Amivantamab Significantly Improves Progression-Free Survival in EGFR exon 20 insertion–positive NSCLC


Amivantamab plus chemotherapy nearly doubled the progression-free survival in patients with EGFR Exon 20-mutated non–small-cell lung cancer.

Nicolas Girard, MD, PhD

Nicolas Girard, MD, PhD

Patients with advanced, EGFR exon 20 insertion–positive non–small cell lung cancer (NSCLC) experienced superior progression-free survival (PFS) with amivantamab-vmjw (Rybrevant) and chemotherapy vs chemotherapy alone, according to findings from the phase 3 PAPILLON trial (NCT04538664) that were presented at the 2023 ESMO Congress and simultaneously published in the New England Journal of Medicine.1,2

Key Findings

Overall, the medianPFS with amivantamab was 11.4 months (95% CI, 9.8-13.7) vs 6.7 months (95% CI, 5.6-7.3) with chemotherapy alone.

At a median follow-up of 14.9 months, the blinded independent central review (BICR)–assessed hazard ratio was 0.395, in favor of the combination (95% CI, 0.30-0.53; P <.0001). Consistent benefit was also seen by investigator assessment, with a median PFS of 12.9 months with the combination vs 6.9 months with chemotherapy alone (HR, 0.38; 95% CI, 0.29-0.51; P <.0001). The 12- and 18-month PFS rates with the combination were 48% and 31%, respectively, vs 13% and 3% with chemotherapy alone.

A trend toward improved overall survival (OS) with the combination was also seen (HR, 0.675; 95% CI, 0.42-1.09; P =.106). Median OS was not evaluable (NE; 95% CI, NE-NE) in the combination arm vs 24.4 months (95% CI, 22.1-NE) in the chemotherapy-alone arm. The 18- and 24-month OS rates in the combination arm were 74% and 72%, respectively, vs 68% and 54% with chemotherapy alone.

“Consistent PFS benefit [was seen] across predefined subgroups by blinded independent central review. Amivantamab-chemotherapy represents the new standard of care for first-line EGFR exon 20 insertion–mutated advanced NSCLC,” Nicolas Girard, MD, PhD, professor of respiratory medicine at Versailles Saint Quentin University, and professor and head of the Curie-Montsouris Thorax Institute at the Institut Curie in France, said in a presentation of the data.

Findings from the trial served as the basis for Janssen’s submission of a supplemental biologics license application to the FDA and a Type II extension of indication application to the European Medicines Agency seeking the expanded approval of amivantamab plus chemotherapy for this population.3,4

Platinum-based chemotherapy remains the frontline standard of care for patients with EGFR exon 20 insertion–mutated, advanced NSCLC despite attempts to improve outcomes with common EGFR TKIs and checkpoint inhibitors.

Amivantamab is an EGFR and MET bispecific antibody currently approved for the treatment of patients with EGFR exon 20 insertion–mutated advanced NSCLC following progression of platinum-based chemotherapy. Because of its immune cell–directing activity, investigators hypothesized that the agent may lead to deeper and more durable responses in combination with chemotherapy.

Previous results from a phase 1 study demonstrated the safety, tolerability, and efficacy of the combination in a small population of 20 patients. In the 5 patients with untreated EGFR exon 20 insertion–mutated NSCLC, 4 achieved partial response.

PAPILLON Trial Design

To be eligible for enrollment in the phase 3 trial, patients had to have untreated, locally advanced or metastatic NSCLC with a documented EGFR exon 20 insertion mutation and an ECOG performance status (PS) of 0 or 1.

A total of 308 patients were randomly assigned 1:1 to amivantamab plus chemotherapy (n = 153) or chemotherapy alone (n = 155). Amivantamab was administered at a dose of 1400 mg (1750 mg if ≥80 kg) for the first 4 weeks, then 1750 mg (2100 mg if ≥80 kg) every 3 weeks, starting at week 7. Chemotherapy was administered on the first day of each 21-day cycle: carboplatin at an area under the curve of 5 for the first 4 cycles and pemetrexed (Alimta) at 500 mg/m2 until disease progression. Patients in the chemotherapy alone arm were allowed to cross over to receive amivantamab monotherapy at the time of progression.

PFS by BICR assessment according to RECIST v1.1 criteria served as the primary end point. Secondary end points included objective response rate (ORR), duration of response (DOR), OS, PFS after first subsequent therapy (PFS2), symptomatic PFS, time to subsequent therapy, and safety.

Patients were stratified by ECOG PS, history of brain metastases, and prior EGFR TKI use.

