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FDA Approval of Amivantamab Plus Lazertinib Builds Upon Success of First-Line TKIs in Advanced EGFR-Mutant NSCLC

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Joshua K. Sabari, MD, discusses the significance of the FDA approval of first-line amivantamab plus lazertinib for patients with EGFR-mutant NSCLC.

Joshua K. Sabari, MD

Joshua K. Sabari, MD

The FDA approval of amivantamab-vmjw (Rybrevant) plus lazertinib (Lazcluze) in locally advanced or metastatic EGFR-mutant non–small cell lung cancer (NSCLC) broadens first-line treatment options for patients with exon 19 deletions or exon 21 L858R substitution mutations, the latter of whom often experience suboptimal responses to current third-generation TKIs, according to Joshua K. Sabari, MD. Sabari added that the approval also sets the stage for future research into managing toxicities and developing next-generation therapies.1

This regulatory decision, made on August 20, 2024, was based on data from the phase 3 MARIPOSA trial (NCT04487080), updated findings from which were presented at the 2024 IASCL World Conference on Lung Cancer. At a median follow-up of 31.1 months the combination (n = 429) led to a median overall survival (OS) that was not estimable (NE; 95% CI, NE-NE) vs 37.3 months (95% CI, 32.5-NE) with osimertinib (Tagrisso; n = 429; HR, 0.77; 95% CI, 0.61-0.96; P = .019).2 Findings from an earlier analysis that had been conducted with a median follow-up of 22.0 months demonstrated that the combination also reduced the risk of progression or death by 30% vs osimertinib (HR, 0.70; 95% CI, 0.58-0.85; P < .001). The median progression-free survival (PFS) for patients treated with the combination was 23.7 months (95% CI, 19.1-27.7) vs 16.6 months (95% CI, 14.8-18.5) for those treated with osimertinib.3

“This is the first therapeutic option that broadly targets EGFR mutations, and it builds upon the standard TKIs that we’ve utilized for the past 10-plus years,” said Sabari, who is an assistant professor in the Department of Medicine at New York University (NYU) Grossman School of Medicine, as well as the director of High Reliability Organization Initiatives at NYU Langone Health’s Perlmutter Cancer Center, in New York.

Despite the combination’s clear efficacy benefits, strategies for managing unique toxicities associated with amivantamab, including infusion-related reactions (IRRs) and skin toxicities, must be improved, Sabari notes.

In an interview with OncLive®, Sabari highlighted the main implications of this approval for patients with select EGFR mutations; key efficacy and safety data with the regimen as seen in the MARIPOSA trial; and ongoing research evaluating amivantamab in a variety of settings and combinations within NSCLC.

OncLive: How did the success of third-generation EGFR TKIs in NSCLC inform efforts to improve upon this standard of care (SOC) with the addition of amivantamab to lazertinib?

Sabari: EGFR-mutant lung cancer is a quite common disease; upwards of 20% to 25% of patients with NSCLC harbor an activating EGFR mutation. Exon 19 deletions are the most common, and then L858R substitutions are the second most common. The third-generation EGFR TKI osimertinib has been a SOC [for this population], with [high] response rates, a median PFS of approximately 19 months, and median OS of approximately 39 months to date. [However], we needed to build upon that because we know that [patients with] different mutation subtypes such as [EGFR] L858R mutations might not perform as well with osimertinib [compared with patients who harbor] exon 19 deletions. [The latter population] tends to do a bit better [with the regimen]. We needed to better understand this population, and we need to build upon the successes of third-generation EGFR TKIs.

Could you describe the design of the MARIPOSA trial, including the patient population, treatment arms, and key end points?

