Building On Immunotherapy, Preventing Acquired Resistance Are Next Steps in Lung Cancer Research

David P. Carbone, MD, PhD

Checkpoint inhibitors and next-generation TKIs have demonstrated improved survival outcomes in patients with non—small cell lung cancer (NSCLC); however, ongoing research efforts are looking to build upon the benefits with combination strategies and prevent acquired resistance to treatment, explained David P. Carbone, MD, PhD.

“It's an incredibly exciting time in lung cancer. We have had 17 FDA approvals in the last 3 years, which is more than we have had in the last 30 years,” explained Carbone. “It's becoming very complicated, but we're seeing more long-term survivors and it's very gratifying to see. It's an exciting field to work in and I encourage more people to focus on lung cancer and help us look at this problem.”

Acquired resistance to therapy continues to be a problem for patients with lung cancer, hindering their long-term survival. For example, in a retrospective analysis, investigators examined patients with NSCLC who had developed resistance to osimertinib (Tagrisso). Genomic profiling was performed using targeted next-generation sequencing encompassing 59 to 1021 cancer-related genes.

Results showed that 44% of all patients had known EGFR-dependent resistant mutations and activation of alternative pathway, with great heterogeneity. Additionally, gain-of-function mutations of CTNNB1 were highly enriched; EGFR V834L, among other suspected resistance mechanisms to osimertinib, were identified. Moreover, pathogenic mutations of TP53 were negatively related to osimertinib efficacy.

In an interview with OncLive^® during the 2020 State of the Science Summit™ on Lung Cancer, Carbone, director of the Thoracic Oncology Center at The Ohio State University Comprehensive Cancer Center—James, discussed advances in immunotherapy and targeted therapy in NSCLC and ongoing research efforts focused on acquired resistance to available therapies.

OncLive: How has immunotherapy impacted lung cancer treatment?

Carbone: The outcome of these [immunotherapy] studies has transformed the prospects for lung cancer in the last few years. I used to tell patients that metastatic lung cancer was incurable but treatable. Now, the latest studies are showing that some of the early patients treated with immunotherapies 5 to 7 years ago are still relapse free, which is an incredible change over the last few years. If you look at patients treated in the first-line setting, approximately 20% of people are alive and progression free at 5 or 6 years, and that was never seen before with chemotherapy.

With the chemoimmunotherapy and double immunotherapy approaches that we're investigating now, we may be able to further improve survival. I always hope that we can find markers for patients to select them better, like we have with targeted therapies. Instead of 20% of patients being alive in 5 years, maybe we'll get 80% alive in 5 years with better patient selection; [we could also] save patients the toxicity and costs of ineffective therapies.

What targetable mutations are currently identified in lung cancer?

Currently, there's at least 6 or 8 validated targets for NSCLC and the most common one is EGFR, and then ALK and ROS1. RET has new drugs that are highly effective and nontoxic. There is also MET exon 14 skipping mutations, BRAF mutations, and NTRK fusions. We have an abundance of these targets that are found in small fractions of patients. Every patient deserves a close look to see whether or not they have those targets.

You were on a study evaluating acquired resistance to osimertinib in NSCLC. Could you discuss those findings?

All of the patients in that study had EGFR mutations and were treated with TKIs. It is a mystery why some patients have very short responses and some patients have very long responses. Some responses are just a few months, while others have responses for many years. Why does the tumor become resistant after these therapies? The point of that study was to investigate the mutational landscape of these tumors and try to associate which mutations occur along with the EGFR mutation, or arise as a consequence of the resistance, might be contributing to this variability.

My own research interest is in preventing resistance rather than tracking [resistance] and determining prognostic factors. I would like to figure out why you don't kill the whole tumor in the first few weeks of therapy and the protective mechanisms that tumors develop in order to co-target those right at the beginning. We have another study from 2 years ago that shows the important role of beta carotene. We just received a grant and we're initiating a clinical trial that looks at co-targeting EGFR and beta carotene at the very start of therapy to try to deepen the response and prolong time to progression. That was discovered by studying these tumors shortly after TKIs. That is more likely to be productive in the long term than trying to figure out why [tumors] become resistant several years after starting therapy.

What are the reasons that tumors develop resistance to therapy?

There are a whole list of them. There are 2 broad categories of resistance mechanisms. One is reactivation of the target, and one of those is C797S, which mutates the cysteine and keeps osimertinib from working. It also can be bypass pathways with MET or histologic transformation to the small cell.

What happens down the road will be less helpful in the long run than trying to figure out how to cure the tumors in the first place. My goal would be to find the right combinations of therapies up front that would cure these patients and prevent a lifetime of drugs and eventual resistance.

In small cell lung cancer (SCLC), rovalpituzumab tesirine (Rova-T) showed early promise against DLL3 but the data were ultimately negative. Could you shed light on the results?

Rova-T was dropped for development mostly because of toxicity and difficulty in establishing really good efficacy, but the concept was good and the target was very interesting. Rova-T targeted a protein called DLL3, which is expressed on most SCLC cases. It's an interesting molecule that inhibits the Notch signaling pathway. In this study, it was used as a beacon to target the therapeutic. Rova-T was an antibody that bound to DLL3 and it had a payload. It had a chemotherapy attached to it to kill cells that it targeted; however, that particular payload was unstable and toxic.

There are other approaches that are being developed that use DLL3 to bring immune cells to the tumor, either using CAR T cells, bispecific antibodies, or other antibody-drug conjugates against that target. The concept was good, and it may end up being effective like trastuzumab (Herceptin) in breast cancer or rituximab (Rituxan) in lymphomas. We haven't had anything like that in the past. Most lung cancers have very heterogeneous antigen expression and they don't express cancer-specific proteins, but DLL3 is one exception that is fairly cancer specific.

Other ways of targeting these cancer-specific proteins are immunologic and there are several studies that look at oncofetal protein expression in tumors. NY-ESO-1 is not expressed in most normal tissues, for example, but is overexpressed in some cancers. This explosion of new ideas and new approaches for lung cancer therapy is very exciting.

What does the future of biomarkers for targeted therapy and immunotherapy look like?

We have made tremendous progress with the targeted therapies by knowing the right biomarker and matching the therapy to the individual tumor characteristics. We are at risk of reverting to the one-size-fits-all approach with immunotherapy, treating everybody with the same immunotherapy. That approach is a bad one. We really need to intensively study why some patients respond and others don't to immunotherapies. That will help us select patients, but it also may give us clues to new therapies or combinations of therapies for specific patients that will let us be taking immunotherapy to the same level where targeted therapy has gone in the last decade.

Zhao J, Lin G, Zhuo M, et al. Next-generation sequencing based mutation profiling reveals heterogeneity of clinical response and resistance to osimertinib. Lung Cancer. 2020;141:114-118. doi: 10.1016/j.lungcan.2019.10.021