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MADRID -- Two positive phase III trials involving amivantamab (Rybrevant)-based regimens introduced new first- and second-line options in EGFR-mutant non-small cell lung cancer (NSCLC), though toxicity with the combination strategies raised some concerns.

In the first-line trial, treatment with the targeted combination of amivantamab plus lazertinib significantly improved median progression-free survival (PFS) by about 7 months over the current standard, single-agent osimertinib (Tagrisso). Early overall survival (OS) assessment showed no significant difference between arms, but Kaplan-Meier curves started to separate in favor of the combination, reported Byoung Chul Cho, MD, PhD, of Yonsei Cancer Center in Seoul, Korea.

And in a study involving patients who had already progressed on osimertinib, adding either amivantamab alone or amivantamab-lazertinib to a standard second-line chemotherapy regimen improved median PFS by about 2 to 4 months, while nearly doubling response rates versus chemotherapy alone. The two investigational strategies improved intracranial PFS as well, though interim OS data showed no significant difference compared with chemotherapy alone, according to findings presented by Antonio Passaro, MD, PhD, of the European Institute of Oncology, IRCCS in Milan.

Increased toxicity showed up in all of the investigational arms -- including more dermatologic toxicities, infusion-related reactions, and venous thromboembolism (VTE) with amivantamab-lazertinib in particular -- a potential concern especially in the upfront setting where patients could stay on treatment for years.

Findings from the two trials, MARIPOSA and MARIPOSA-2, were presented here during a late-breaking session at the congress, and challenge the current treatment landscape in locally advanced unresectable and metastatic EGFR-mutant NSCLC.

Osimertinib has become the preferred first-line therapy for newly diagnosed EGFR-mutant disease, based on established PFS and OS gains over older EGFR inhibitors in the landmark FLAURA trial. And just last month, researchers from FLAURA2 reported that the addition of pemetrexed and platinum chemotherapy to osimertinib improved PFS in the first line over single-agent osimertinib.

Amivantamab, meanwhile, is an intravenously delivered central nervous system (CNS)-penetrant EGFR- and MET-directed bispecific antibody currently approved for NSCLC with EGFR exon 20 insertions, where it is now considered standard first-line in that patient population. Lazertinib, an oral third-generation EGFR inhibitor like osimertinib, remains an investigational therapy.

Based on FLAURA, FLAURA2, and MARIPOSA, "we now have three first-line options for our patients with EGFR-mutant non-small cell lung cancer," said ESMO discussant Zosia Piotrowska, MD, MHS, of Massachusetts General Hospital Cancer Center in Boston, who suggested that treatment will likely need to be individualized based on patient preferences.

"But for most patients, first-line osimertinib is likely to remain my preferred approach for now given the lack of OS benefit and toxicity concerns with the combination regimens," said Piotrowska. "Chronic dermatologic toxicities can have a significant impact, particularly for patients who are remaining on first-line therapy for 2 years or more."

Upon progression on first-line therapy, most patients in the clinic currently undergo a biopsy to look for targetable resistance mechanisms, said Piotrowska, but the majority ultimately receive carboplatin-pemetrexed in second-line, the regimen used as the comparator arm in MARIPOSA-2.

While the two amivantamab-based chemotherapy regimens in the study represent new post-osimertinib options, if approved, the combined dermatologic and hematologic toxicities pose a challenge in the clinic, she said.

But again, even in the second-line setting, she cited safety concerns and the lack of OS benefit, adding that "carboplatin-pemetrexed will likely remain my preferred regimen for most patients."

First-Line Trial

The three-arm randomized 1,074 patients with locally advanced or metastatic NSCLC in a 2:2:1 ratio to first-line treatment with either intravenous amivantamab plus oral lazertinib, osimertinib, or lazertinib alone (this third arm was aimed at assessing the contribution of lazertinib). Eligibility criteria required documented EGFR exon 19 deletion or L858R mutations. The primary endpoint was PFS by blinded independent central review.

At baseline, patients had a median age of about 63 years, over 60% were women, 59% were Asian, 38% were white, and approximately 40% had a history of brain metastases.

