Manochakian Calls for Repeat Genomic Testing Upon Osimertinib Progression in EGFR+ NSCLC

Rami Manochakian, MD

Because no standard approaches exist for patients with EGFR-mutated non–small cell lung cancer (NSCLC) who progress on standard frontline osimertinib (Tagrisso), repeat genomic testing should be done to identify potential resistance mechanisms that can help guide the next step in the treatment journey, said Rami Manochakian, MD.

“This is a very hot topic now. There are potentially some rare resistance mechanisms that could be a secondary actionable mutation, such as MET amplification, where you can potentially give patients another targeted therapy,” Manochakian explained. “For some other promising resistance mutations, you can enroll patients on trials, whether you have them at your institution or elsewhere. Definitely, for any patient of mine who progresses on osimertinib, I do recommend repeat genomic testing.”

In an interview with OncLive® during a 2020 Institutional Perspectives in Cancer webinar on lung cancer, Manochakian, a thoracic medical oncologist at Mayo Clinic, discussed the optimization of osimertinib in patients with EGFR-mutated NSCLC and strategies for treatment following progression on the third-generation tyrosine kinase inhibitor (TKI).

OncLive®: How would you characterize the past year of treatment in EGFR-mutated NSCLC?

Manochakian: EGFR mutations are present in roughly 15% to 20% [of patients with lung cancer] depending on their geographical area. In all patients with stage IV disease, EGFR is an oncogene driver for the cancer growth. Over the past decade or so, FDA-approved drugs to target this mutation and inhibit the cancer growth [have emerged]. Patients whose cancer harbors these mutations live longer and better because of these new drugs.

Three major trials have either led to FDA approvals or [have examined] practice-changing drugs. Osimertinib in the first-line setting [is one example], and this is something that we have had for the past 2 years, since 2018; it is a third generation TKI that is now the first-line standard of care for patients with stage IV NSCLC.

The second trial is something that’s very new, as it was just published very recently. [The FDA recently approved] osimertinib for [the adjuvant treatment of] patients with early-stage NSCLC and an EGFR mutation who have undergone resection. We took the drugs that are helping patients in the advanced setting and we’re giving it to them in earlier settings.

Lastly, [there is] another option for patients with stage IV disease. A trial tested an older-generation TKI, erlotinib [Tarceva], in combination with ramucirumab [Cyramza], compared with placebo. That combination showed a significant difference in activity, which led to its approval.

What factors do you consider when selecting among these options in the frontline setting?

I feel we have a clear winner between the 2 options. For patients with stage IV NSCLC who harbor EGFR mutations, right now, the standard of care is osimertinib. The other option for patients who cannot receive osimertinib, maybe [because they are] in certain countries where it is not available, is combining erlotinib, which is an older-generation TKI, with ramucirumab, rather than giving single-agent erlotinib.

To me right now, it’s a clear [decision]—the standard of care is to use your best agent up front, and that is osimertinib. [This agent] has better efficacy compared with older-generation [agents]; it has better central nervous system activity and it has shown improvements in progression-free survival and in overall survival.

Interestingly, we know that [the combination of] EGFR inhibitors with VEGF inhibitors, such as erlotinib and ramucirumab, is probably going to eventually be taking over. We have trials looking into osimertinib plus a VEGF inhibitor. That [kind of approach] could be the future, but we don’t have final definitive data yet.

How do you approach sequencing after osimertinib? Are resistance mechanisms helping to guide which TKI to pursue?

Absolutely. Right now, if a patient is on first-line osimertinib [and progresses], we don’t have a standard-of-care TKI or targeted therapy. If you have a clinical trial that you can enroll that patient on, that would be great. However, if you don’t, then the [best] option would most likely be chemotherapy plus or minus immunotherapy. There are very few data [with this approach in] patients with EGFR-positive disease. [We know that] single-agent immunotherapy is not the best option for a patient with a mutation. However, I do recommend checking for resistance mutations in every patient who has progressed on osimertinib.

Sometimes you can check that from the blood and by [looking at] the circulating DNA. Preferably, if you’re able to get a repeat biopsy and check the next-generation sequencing from the tissue, [you should]. But it is important to remember that in a small percentage of patients, [we can see] a transformation to other types of cancer, such as small cell lung cancer.

What are the clinical implications of the approval of osimertinib in the adjuvant setting?

Once you get these drugs approved in the adjuvant setting, then you’re going to have another problem: What are you going to do if a patient progresses? I want to call this a good problem. Of course, we hope that a patient doesn’t progress. But if they recur while on osimertinib, what approach should you take? Of course, you get a biopsy and go through the pathway. But what do you do if they recur after being off the drug for a while? Do you rechallenge or not? This is an area with a lot of good questions and research. I know that many investigators nationwide and internationally are looking into these questions. I expect [we will] know more soon.

Where are ongoing efforts being focused?

It’s a great era for lung cancer management. A lot of research is [being done] and the landscape is changing every day. We looked at combining, for instance, a TKI with immunotherapy, but this was too much in terms of toxicity and not necessarily enough benefit.

What we’re looking at right now is: Can we target EGFR better? Can you get more than 1 combination of agents that can help to target [this mutation] better? What can you offer to make the response rate more durable and decrease the odds of resistance? Or, if you pick up a resistance [mutation], what can you do to reverse it?

We know that TKIs are great drugs; the response rates [with these agents] are very high. The majority of patients have a response or stable disease, although the majority achieve a response. It’s going to be the backbone of treatment. But many potential pathways are being looked at in general for patients who have NSCLC, but particularly for those who carry certain mutations like EGFR.