EGFR-Mutant NSCLC Landscape Evolves Among Adjuvant Approaches and Emerging Agents

The therapeutic armamentarium of EGFR-mutant non–small cell lung cancer (NSCLC) has been the subject of significant clinical research, marked most recently by the integration of osimertinib (Tagrisso) into the adjuvant setting, said Joshua M. Bauml, MD, who added that targeted options for patients with EGFR exon 20 insertion mutations are rapidly evolving with the anticipated approvals of amivantamab (JNJ-61186372; JNJ-6372) and mobocertinib (formerly TAK-788).

“The really critical point to remember about EGFR-mutant NSCLC is that this is a field that is constantly changing,” said Bauml. “We are trying to get better treatments for our patients and after [many] years, we are really seeing improvement. This is a very exciting time to be doing this research.”

In 2018, the FDA approved osimertinib for the first-line treatment for patients with NSCLC whose tumors harbor EGFR mutations (exon 19 deletions or exon 21 L858R substitution mutations).¹ In December 2020, the FDA approved osimertinib also for use as an adjuvant treatment following tumor resection in patients with NSCLC whose tumors harbor EGFR exon 19 deletions or exon 21 L858R mutations, as detected by an FDA-approved test.²

Although the field is awaiting overall survival (OS) data from the phase 3 ADAURA trial, findings from which served as the basis for the new indication, the trial demonstrated improved disease-free survival (DFS) with adjuvant osimertinib vs placebo in patients with stage IB/II/IIIA EGFR-mutated NSCLC.

In addition, amivantamab and mobocertinib demonstrated activity in a subpopulation of patients who harbor EGFR exon 20 insertions. Both agents received breakthrough therapy designations from the FDA.^3,4

In an interview with OncLive^® during an Institutional Perspectives in Cancer webinar on lung cancer, Bauml, an assistant professor of medicine at the Hospital of the University of Pennsylvania and a physician at Penn Medicine, discussed the use of osimertinib in EGFR-mutant NSCLC, the utility of the agent as adjuvant therapy, and emerging targeted agents for patients with EGFR exon 20 insertions.

OncLive^®: How has osimertinib continued to reshape the standard of care in EGFR-mutant NSCLC?

Bauml: EGFR mutations are very important targets that we need to consider in NSCLC. We know that the classical mutations, [such as], exon 19 deletions and L858R [mutations] occurring in exon 21, lead to heightened sensitivity to TKIs. Currently, the standard-of-care [treatment for patients with EGFR mutations] is osimertinib, based upon the FLAURA data. We have seen some very interesting data recently looking at whether we can move treatment with osimertinib up earlier into the adjuvant setting based upon the ADAURA trial.

[The ADAURA trial] showed that the addition of 3 years of osimertinib was associated with a marked improvement in DFS for patients with EGFR-mutant NSCLC who have had surgery and chemotherapy as appropriate. We don’t have OS data yet, but [osimertinib] was granted FDA approval [in this setting].

What was the significance of the FLAURA data?

FLAURA was a trial that compared osimertinib with gefitinib [Iressa] or erlotinib [Tarceva] by investigator’s choice. There was an improvement in OS and progression-free survival [with osimertinib compared with gefitinib or erlotinib]; this was really quite remarkable. No [other] trial to date has ever shown a survival benefit comparing 2 TKIs, but that is exactly what we saw here. That is wonderful for patients.

Osimertinib was better tolerated [vs] the standard-of-care TKIs. In addition, [osimertinib] has excellent central nervous system [CNS] penetration.

In my view, [osimertinib] is the standard of care for the first-line management of EGFR-mutant, metastatic NSCLC.

Do you recommend molecular testing for all patients with stage IB, II, or III NSCLC who undergo surgery since osimertinib is also approved in the adjuvant setting? Should patients receive the agent if an EGFR mutation is identified?

It is critical that we perform testing on all patients after surgery to identify patients who would be candidates [for adjuvant osimertinib]. If a patient with EGFR-mutant lung cancer is identified, one must have a discussion with the patient to talk about these data [from the ADAURA trial].

Granted, the goal in the adjuvant setting is cure, and we don’t have OS data [from ADAURA]. However, with the degree of DFS [benefit], osimertinib must be offered to any patient with stage IB, II, or III NSCLC harboring an EGFR mutation after surgery and appropriate chemotherapy. [The agent] should be given for 3 years. Appropriate patients should still receive chemotherapy, but I do think [osimertinib] is appropriate for any patient as per the eligibility [of ADAURA].