MARIPOSA is a randomized, trial of frontline amivantamab plus lazertinib in patients with activating EGFR mutations. Amivantamab is a novel EGFR-MET bispecific [antibody], and lazertinib is a third -generation EGFR inhibitor. [The study] compared [the combination] with osimertinib as the control arm. There was a third arm [assessing the] contribution of [individual] components [by administering] lazertinib alone. Over 1000 patients were randomly assigned 2:2:1 onto [the combination arm] vs the control arm [vs the lazertinib monotherapy arm]. The primary end point of this trial was PFS [for the combination arm vs the osimertinib arm] by blinded independent central review. We also looked at secondary end points, such as OS, which is still immature, overall response rate, duration of response, and intracranial PFS.

This study was designed specifically for patients with locally advanced or metastatic NSCLC who harbored common EGFR mutations. They all had a good ECOG performance status of 0 or 1. We did allow patients with a history of brain metastases to enroll, but those needed to be treated. We also monitored the central nervous system very closely.

In this study, we stratified [patients] by a couple of factors [including the] EGFR mutation [subtype]...race, and history of brain metastases. This is a common patient population that most thoracic medical oncologists or community oncologists will see in their clinical practice on a day-to-day basis.

What efficacy data from MARIPOSA supported the FDA approval of this combination?

The major takeaway, and what led to the FDA approval, is [that the study met its] primary end point of PFS [with the combination]. Amivantamab plus lazertinib reduced the risk of progression or death by 30% and improved the median PFS by 7.1 months. When you compare amivantamab plus lazertinib [with] osimertinib, the median PFS was 23.7 months vs 16.6 months, [respectively]. The Kaplan-Meier curves show a nice separation. [The] 12-month [PFS rates were] 73% in patients treated with amivantamab plus lazertinib vs 65% with osimertinib. If you look at [PFS rates] at 2 years, it is quite dramatic; 48% of patients are progression free on amivantamab plus lazertinib vs 34% on osimertinib. This is what you expect to see in clinical practice. I tell most patients on osimertinib that in 19 to 20 years, we’re going to see approximately half of our patients progress on this therapy.

What unique toxicities were observed with the combination in this study?

Amivantamab has a unique safety profile compared with other EGFR inhibitors. Traditionally, when we think about [toxicities associated with] third-generation EGFR TKIs, we think about things like perioral rash, dermatitis, loose stools, diarrhea, or some fatigue. [However], amivantamab has a unique set of EGFR-mediated toxicities, as well as MET-directed toxicity. The most common adverse effects [AEs] that we saw with the [doublet] were IRRs, [as] this is an intravenous [IV] formulation of amivantamab. High rates of IRRs can be mitigated by splitting the dose [across 2 days] in cycle 1 and by giving prophylactic therapies such as steroids, dexamethasone, antipyretics, and other medications. We know with the subcutaneous formulation of amivantamab that the rate of IRRs, which was approximately 60% to 70% with IV [amivantamab], decreased to approximately 10% with the subcutaneous formulation. [However, this formulation] is not yet FDA approved.

Other toxicities that we saw with amivantamab, and the most concerning, are the skin toxicities. [This includes] things like dermatitis, paronychia, erythematous-type reactions in the scalp, and pustular reactions on the scalp.

Multiple ongoing studies are now looking at prophylactic management of EGFR-mediated toxicities [associated with] amivantamab. [This includes] upfront utilization of doxycycline, antibiotics, topical emollients with ceramides, and different creams to see if we can mitigate this reaction. Lastly, we did see an increased risk of venous thromboembolism in the amivantamab arm vs the osimertinib [arm]. Because of those data, we are recommending prophylactic anticoagulation [agents] for all patients receiving amivantamab and lazertinib, at least for the first 4 months [on treatment]. Interestingly, the 1 toxicity that we saw more commonly [with] osimertinib was EGFR-mediated toxicity of diarrhea compared with the amivantamab and lazertinib arm.

How has this approval opened avenues for future research and drug development in EGFR-mutant NSCLC?

