medwireNews: Three phase 3 trials presented at the ESMO Congress 2023 have shown improved outcomes with amivantamab combinations in different populations of patients with advanced non-small-cell lung cancer (NSCLC).
Amivantamab is a bispecific antibody targeting EGFR and MET that has previously shown antitumor activity and a manageable safety profile, alone and combined with other agents, in various populations of NSCLC patients in phase 1 studies.
As reported in Madrid, Spain, the PAPILLON trial recruited untreated patients with EGFR exon 20 insertions, while the participants of MARIPOSA and MARIPOSA-2 harbored common EGFR mutations, with the former being treatment-naïve and the latter osimertinib-treated.
PAPILLON trial results
The PAPILLON study enrolled 308 patients who had not received prior treatment for locally advanced or metastatic NSCLC positive for EGFR exon 20 insertion mutations. They were randomly allocated to treatment with carboplatin plus pemetrexed with or without amivantamab given intravenously at a dose of 1400 mg every week for the first 4 weeks and then at 1750 mg every 3 weeks (the respective doses were 1750 and 2100 mg for those weighing ≥80 kg).
After a median follow-up of 14.9 months, the primary endpoint of independently assessed progression-free survival (PFS) was almost doubled with versus without amivantamab, at a median of 11.4 and 6.7 months, respectively. This equated to a significant hazard ratio (HR) for progression or death of 0.395 in favor of amivantamab.
At the 12-month mark, 48% of patients in the amivantamab arm were alive and progression-free compared with 13% of those in the control arm, while the 18-month rates were 31% and 3%, respectively.
The objective response rate (ORR) was also significantly higher with the addition of amivantamab to chemotherapy, at 73%, versus 47% with chemotherapy alone, and the median duration of response was longer, at 9.7 versus 4.4 months.
Investigator Nicolas Girard, from Institut Curie in Paris, France, reported that in a prespecified interim analysis of overall survival (OS), the median duration was unreached in the amivantamab group and 24.4 months in the control group. There was a trend toward a reduced risk for death with amivantamab despite two-thirds of patients in the chemotherapy group crossing over to receive amivantamab monotherapy after disease progression.
“But the data are not mature enough, with too few events to draw any robust conclusions,” he added.
The incidence of treatment-emergent adverse events (TEAEs) of grade 3 or worse was higher among amivantamab-treated participants than those given chemotherapy alone, at 75% versus 54%, as was the rate of discontinuation of any agent, at 24% versus 10%.
But the rate of serious AEs and fatal AEs was “comparable between arms,” noted Girard, at 37% versus 31% and 5% versus 3%, respectively, and an identical 8% of patients in each group discontinued all study agents due to AEs.
The presenter concluded that PAPILLON is “the first phase 3 study to demonstrate a clinical benefit” in people with EGFR exon 20 insertions, “and based on these results, amivantamab plus chemotherapy represents the new standard of care for the first-line treatment of these patients.”
The findings appeared simultaneously in The New England Journal of Medicine.
Data from MARIPOSA
The MARIPOSA investigators recruited 1074 individuals with treatment-naïve locally advanced or metastatic NSCLC harboring an EGFR exon 19 deletion or L858R mutation, and randomly assigned them to receive amivantamab alongside the third-generation EGFR–tyrosine kinase inhibitor lazertinib, osimertinib monotherapy, or lazertinib alone. Amivantamab was administered at a dose of 1050 mg (1400 mg if ≥80 kg) weekly for the first 4 weeks, then every 2 weeks, while lazertinib and osimertinib were given at daily doses of 240 mg and 80 mg, respectively.
Analysis of the primary endpoint of PFS – as assessed by blinded independent central review – in the amivantamab plus lazertinib versus osimertinib groups showed a significant improvement with the combination, at medians of 23.7 and 16.6 months, respectively, and an HR of 0.70.
The PFS rates at 12 months were 73% versus 65% and at 18 months were 48% versus 34%.