What are some of the concerns surrounding the ADAURA data?

The most common critique surrounds the lack of OS data, which is a very valid point. However, this was a randomized trial. I’m not sure how, ethically, [investigators] would continue randomization with that degree of DFS benefit, which, admittedly, was the primary end point of the trial and had been agreed to prior to the trial initiation.

The other concerns that I’ve seen are about how only about 50% to 60% of patients received adjuvant chemotherapy. However, there again, we must consider the fact that this was a global trial and adjuvant chemotherapy use does not always align with our practices in the United States. Patients may refuse chemotherapy. The incremental benefit of adjuvant chemotherapy is modest, and clearly, the DFS benefit with osimertinib was quite remarkable.

What population of patients could benefit from the anticipated approvals of amivantamab and mobocertinib?

Patients with EGFR exon 20 insertion [mutations] represent about 10% of EGFR alterations. To date, no targeted therapies have been approved to treat this subpopulation; however, we are now seeing new data looking at some new drugs that have been granted breakthrough therapy designations by the FDA.

Specifically, amivantamab is an EGFR/MET bispecific antibody, as well as mobocertinib, which is a TKI working at the intracellular domain of EGFR. Both [agents] showed very intriguing data at the [International Association for the Study of Lung Cancer 2020 World Conference on Lung Cancer], and I believe both are on track to be approved in the near future.

If amivantamab and mobocertinib enter the treatment arena, how will you select between them without head-to-head data?

The drugs for EGFR exon 20 insertions are quite distinct. Amivantamab is a large bispecific monoclonal antibody that acts on the extracellular domain of the EGFR receptor. Mobocertinib is a TKI acting on the intracellular component [of the EGFR receptor].

The data with amivantamab indicates efficacy across a wide range of exon 20 insertions, which is what we would expect because the mutations are on the intracellular domain that should not affect the function of amivantamab.

We don’t yet have data on the relative efficacy of mobocertinib as a function of specific exon 20 insertions, although I would suspect that may affect outcomes.

Looking at the relative efficacy, the response rate with mobocertinib was in the 25% to 30% range, whereas the response rate with amivantamab was 40%. [Amivantamab yielded] a higher [response rate], but of course these are cross-trial comparisons of small data [sets]. Both of these agents will be approved and are reasonable to try.

Looking to the future, I’m interested in combination trials that are adding amivantamab to a TKI to see if we can yield even better responses.

Looking at toxicity, amivantamab has a rather unique infusion-related reaction that usually happens on day 1 of cycle 1. It’s dramatic but not dangerous in most cases. Mobocertinib has a

relatively high rate of grade 3 or higher diarrhea, which can have a profound effect on quality of life. [Toxicity] is something that we are going to have to discuss with our patients, but my suspicion is that most patients will get both of these agents at some point during their treatment. The question is: Which agent should they get first?

The tolerability profile of amivantamab is pretty good; no real dose-limiting toxicities [were observed. However], dose reduction, as well as diarrhea management is going to be critical to the rollout of mobocertinib. We know that TKIs are often dosed at a higher level than what is needed for cancer control. On the other hand, exon 20 is difficult to inhibit given the biologic nature of what the tyrosine kinase looks like in that mutation.

References

1. FDA approves osimertinib for first-line treatment of metastatic NSCLC with most common EGFR mutations. FDA. Published April 18, 2018. Accessed April 1, 2021. https://bit.ly/3ufWsMw.
2. FDA approves osimertinib as adjuvant therapy for non-small cell lung cancer with EGFR mutations. FDA. Published December 18, 2020. Accessed April 1, 2021. https://bit.ly/2QYac0e.
3. Janssen announces U.S. FDA breakthrough therapy designation granted for JNJ-6372 for the treatment of non-small cell lung cancer. Janssen. Published March 10, 2020. Accessed April 1, 2021. https://prn.to/2Q0EhsA.
4. Takeda announces U.S. FDA breakthrough therapy designation for mobocertinib (TAK-788) for the treatment of NSCLC patients with EGFR exon 20 insertion mutations. Business Wire. Published April 27, 2020. Accessed April 1, 2021. https://bwnews.pr/2y3hRRM.