Amivantamab is one of the first therapeutic options I’ve seen that has shown broad activity across all EGFR mutations. We have a second-line approval [for amivantamab] in [NSCLC harboring EGFR] exon 20 mutations. More recently, in March 2024, we saw a frontline approval of the phase 3 PAPILLON trial [NCT04538664] regimen of amivantamab plus chemotherapy for [EGFR exon 20 mutation–positive NSCLC], and we now have our first indication in combination with lazertinib for [patients with] common EGFR mutations. Lastly, the phase 3 MARIPOSA-2 trial [NCT04988295] regimen of [amivantamab plus lazertinib], which is recommended by the National Comprehensive Cancer Network in the second-line setting, is likely be approved by the FDA shortly.We’re seeing broad activity [with amivantamab] across all EGFR-mutant NSCLC [subtypes]. At the 2024 ASCO Annual Meeting, we saw data on the [P-loop alpha-C-helix–compressing] mutations G719X, S768I, formerly known as atypical mutations. These mutations are largely refractory to osimertinib, and we were generally using second-generation EGFR inhibitors such as afatinib [Gilotrif] for patients harboring these mutations].

What we need to do now is work on managing and mitigating toxicities in patients. We also need to think about the next generation of inhibitors, building upon the therapies that we have.

Looking to the future, [we think of] EGFR- and MET[-targeted] antibody-drug conjugates. Remember, MET [is] a common resistance mechanism in 10% to 12% of third-generation EGFR–treated patients. We also are thinking about engaging the immune system in a more novel fashion, and amivantamab has that opportunity to target immune activation through the Fc receptor portion of the bispecific. CD3/EGFR-directed bispecific antibodies—these are T-cell engagers—are also a very exciting, but [this is an] early opportunity and foray into this space.

What are some of the most promising ongoing studies of amivantamab in NSCLC?

Multiple ongoing studies are looking at amivantamab. There’s the phase 3 PALOMA-3 trial [NCT05388669], which is [examining] a subcutaneous formulation of amivantamab. Lots of work [is exploring] the subcutaneous formulation to mitigate a lot of the toxicities we talked about, particularly IRRs. We saw some data, and I was fortunate to be part of that study where we saw the rates of IRRs reduced to about 10% [with the subcutaneous formulation] compared with 65% to 70% with the IV formulation. [Even] more important, in PALOMA-3, we saw an improvement in survival. So, [this represents] an exciting opportunity as the subcutaneous formulation [may have] a significant benefit to patients; that’s still being worked out in this patient population. We’re looking at studying this drug across all EGFR mutations with the hope [that] this [will] be a therapeutic option that’s available for all [patients with] EGFR mutations. We’re also now starting to look at this agent in other diseases, such as colorectal cancer. We know the role of EGFR inhibition [in that disease] with panitumumab [Vectibix] and cetuximab [Erbitux] in that population.

*Editor’s Note: This interview took place before the updated presentation at the IASLC World Conference on Lung Cancer.

References:

  1. Rybrevant (amivantamab-vmjw) plus Lazcluze (lazertinib) approved in the U.S. as a first-line chemotherapy-free treatment for patients with EGFR-mutated advanced lung cancer. News release. Johnson & Johnson. August 20, 2024. Accessed September 5, 2024. https://www.investor.jnj.com/news/news-details/2024/RYBREVANT-amivantamab-vmjw-plus-LAZCLUZE-lazertinib-approved-in-the-U.S.-as-a-first-line-chemotherapy-free-treatment-for-patients-with-EGFR-mutated-advanced-lung-cancer/default.aspx
  2. Gadgeel S, Cho BC, Lu S, et al. Amivantamab plus lazertinib vs osimertinib in first-line EGFR-mutant advanced NSCLC: longer follow-up of the MARIPOSA study. Presented at: IASLC 2024 World Conference on Lung Cancer; September 7-10, 2024; San Diego, CA. Abstract OA02.03.
  3. 3.Cho BC, Lu S, Felip E, et al. Amivantamab plus lazertinib in previously untreated EGFR-mutated advanced NSCLC. N Engl J Med. Published online June 26, 2024. doi:10.1056/NEJMoa2403614
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