Over a median follow-up of 22 months, combination treatment with amivantamab-lazertinib reduced the risk for disease progression or death by 30% compared with single-agent osimertinib (HR 0.70, 95% CI 0.58-0.85, P<0.001), with median PFS values of 23.7 months versus 16.6 months, Cho reported. (Median PFS in the lazertinib monotherapy arm reached 18.5 months.)

Despite nearly identical response rates in the amivantamab-lazertinib and osimertinib arms (86% vs 85%), the combination yielded more durable responses (median 25.8 months vs 16.8 months).

Interim OS data showed a trend favoring the combination over osimertinib (HR 0.80, 95% CI 0.61-1.05), with 2-year rates of 74% and 69%.

Combination treatment "showed consistent benefit in patients with and without brain metastases, more durable responses -- with a 9-month improvement in median duration of response -- and a favorable trend in OS," said Cho. "Based on the MARIPOSA study, amivantamab plus lazertinib represents a new standard of care."

But Piotrowska suggested that mature OS data will be needed to change practice, given that chronic toxicities of a regimen given over a long treatment duration pose a particular challenge in the frontline setting.

Amivantamab-lazertinib was associated with higher rates of grade ≥3 adverse events (AEs) versus single-agent osimertinib (75% vs 43%), as well as higher rates of serious AEs (49% vs 33%), treatment interruptions (83% vs 39%), dose reductions (59% vs 5%), and discontinuation of any agent (35% vs 14%). Rates of all-grade VTE, an AE of special interest, occurred in 37% of patients assigned to the combination versus 9% of those on osimertinib, though most were low-grade, said Cho.

Second-Line Trial

enrolled 657 patients with locally advanced or metastatic NSCLC whose disease had progressed on first-line osimertinib. Patients were randomized in a 1:1:1 ratio to the four-drug regimen of amivantamab-lazertinib plus carboplatin-pemetrexed, carboplatin-pemetrexed alone, or the three-drug regimen of amivantamab plus carboplatin-pemetrexed.

Dual primary endpoints of the trial were PFS for the two amivantamab arms versus the chemotherapy-alone arm.

At baseline, patients had a median age of about 62 years, over 60% were women, 48% were Asian, 47% were white, and at least 44% of patients in each arm had a history of brain metastases.

Over a median follow-up of 8.7 months, both amivantamab-based regimens resulted in a greater than 50% reduction in the risk for disease progression or death compared with chemotherapy alone (P<0.001 for both):

• Amivantamab-lazertinib plus chemotherapy: HR 0.44 (95% CI 0.35-0.56)
• Amivantamab plus chemotherapy: HR 0.48 (95% CI 0.36-0.64)

Median PFS values reached 8.3 months with the four-drug regimen, 6.3 months with the three-drug combination, and 4.2 months with chemotherapy alone. Landmark analysis showed 1-year PFS rates of 37%, 22%, and 13%, respectively.

Response rates were significantly higher in both investigational arms, at 64% in the amivantamab arm, 63% in the amivantamab-lazertinib arm, and 36% in the chemotherapy-alone arm.

Interim OS analysis showed no significant improvement in either the amivantamab arm (HR 0.77, 95% CI 0.49-1.21) or amivantamab-lazertinib arm (HR 0.96, 95% CI 0.67-1.35) compared with the chemotherapy-alone arm.

Intracranial PFS was significantly higher in the two investigational arms, though with similar benefit with or without lazertinib (HRs of 0.58 and 0.55, respectively, P<0.001 for both).

"While we may not be sure what lazertinib is adding in the CNS, it is clear that it's adding to the toxicities of these regimens," said Piotrowska. "I think it will be really important to understand what its contribution is and whether there are patients who truly need it."

Treatment-emergent grade ≥3 AEs increased from 48% with carboplatin-pemetrexed chemotherapy, to 72% with the addition of amivantamab, and to 92% with the addition of amivantamab and lazertinib. In this study, VTE of any grade occurred in 22% of patients on the four-drug regimen, 10% of those on the three-drug regimen, and 5% of those on chemotherapy alone.

AEs leading to death were numerically higher with the four-drug therapy versus the other two regimens (5% vs 1-2%), though these were not all considered treatment-related.

Given the increased toxicity, Passaro said the four-drug combination given concurrently cannot be considered at this time, but called the combination of amivantamab plus chemotherapy "the new standard of care for patients who progress after osimertinib."