Assessing the Advantages of Adjuvant Targeted Therapy in Lung Cancer

David Spigel, MD

Adjuvant osimertinib [Tagrisso] has become a new standard of care for patients with non–small cell lung cancer whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, explained David Spigel, MD, who cautioned that the approval does not give license to bring other targeted therapies into the adjuvant setting without prospective research or replace other established standards, such as durvalumab [Imfinzi], with the TKI.

“I mentioned it with ADAURA, but with PACIFIC too, a lot of people are wondering, if a patient has a target, do I need to give platinum-based chemotherapy in the adjuvant setting, or in the case of unresectable, stage III disease, maybe I could forego durvalumab because the patient has an EGFR mutation. We don’t know that [that is the right thing to do],” said Spigel. “[However,] it does indicate that we need prospective research to solve these questions. Otherwise, we’re just guessing.”

In an interview with OncLive^® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, David Spigel, MD, chief scientific officer, director, Lung Cancer Research Program, principal investigator, Sarah Cannon Research Institute, discussed the future of adjuvant targeted therapy in lung cancer.

OncLive^®: How have you interpreted the results of ADAURA?

Spigel: The most recent relevant story is the role of oncogenic drivers in early-stage disease and addressing those. In this case, it is with EGFR and osimertinib. Even if you’re a critic [who says osimertinib is not] ready for primetime in terms of a change in how we approach care now for early-stage disease––except I’d say stage III, which is certainly ready––you would accept a lot is happening that’s exciting to see.

By and large, most people who spend time talking about these kinds of things feel like an advance has been made, and that EGFR is something we should consider as a new standard [mutation to] test for patients with certainly stage II, and resectable stage III disease.

I certainly have the conversation [about adjuvant osimertinib with my patients] now. I think it will be a standard [approach]. If there are a lot of shortcomings, we’ll question whether it [was] a little premature to approve [the drug] without more data. But I think we all accept these things. We accept that the use of osimertinib for 3 years after resection, and hopefully, after adjuvant platinum-based chemotherapy, delays disease recurrence. There seems to be no doubt about that.

We learned at the 2020 ESMO [Congress] that [osimertinib] seems to reduce, at least at this time point, the chance of central nervous system [CNS] recurrence, which is quite remarkable. There’s about a 10% chance of recurring in the CNS versus probably a less than 1% chance with osimertinib. Whether that leads to patients living longer, we don’t know. However, we’re at a point now where I think, with a patient in front of you, and a discussion about those findings, it’s hard to not want those things, knowing how aggressive lung cancer can be. Can we wholeheartedly say that if you’re just waiting to give osimertinib when the patient recurred later, they would live just as long and just as well; no, we can’t say that. However, it’s likely that patients will do better if you delay recurrence, certainly in the CNS than if you wait for it to happen and see if you can rescue patients at that point.

Is EGFR the only mutation that should be tested for in the early-stage setting?

For testing in lung cancer, we’re really talking about stage IV disease. Although I tend to do it a lot in stage III disease, too, but [should be done primarily in] stage IV disease where the therapies have approved indications. In early-stage disease, based on ADAURA, the only test that makes sense at this point is EGFR testing. Should we test for ALK because we have these great drugs? Would the results be the same as ADAURA if we gave lorlatinib [Lorbrena] or alectinib [Alecensa] or brigatinib [Alunbrig] in the adjuvant setting?

My guess is yes; they probably would look like the ADAURA results, if you did the trial the same way. My guess is that it would take a very long time to prove that in a randomized trial, just because the frequency of [ALK] alterations is lower than EGFR mutations. The ALCHEMIST study is hopefully going to solve this question, or at least give us some early answers. I imagine pharmaceutical companies that make these TKIs are working on their versions of ADAURA to get some data to show that the FDA should justify some early strategy or accelerated approval.

It’s really difficult if you start getting into really narrow indications like ROS1, NTRK, and RET. What if you had a RET fusion in the adjuvant setting? Wouldn’t selpercatinib [Retevmo] or pralsetinib [Gavreto] be a great option in the adjuvant setting? We don’t know. You’d like to have some data to tell you that that even makes sense. The only similar story is in colorectal cancer. When I was in training, bevacizumab [Avastin] had a proven role in the stage IV setting, but in resectable disease, in the adjuvant setting, bevacizumab did not lead to improved advances. Therefore, just because a drug is quite effective and leads to an OS advantage in the stage IV setting, it may not do so in earlier stages of disease. However, that’s colon cancer; that’s not an onco-driven target, and [bevacizumab is] not a TKI, so it’s really not a fair comparison.

Do the results of PACIFIC affect your likelihood of recommending adjuvant osimertinib to a patient with an EGFR mutation?

We do know that in the intention-to-treat population, platinum-based chemotherapy in all-comers and immunotherapy, in this case, durvalumab in PACIFIC in stage III unresectable disease, leads to an OS advantage. To try to make assumptions that certain subsets aren’t going to benefit is premature. We have to not give up proven effective therapies that have led to survival advantages, because we think something might be better. If you didn’t have something in that space, okay, conjecture is great; great guessing, and taking a chance is probably worthwhile, but you have proven therapies in these settings. Before I gave those up, I would want to know that what I’m replacing that with has been proven to be better.