New First-Line Standard for Lung Cancers With EGFR Exon 20 Insertions

MADRID — Amivantamab (Rybrevant) confirmed its clinical benefit in advanced non-small cell lung cancer (NSCLC) with EGFR exon 20 insertions, and in doing so has established a new first-line standard for this patient population.

In the randomized PAPILLON trial, the addition of the bispecific antibody to chemotherapy reduced the risk of progression or death by 60% over chemotherapy alone, resulting in a median progression-free survival (PFS) of 11.4 months versus 6.7 months, respectively (HR 0.40, 95% CI 0.30-0.53, P<0.001).

The combination demonstrated a consistent PFS benefit across subgroups, and an interim overall survival (OS) analysis showed a trend favoring the amivantamab arm despite the trial’s crossover design, reported Nicolas Girard, MD, PhD, of the Institut Curie in Paris.

Response rates with amivantamab plus chemotherapy were significantly improved versus chemotherapy alone (73% vs 47%), and these responses occurred faster and proved more durable, according to findings of the phase III study presented here at the European Society for Medical Oncology (ESMO) congress and simultaneously published in the New England Journal of Medicine.

“Based on these results, amivantamab plus chemotherapy represents the new standard of care for the first-line treatment of these patients,” said Girard.

‘New Standard’ in Tough-to-Treat Disease

EGFR exon 20 insertion mutations account for 12% of all EGFR-mutant NSCLCs and are associated with rapid cell growth. Outcomes for newly diagnosed NSCLC patients with these insertions are poor, with a 5-year OS rate below 10%, Girard explained.

Importantly, he noted, these patients cannot be treated with typical EGFR tyrosine kinase inhibitors “and immunotherapy-based regimens do not improve survival as compared to chemotherapy alone, which has remained the standard of care for these patients.”

Based on single-arm tumor-response data, the EGFR-directed and MET-receptor-directed antibody had received accelerated approval in 2021 for treating NSCLC patients with EGFR exon 20 insertions whose disease had progressed on or after platinum-based chemotherapy.

With benefit confirmed in this phase III study and others, amivantamab is set to be the only drug on the U.S. market for this patient population following the planned withdrawal of mobocertinib (Exkivity) after a failed confirmatory trial.

ESMO-invited discussant Benjamin Besse, MD, PhD, of the Gustave Roussy in Villejuif, France, agreed that PAPILLON has “established a new standard of care” in this setting, adding that both the efficacy and toxicity of combining the bispecific drug with chemotherapy seems “quite additive.”

Prior studies in heavily pretreated patients suggested a similar PFS with single-agent amivantamab and platinum-based chemotherapy, “so it was wise to combine chemotherapy and amivantamab.”

But “this is not completely an easy drug,” he said, and side effects have to be managed aggressively.

Besse pointed out that in the combination arm, dose interruptions for adverse events (AEs) occurred in 42% of patients for either amivantamab or chemotherapy and in 29% for amivantamab specifically; dose reductions were recorded in 36% and 18%; and discontinuation occurred in 15% and 7%.

Study Details

PAPILLON enrolled 308 NSCLC patients with EGFR exon 20 insertions from 2020 to 2022, randomizing them 1:1 to chemotherapy plus amivantamab or chemotherapy alone, with crossover to the targeted agent allowed at progression in the control arm. Mutational status was determined by local testing of tissue (92%) or plasma (8%). PFS per blinded independent central review was the study’s primary endpoint.

Patients had a median age of 61-62 years, a majority were women, over 60% were Asian, and a little over a third were white. More than 40% had a history of smoking in each arm, 23% had brain metastases at baseline, and 65% had an Eastern Cooperative Oncology Group performance status of 1.

At data cutoff, 46% of patients remained on amivantamab-chemotherapy as compared with 15% of those assigned to chemotherapy alone.

Partial response rates reached 69% in the combination arm versus 47% with chemotherapy alone, said Girard, including complete responses in 4% and 1%, respectively. Responses to the combination proved more rapid than chemotherapy alone (6.7 vs 11.4 weeks) and more durable (9.7 vs 4.4 months).

And he noted that the PFS curves separated early, widened, and that the combination showed a “sustained benefit” out to 18 months:

• 6 months: 77% vs 51%
• 12 months: 48% vs 13%
• 18 months: 31% vs 3%

In an interim analysis, median OS was not reached in the amivantamab arm versus 24.4 months with chemotherapy alone (HR 0.67, 95% CI 0.42-1.09). OS rates favored the amivantamab-chemotherapy group at all time points:

• 12 months: 86% vs 82%
• 18 months: 74% vs 68%
• 24 months: 72% vs 54%

While immature, the OS data showed “evidence of a survival benefit” with the combination, despite the fact that two-thirds of control-arm patients crossed over to receive amivantamab, said Girard.

Grade ≥3 treatment-emergent AEs were higher with amivantamab-chemotherapy (75% vs 54% with chemotherapy alone), though these patients also stayed on treatment for a median 3 months longer, Girard noted. In the combination arm, the most common grade ≥3 treatment-emergent AEs included neutropenia (33%), rash (11%), anemia (11%), leukopenia (11%), and thrombocytopenia (10%). Four (3%) patients experienced grade 3 pneumonitis while on the combination, with all cases resolved at data cutoff.

Serious AEs occurred in 37% of patients in the amivantamab arm compared with 31% of those in the control arm. AEs leading to death were recorded in 5% and 3%, respectively.

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