Byoung Chul Cho (Yonsei Cancer Center, Seoul, South Korea) told the audience that “lazertinib monotherapy demonstrated meaningful clinical activity, with a median PFS of 18.5 months, indicating that lazertinib is a wonderful combination partner for amivantamab.”
Treatment with amivantamab plus lazertinib resulted in an ORR that was similar to that with osimertinib alone, at 86% and 85%, respectively, but the median duration of response was longer with the combination, at 25.8 versus 16.8 months.
Once again, the OS data were not mature at the time of data cutoff at a median follow-up of 22 months but showed “a strong trend” in favor of amivantamab–lazertinib, at an HR of 0.80, reported Cho.
TEAEs of at least grade 3 were more common among patients in the combination than osimertinib group, at 75% versus 43%, and so were any AE-related treatment interruptions (83 vs 39%), dose reductions (59 vs 5%), and discontinuations (35 vs 14%) of any agent. But the incidence of any AEs leading to death was similar, at 8% and 7%, respectively.
Cho said in conclusion that “based on the MARIPOSA study, amivantamab plus lazertinib represents a new standard of care in patients with [untreated] EGFR-mutant advanced NSCLC.”
MARIPOSA-2 findings
The third trial – MARIPOSA-2 – investigated amivantamab plus chemotherapy, with or without lazertinib, in people with locally advanced or metastatic disease positive for an EGFR exon 19 deletion or L858R mutation who had progressed on or after osimertinib monotherapy
Participants were followed up for a median of 8.7 months, at which point the primary endpoint of PFS by independent assessment was a median of 8.3 months for the 263 patients who were randomly assigned to receive amivantamab (on the same dosing schedule as in PAPILLON) plus lazertinib 240 mg/day alongside carboplatin plus pemetrexed.
This was significantly longer than the median of 4.2 months observed among the 263 patients treated with chemotherapy alone, and equated to an HR of 0.44.
The median PFS duration of 6.3 months achieved by the 131 participants given amivantamab plus chemotherapy was also significantly longer than that among chemotherapy-treated patients, and gave an HR in favor of adding amivantamab of 0.48.
The 6-month PFS rates were 59%, 51%, and 30% in the amivantamab, lazertinib plus chemotherapy, amivantamab plus chemotherapy, and chemotherapy alone groups, respectively, with corresponding 12-month rates of 37%, 22%, and 13%.
The ORRs were also significantly higher with the addition of amivantamab–lazertinib and amivantamab to chemotherapy, at 63% and 64%, respectively, versus 36% with chemotherapy alone. The respective median durations of response were 9.4, 6.9, and 5.6 months.
The presenting author reported that the interim OS analysis pointed to “a positive trend” with the combination of amivantamab plus chemotherapy versus chemotherapy alone (HR=0.77), but not with amivantamab and lazertinib plus chemotherapy versus chemotherapy alone (HR=0.96).
Antonio Passaro (European Institute of Oncology, Milan, Italy) highlighted, however, that the triplet arm underwent a protocol amendment following an increase in the incidence of hematologic toxicities, whereby lazertinib was initiated after completion of carboplatin. And the median follow-up for the modified regimen is only 5.4 months.
With regard to safety, the addition of amivantamab to chemotherapy, with or without lazertinib, was associated with a higher rate of TEAEs of grade 3 or more than chemotherapy alone, at 92% and 72% versus 48%, respectively.
Patients receiving amivantamab-containing regimens were more likely than their counterparts given chemotherapy alone to require interruptions (77 and 65 vs 33%), dose reductions (65 and 41 vs 15%), and discontinuations (34 and 18 vs 4%) of any agent. However, the proportion who experienced fatal AEs was “very, very low,” said Passaro, at 5% and 2% versus 1%, respectively.
And he concluded that on the basis of the efficacy and safety data, “we can say that amivantamab plus chemotherapy is the new standard of care for patients that progress after osimertinib.”
The trial results are published simultaneously in the Annals of Oncology.
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ESMO Congress 2023; Madrid, Spain: 20–24 October (LBA5)
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