Does an Additional First-Line Option Alter Approach in EGFR-Mutant NSCLC?

In August, the FDA approved another first-line treatment option for patients with EGFR-mutant non-small cell lung cancer (NSCLC): the third-generation EGFR tyrosine kinase inhibitor (TKI) lazertinib (Lazcluze) in combination with the bispecific antibody amivantamab (Rybrevant).

“That is where the landscape is now; we have three legitimate first-line options,” said Timothy F. Burns, MD, PhD, of the UPMC Hillman Cancer Center at the University of Pittsburgh, referring to the third-generation EGFR TKI osimertinib (Tagrisso), or osimertinib plus pemetrexed and platinum-based chemotherapy.

According to National Comprehensive Cancer Network guidelines, osimertinib monotherapy remains the “preferred” option, with the other two categorized as “other recommended.” However, when to use each regimen is still “widely debated” and “evolving,” Burns said.

New Option

Lazertinib plus amivantamab was approved based on results from the phase III MARIPOSA trial, which compared the combination with osimertinib monotherapy or lazertinib monotherapy. Lazertinib plus amivantamab reduced the risk of progression or death by 30% compared with osimertinib, with a median progression-free survival (PFS) of 23.7 months compared with 16.6 months, respectively.

A secondary analysis of MARIPOSA showed that lazertinib plus amivantamab also improved median PFS in patients with biomarkers of high-risk disease, such as TP53 co-mutation, and among patients with circulating tumor (ct)DNA clearance.

“Patients with brain metastases and liver metastases also did better with the combination,” said Danny Nguyen, MD, of City of Hope Orange County Lennar Foundation Cancer Center in Irvine. “All that data together helped lead to the recent approval.”

Who’s Using It?

Whether clinicians are selecting lazertinib/amivantamab or osimertinib with or without platinum-based chemotherapy likely varies from one oncologist to the next, Nguyen said.

“For now, I am offering all three options to my patients and I will decide on the best treatment for the patient after a frank discussion about the risks and benefits,” he explained. “When patients are involved in the decision-making process about their own treatment, many are willing to take the risk of increased side effects for the chance to have better cancer control and live longer with the amivantamab/lazertinib combination.”

Burns said that he is rarely choosing lazertinib/amivantamab. That is partly because “in the first-line setting, the MARIPOSA study did not have an amivantamab-alone arm, which is why there is at least some question as to whether you need lazertinib at all.”

In addition, amivantamab, which is an intravenous drug, is also associated with higher rates of toxicities compared with the EGFR TKIs, including higher rates of rash and peripheral edema, and, when combined with lazertinib, a higher rate of blood clots, Burns said. “Choosing a regimen is a shared decision-making process, and a lot of my patients are choosing oral therapy.”

In contrast, Nguyen said, “After I discuss the option with patients, the majority seem to be in favor of the combination therapy,” indicating that “everyone has different experiences.”

Could That Change?

“My sense from talking to other providers is that there needs to be a bit more education surrounding the uptake of this regimen,” Nguyen said. “More education is needed around the nuances of the improvement in patient outcomes, and I think providers are still becoming more familiar with the newer side effects.”

Several efforts are underway to try to mitigate some of the adverse events associated with amivantamab. For example, there is a study exploring the use of prophylactic dermatologic management among patients receiving first-line lazertinib/amivantamab.

A subcutaneous formulation of amivantamab is also being explored as a way of mitigating side effects and eliminating the time commitment of intravenous infusions. The phase III PALOMA-3 study compared subcutaneous versus intravenous amivantamab in combination with lazertinib in refractory EGFR-mutant NSCLC, with the subcutaneous formulation demonstrating noninferiority.

“Importantly, the rates of infusion[-related reactions], which they quote as around 60%, but in my clinic is closer to 90% on day 1, went down from 66% in this study to 13%,” Burns said. “The potential for a subcutaneous formulation would mean that many patients could be on an oral medication and only have to come in about once a month for an injection.”

The subcutaneous group also seemed to have less venous thromboembolism when compared with intravenous amivantamab.

No Clear Answer

For now, the question remains: which drug should patients get first? That is difficult to answer, Burns said, because there has been no crossover on the trials.

“The issue with MARIPOSA, for example, with its trend toward slightly better overall survival, is that if the patient got osimertinib, they never got amivantamab,” he explained. “Unfortunately, the overall survival should be better here because amivantamab is a good drug. If you said give amivantamab upfront or never, I would expect overall survival to be better.”

Clinicians still cannot say for sure whether a patient should get amivantamab first or second.

“There is an argument that will be made that you will lose some percentage of patients with osimertinib first-line before they are exposed to amivantamab,” Burns said. “I have to be honest. I have not seen that. I can count on one hand the number of patients that haven’t been able to get to second-line treatment.”

When making decisions about first-line regimens, it is not always as easy as picking the combination with better efficacy, especially in situations in which that efficacy comes with higher toxicity.

Burns said research from Helena Yu, MD, at Memorial Sloan Kettering Cancer Center in New York City, will explore these nuances.

Yu and colleagues are conducting a phase II study that initiates patients on osimertinib for three cycles and then tests for ctDNA clearance. Patients without clearance will be randomly assigned to osimertinib alone or in combination with chemotherapy.

“I don’t think there is a right or wrong answer [to this question],” Nguyen said, “but we still need to learn more about the nuances.”