Dr. Rami Manochakian Discusses Targeted Therapies for Actionable Mutations in NSCLC

As thoracic oncology moves forward, it’s critical to translate those advances into practice and bring them from academic centers and clinical trials to the community setting. That need was the inspiration behind The Oncology Brothers Advancements in Oncology event, which was held during the 2024 American Society of Clinical Oncology Annual Meeting.

Rahul Gosain, MD, MBA, and Rohit Gosain, MD, collectively known as The Oncology Brothers, invited panelist Rami Manochakian, MD, FASCO, of the Mayo Clinic, Florida, to share his insights about lung cancer data from the annual meeting and how treatment is evolving.

When it comes to treating non-small cell lung cancer (NSCLC), it’s critical to gain a full picture of the disease. The presence or absence of actionable mutations can greatly influence a patient’s course of treatment, making next-generation sequencing (NGS) a critical step.

“NGS is becoming a must, and it’s a standard of care for every patient,” Dr. Manochakian said. “With early stage, you could argue for the IA, maybe it’s not helping a lot. But do it now or do it later. At some point, you need to do it. We are not doing our patients any favors if we’re not doing NGS.”

He emphasized that full NGS testing is important to mention because doing multiple individual polymerase chain reaction (PCR) and fluorescence in situ hybridization (FISH) tests is “not any more helpful for the patient.” There are also financial considerations surrounding testing.

“Cost is very important,” Dr. Manochakian said. “If you do a PCR for EGFR, FISH for ALK and ROS1, you use so much tissue at almost the same cost as the full NGS testing.”

The conversation shifted to stage III unresectable NSCLC, with Dr. Rohit Gosain discussing the current state of treatment for the disease and how the phase 3 LAURA trial presented at the American Society of Clinical Oncology Annual Meeting may change practice in this setting.

“Based on the LAURA trial, what we’ll see is if osimertinib, in this setting, can be replacing durvalumab, though enough people are already doing this off-label,” Dr. Rohit Gosain said. “What are your thoughts on how that’s going to change your practice, postchemoradiation?” he asked. “Also, talking about the targeted therapy we have been utilizing for ALK-positive [disease], alectinib has been playing some role in that setting as well, though again, it’s not [US Food and Drug Administration] approved. [What are] your thoughts here?

Dr. Manochakian replied: “My first thought is, for me, the jury is out with EGFR and ALK [mutations]. I don’t want to give [immuno-oncology].… The good news is, right now, we don’t need to address that because if we know they have an EGFR and ALK, or ALK, we need to immediately think of the targeted therapy.”

He spoke about how he would currently approach a patient with stage III unresectable EGFR-mutated NSCLC in light of the LAURA trial, which was featured in a plenary session the day following the Advancements in Oncology event.

LAURA, a double-blinded and placebo-controlled phase 3 trial, assessed the efficacy and safety of osimertinib in adults with unresectable stage III EGFR-mutated (Ex19del/L858R) NSCLC who received definitive platinum-based concurrent or sequential chemoradiotherapy and did not have progression.

“It’s fair to say, right now, if I have a stage III [patient] with an EGFR [mutation], I am more likely going for concurrent [chemoradiation], and absolutely—there is a reason why it’s a plenary—we’re going to go with osimertinib afterward,” Dr. Manochakian said.

He explained that the LAURA results will likely “generate the same debates that we’ve seen with the ADAURA” trial.

“Depending on what the patient got in second line, are we just delaying the inevitable or are we causing different survival?” Dr. Manochakian said. “That’s an important thing also to bring to the questions, regardless of the debate. Even if it is a progression-free survival [PFS] or a disease-free survival [benefit] after surgery, there are a lot of patients [who] would take that, in my opinion.”

He spoke about the implications of the LAURA trial for clinical practice and what he plans to take home to his own practice.

“This is going to be practice changing, and we will be offering it,” Dr. Manochakian said. “We will relieve some patients from the surgical path by saying it’s [chemoradiation] followed by osimertinib,” he said.

Dr. Manochakian explained what he thinks could happen in the future for targeted therapies in NSCLC.

“We’re hoping, in the next few years, we’re going to see all these targeted therapies in the metastatic setting, making it to post-[chemoradiation] for stage III, adjuvant or neoadjuvant.”

The conversation continued with a discussion of treatment options for patients with metastatic disease who have actionable mutations.

“Sticking with the theme of actionable mutations, as you can see, there’s so much happening here, and that’s the reason why it’s important to look for NGS rather than hotspot testing,” Dr. Rahul Gosain said. “I’ll continue to piggyback on this idea of ALK… [the] CROWN trial was presented with lorlatinib. Phenomenal PFS, but that had more side effects than crizotinib. I’m not surprised, because that is what we’ve seen in our clinic.”

In light of the 5-year follow-up data from CROWN, Dr. Rahul Gosain asked Dr. Manochakian what he will do on the coming Monday when a patient with ALK-positive disease asks which ALK inhibitor they should take. “Out of the ALK inhibitors that you have, what’s your go-to, and what are your takeaways from CROWN?” he asked.

Dr. Manochakian explained that the 5-year CROWN follow-up showed a “very, very impressive result, saying that “we owe it to our patient to list the 3 options that we have right now: lorlatinib, alectinib, brigatinib. Crizotinib is totally out.”

He spoke about what he plans to tell patients with ALK-positive disease about their treatment options.

“I do tell my patients that we believe that lorlatinib appears to be the most potent, possibly, but is it the right one to start? It is a question [for] debate… I may still be leaning toward alectinib, because I think lorlatinib, in the second line, we forget that it also does a very good job,” he said.

Dr. Manochakian noted that the second-line lorlatinib is “the path that we have seen, and we probably have some stronger data about,” saying that “I think that’s sometimes psychologically important.”

Dr. Rahul Gosain responded: “Absolutely, and again, a few things to reiterate when we’re comparing alectinib or lorlatinib, [they have] different side effects, so picking the right patient is also important, and that sequencing is going to play a big role.”