Targeted Therapies in Lung Cancer Continue to Improve Outcomes

Benjamin Levy, MD

Targeted and immunotherapies have greatly improved outcomes for many patients living with EGFR-mutated lung cancer.

Therapies such as osimertinib (Tagrisso) and nivolumab (Opdivo) in both the adjuvant and neoadjuvant settings have helped to greatly improve progression-free survival (PFS) in this patient population. Targeted therapies have even been curative for some patient, according to Benjamin Levy, MD, a thoracic medical oncologist and clinical director of medical oncology at the John Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital.

EGFR mutated lung cancer is not the only space that has seen tremendous progress, according to Levy. Developments for the treatment of BRAF-mutant lung cancer such as the combination of dabrafenib (Tafinlar) and trametinib (Mekinist), have also improved outcomes. According to Levy, it’s important to try and take drugs that are effective in later-line settings and move them up to earlier lines.

In an interview with Targeted Oncology, Levy discusses the importance of molecular testing in lung cancer, the efficacy and future of targeted therapies, and upcoming practice-changing trials.

TARGETED ONCOLOGY: Can you provide a brief overview of your presentation at the Physician’s Education Resource Meeting?

LEVY: My presentation was precision medicine to cure. And essentially, it's an overview of all the drugs that we know work in the advanced stage setting that we're now using in the earlier stages. And the goal here is not to palliate or prolong life. The goal here is to cure. My talk had 2 sections at a very high level. One was on targeted therapy and their role to potentially cure patients in some of the earlier stage diseases that have been done with targeted therapy. And also, the second section was immunotherapy, looking at the role that immunotherapy may play in cure for resected lung cancer.

What were some of the targeted therapies that you touched on that have recently seen development?

What the most mature data that we have for targeted therapies for resected lung cancer is with osimertinib, and we know osimertinib is the standard of care for advanced-stage EGFR-mutant lung cancer. It provides a survival advantage, better tolerated, better intracranial response. And building on that science, we're taking that drug and putting it in the adjuvant setting. So, the ADAURA trial (NCT02511106) was a very clean study,1:1 randomization. For patients who had received surgery, who were stage 1b to 3a resected, EGFR-mutant lung cancer, randomized again to osimertinib versus placebo.

Patients were allowed to get chemotherapy at the discretion of the physician. What we found out in the American Society of Medical Oncology (ASCO) presentation 2020, which is now published in the New England Journal of Medicine (NEJM), was a market improvement in disease-free survival (DFS), as well as more recently at an Eurpean Spciety of Medical Oncology Congress presentation, an improvement in the decreased relapse rate in the brain. The benefit and DFS I think justifies potentially using this drug despite it not having an FDA approval yet. The challenge of the study is that there was really no overall survival shown because it's just too immature. And there's costs of the drug as well. So, there's a lot of challenges to the study, but I think the PFS benefit was profound enough to make us think we should be using it.

I also talked about a trial that was presented at ASCO evaluating the role of stereotactic body radiation therapy or local ablative radiation approaches for patients with advanced adenocarcinoma that are EGFR mutated. It was a very small study, randomizing patients that are EGFR positive that only have 5 sites of disease, oligometastatic disease to either a tyrosine kinase inhibitor (TKI) alone, which is the standard or radiating all sites of disease and then delivering the TKI. And the question being can we layer in local ablative approaches that will improve outcomes for these patients? And we saw a benefit in that trial as well in terms of both PFS and OS and it begs the question should we be considering more for our oligometastatic patients, such as local ablative approaches in conjunction with the TKI? The third thing I talked about was ALK. And what I said was we just got some great ALK directed therapies. And we're learning that the median survival time now for an ALK lung cancer patient who receives a TKI, at least 2 TKIs is 81 months. And that to me is pushing the envelope. And maybe we will cure some of these patients. I think we're just beginning to scratch the surface. There will be other studies looking at neoadjuvant targeted therapies for early-stage lung cancer harboring actionable mutations, which may translate into survival. We'll just have to see.

Can we move into the immunotherapy portion of your talk?

I think immunotherapies mirror the data we've had for targeted therapy. We know that immunotherapy, 9 approvals for immunotherapy in lung cancer, advanced lung cancer without an actual mutation. We know that there's a tail of the curve for some of these trials, meaning there are patients who are cured by this. We've got the phase 1 nivolumab experience that has been presented and published showing a 5-year overall survival rate of 16%. For patients that were on the phase 1 part, this is way back when on nivolumab with lung cancer received nivolumab as an average line of therapy of 3- and 5-year survival rate of 16%. So, there is a tail to the curve.

I think building on that is how do we use these drugs in earlier-stage disease and perhaps where immunotherapy is being leveraged the most right now is in the neoadjuvant setting, prior to surgery. I talked about some of the data that my institution is generated with neoadjuvant nivolumab showing a major pathological response, which is a surrogate for overall survival and defined by less than 10% viable tumor on a surgical specimen. So, major pathological response of 41% with neoadjuvant nivolumab.

I also talked about a trial that was recently published in The Lancet Oncology. I presented the abstract form of it in the NADIM trial (NCT03081689) looking at the role of neoadjuvant chemotherapy immunotherapy, not just immunotherapy alone, but neoadjuvant chemotherapy, immunotherapy showing a major pathological response of 80% and a complete pathological response of 60%. That's unheard of. And the question will be can we recapitulate this in a phase 3 trial. I would make the argument that if we see these types of results in a phase 3 setting, neoadjuvant chemoimmunotherapy may become the standard of care for our patients, I look forward to that data. It’s a very exciting time to be in the field where we've got all these great drugs in the stage-4 setting, and it's time to move them up to the earlier-stage disease. So, I'm excited about both the genotype-directed therapy front and the immunotherapy front.

Could you speak to the use of combination dabrafenib and trametinib (Mekinist) and BRAF mutated lung cancer and maybe go into what the role this combination might play in the future?

I think that for BRAF v600e mutations in lung cancer, which occurs in around 3% of patients, we do have approved therapies with dabrafenib and trametinib. This is a combination BRAF MEK inhibitor, respectively showing the combination elicits response rates in north of 50% of patients with a PFS of 9 to 12 months I nearly 60%. Because of that, it is the standard of care if you have a BRAF v600e mutation, that is generally what should be offered. I will say, however, that BRAF v600e mutations also respond to chemotherapy with immunotherapy. But we want to use our best drugs first, and that would be the best drugs for our patients I believe. Whether these drugs will play a role for cure for BRAF v600e, we really don't know. I think one of the trials, the LCMC4 trial (NCT04712877), is looking at the role of many different targeted therapies for particular genotypes in the neoadjuvant setting and BRAF is one of those. Hopefully we will have answers on this combination soon.

For any of your colleagues who might not be able to make your talk, what would you say is your take home message to them?

The take-home message is test. Test your patience for molecular drivers. Do it in tissue and do it in liquid. The other thing I'll say is for patients with resected, EGFR-mutant lung cancer, look at the data with ADAURA and make your own decision. But look at the data that's been presented at ASCO and the NEJM paper, to help inform decisions. The drugs not approved yet. But the data is compelling. And I'd ask that everyone looked at the data to make a decision on whether to give it or not.