convenient for patients. Circulating tumor DNA testing has been a major advance in cancer management.

Where does immunotherapy fit into this space?

Thirdly, I would like people to understand the importance of nuancing. It is not just about understanding mechanisms of resistance, because not all patients have this. We need to think about oligometastatic disease where locally ablative treatments can have an impact. Old-fashioned chemotherapy also still has value for some of our patients. Studies now are showing promise in other types of treatments. These nuancing aspects have been very important for patients who have many, many more years to live. We can make this even better in the long term.Many of the oncogene-driven cancers occur in patients who are never-smokers and tend to be cancers that have a low mutation burden. These are the specific subsets of EGFR-, ALK-, or ROS1-mutated cancers. Immunotherapy seems to have little value in these patients, and by little value I mean approximately 4% response rates. Importantly, there is less benefit than second-line chemotherapy, which in itself is not a good treatment choice.

What assays are used to identify these mutations?

What is the take-home message from all of this?

Single-agent immunotherapy is just an experimental approach for these patients, but it is nice to see from the IMpower150 study that there seems to be benefit from the addition of immunotherapy [atezolizumab] to chemotherapy and bevacizumab (Avastin) for these patients. Although this is a very small subset, this suggests that immunotherapy could have some value. These studies are being planned. For each individual subset, there are different assays that we use to identify them. These can be sequencing assays for the EGFR mutations, as an example. Next-generation sequencing assays can cover the whole spectrum of aberrations. The idea is to use an assay that covers all of these, but it is unrealistic right now. It depends on the practice. I hope that we only continue to learn that it is important to invest in biomarkers. Admittedly, the ability to use immunotherapy or chemoimmunotherapy without biomarkers seems to dampen that enthusiasm. That is the wrong step forward. We need to continue to invest not only in figuring out the right agent upfront, but also when patients progress. We need to optimize their treatment not just in the first encounter, but throughout the whole treatment continuum.

Lorlatinib prescribing information. FDA. Published November 2, 2018. https://bit.ly/2P6uini. Accessed November 2, 2018.