Combination Therapies for Lung Cancer

Pasi A. Jänne, MD, PhD

Today, as part of Cancer Network’s coverage of the American Association for Cancer Research (AACR) Annual Meeting, we are speaking with Pasi Jänne, MD, PhD, director of the Lowe Center for Thoracic Oncology at the Dana-Farber Cancer Institute in Boston, who gave a presentation on combination therapies for lung cancer as part of a plenary session at the meeting.

-Interviewed by Anna Azvolinsky, PhD

Cancer Network: Dr. Jänne, epidermal growth factor receptor (EGFR) inhibitors are a mainstay of therapy for those advanced-stage lung cancer patients with tumors that harbor specific EGFR mutations. What have we learned in the last few years about which patients respond to which oral agents and antibodies against EGFR?

Dr. Jänne: Certainly having an EGFR mutation is the number one requirement for response to an EGFR kinase inhibitor. There are two major classes of EGFR mutations: the so-called exon 19 deletion mutation and the L858R point mutation in exon 21. And together, these comprise approximately 85% of all EGFR mutations and these are the ones that commonly respond to EGFR kinase inhibitors. There are other rare ones-one in particular, the exon 20 insertion mutation in EGFR is resistant to EGFR kinase inhibitors. Some of the rarer ones are in fact resistant and the common ones are sensitive to EGFR kinase inhibitors. This is in contrast to the antibodies against EGFR. Unlike for colorectal or head and neck cancers, EGFR-directed antibodies by themselves or in combination with chemotherapy have very little role in the treatment of lung cancer. There have been studies that evaluated them, and their benefits are marginal at best.

Cancer Network: Is there preclinical or clinical data on the rationale for combining EGFR inhibitors with other therapies that you can highlight?

Dr. Jänne: There are certainly preclinical data. And, really, that has to do with the resistance mechanisms of the EGFR kinase inhibitors. First I will say that the resistance mechanisms to EGFR kinase inhibitors are predominantly mediated by single mechanisms, the so-called T790M secondary mutation. This mutation occurs in about 60% of patients who initially responded to EGFR kinase inhibitors, and then developed resistance. And for that particular mechanism, we are now starting to have therapies that are entering the clinic that are showing some promise. The idea and the hope would be that combining other targeted therapies with that class of agents would be beneficial. The other mechanisms of resistance are activation of other signaling pathways, like MET or HER2 pathway activation, and by combining agents that target these with the newer class of EGFR agents, we hope to develop promising combinations. I think the challenge to date has been combining agents with our current approved EGFR kinase agents such as erlotinib or afatinib because they are toxic and because they are not effective against this common mechanism of resistance, and hence, they have not been therapeutically effective.

Cancer Network: What about other recent developments-are there other novel targets you can highlight and are there any results you can highlight from the AACR meeting?

Dr. Jänne: Certainly there is a lot of activity still continuing to generate better EGFR inhibitors. And as I mentioned, the next generation of EGFR inhibitors are mutant-selective EGFR inhibitors, meaning that they have selectivity against the mutant forms of EGFR, not the wild type or the normal form of EGFR. And the efficacy of the current EGFR inhibitors comes from treating the mutant and not the wild-type form of EGFR, whereas the toxicity comes from targeting the wild type and not the mutant form. So, by developing drugs that have the ability to be more preferentially active against the mutant form compared to the wild-type form will hopefully result in more effective therapy. There were a number of posters from different companies presenting their version of these types of new drugs at the AACR meeting. And secondarily, there is a lot of activity on using this class of agents that were presented at the AACR meeting, and the hope is that we can build rational combination cocktails that will be effective and will give long-term effects in patients with lung cancer.

Cancer Network: Are there any new lung cancer targets that appear promising?

Dr. Jänne: At the genomic level, there continues to be active efforts in identifying other genomic subsets of lung cancer that may harbor the same promise as EGFR inhibitors for EGFR-mutated cancers. Some of these are relatively rare subsets of patients, but this is now extending into different subtypes such as squamous and small-cell lung cancer. I think the biggest development in lung cancer in terms of targeted therapies has to do with immunotherapies, the recognition that immune modulation is a therapeutic strategy for lung cancer patients. There was a presentation at AACR on the biomarkers for some of these immune-modulating therapies and further trying to understand the specific biomarkers that could predict response or lack of response to this new class of agents, the anti–PD-1 and the anti–PD-L1 therapies. To me, that is the biggest area of interest at the moment-how to use these agents and how to identify patients that will respond. But they are clinically effective, which is very exciting.

Cancer Network: What is your perspective on combining these anti–PD-1 and anti–PD-L1 therapies and other immunotherapies with targeted therapies? Is that starting to happen?

Dr. Jänne: That is starting to happen, slowly, but it is starting to happen. I think the obvious thing is to understand how the genomic subsets of lung cancer interact with the immune system. For example, there are preliminary data to suggest that EGFR-mutated lung cancers express PD-L1, so now we need to understand how we would potentially combine EGFR inhibitors with anti–PD-1 and anti–PD-L1 agents. If this also is true for other genomic subsets, such as KRAS-mutated or ALK-rearranged lung cancer, remains to be seen. We need the data to evolve in those subsets, and several investigators are currently looking at that. We also need to figure out what happens during treatment. If you use an EGFR inhibitor, does that downregulate your immune target of choice? Should you use that immune agent at the same time as the EGFR inhibitor or later on during the course of therapy? These types of questions will all be part of active clinical investigations, but certainly there is interest in doing these combination studies with the targeted agents. Also, there is interest in doing combinations of immune therapies, as it has been shown to be successful in melanoma, and the idea is that that same degree of efficacy could be seen in lung cancer, so this is also an active area of investigation.

Cancer Network:Thank you so much for joining us today, Dr. Jänne!

Dr. Jänne: My pleasure.