Secondary End Points

Of the 153 and 155 patients who were randomly assigned to the combination and chemotherapy alone, 151 and 155 received their respective treatment regimens. In the combination arm, 54% discontinued treatment due to disease progression (33%), an adverse effect (AE; 9%), patient withdrawal (8%), other reason (3%), or death (1%). In the chemotherapy-alone arm, 85% of patients discontinued treatment because of disease progression (69%), an AE (9%), patient withdrawal (3%), other reason (3%), or death (1%). Of these patients, 65 crossed over to receive amivantamab as part of the study; another 6 patients received the agent off-protocol, leaving 15% of patients in ongoing treatment in the chemotherapy arm and 46% in the combination arm.

Regarding baseline characteristics, the median patient age was 61 years (range, 27-86) and 62 (range, 30-92) years in the combination and chemotherapy-alone arms, respectively. Moreover, most patients in both arms were female (56% vs 60%), Asian (64% vs 59%), and did not have a history of smoking (58% vs 59%). Most patients had an ECOG PS of 1 (65% vs 65%), no history of brain metastases (77% vs 77%), no prior exposure to an EGFR TKI (99% vs 98%), and adenocarcinoma (99% vs 99%).

Additional efficacy results demonstrated that the BICR-assessed ORR was 73% (95% CI, 65%-80%) with the combination vs 47% (95% CI, 39%-56%) with chemotherapy alone (odds ratio, 3.0; 95% CI, 1.8-4.8; P <.0001). The mean percentage change of the sum of diameters was –53% with the combination and –34% with chemotherapy alone. Best response consisted predominantly of partial responses in both the combination and chemotherapy alone arms, respectively (69% vs 47%), though complete responses (4% vs 1%), and stable disease (19% vs 41%) also occurred. Few patients experienced progressive disease (3% vs 11%), and 10 patients were not evaluable, 5% in the combination arm and 1% in the chemotherapy alone arm.

The median time to response was 6.7 weeks (range, 5.1-72.5) with the combination vs 11.4 weeks (range, 5.1-60.2) with chemotherapy alone.

Similar results were seen by investigator assessment, with an ORR of 66% with the combination and 43% with chemotherapy alone (odds ratio, 2.6; P <.0001).

The BICR-assessed median DOR was 9.7 months (95% CI, 8.2-13.5) with the combination vs 4.4 months (range, 4.1-5.6) with chemotherapy alone. At data cutoff, 49% of patients in the combination arm remained in response compared with 17% in the chemotherapy alone arm. The 12- and 18-month DOR rates were 43% and 34% with the combination, respectively, vs 8% and 4% with chemotherapy alone. Median DOR per investigator assessment was similar to that seen by BICR assessment, at 13.5 months with the combination vs 6.8 months with chemotherapy alone.

PFS2 was also improved, having not been reached (95% CI, 22.8-not evaluable) in the combination arm vs 17.2 months (95% CI, 14.0-21.5) with chemotherapy alone (HR, 0.493; 95% CI, 0.32-0.76; P =.001). The 18- and 24-month PFS2 rates were 67% and 57% with the combination, respectively, vs 46% and 35% with chemotherapy alone.

The most common first subsequent systemic therapy in the 43 and 71 patients in need of another treatment in the combination and chemotherapy alone arms, respectively, was chemotherapy (n = 13) and amivantamab (n = 71).

The median duration of treatment was 9.7 months (range, 0.1-26.9) with the combination vs 6.7 months (range, 0-25.3) with chemotherapy alone.

Regarding safety, grade 3 or greater AEs occurred in 75% of patients in the combination arm vs 54% of patients in the chemotherapy alone arm. Serious AEs and AEs leading to death were comparable between arms, Girard noted.

The most common grade 3 or greater AEs associated with EGFR inhibition were rash (11% vs 0% with the combination and chemotherapy alone, respectively), paronychia (7% vs 0%), and dermatitis acneiform (4% vs 0%). The only 2 grade 3 or greater AEs associated with MET inhibition were hypoalbuminemia (4% vs 0%) and peripheral edema (1% vs 0%). Other common grade 3 or greater AEs included neutropenia (33% vs 23%), anemia (11% vs 12%), and leukopenia (11% vs 3%). Other reported toxicities were infusion-related reactions, constipation, nausea, thrombocytopenia, decreased appetite, alanine aminotransferase increase, aspartate aminotransferase increase, COVID-19, hypokalemia, and vomiting.

“The safety profile of amivantamab-chemotherapy was consistent with the individual agents, and low rates of treatment-related discontinuations [occurred] with amivantamab at 7%,” Girard concluded.

Disclosures: Dr Girard reported consulting or advisory roles for Roche, Eli Lilly, AstraZeneca, Novartis, Pfizer, Bristol Myers Squibb, Merck Sharp & Dome, Takeda, Janssen, Sanofi, Amgen, Gilead Sciences, BeiGene, AbbVie, Daiichi Sankyo/AstraZeneca, LEO Pharma, and Ipsen; employment of family member at AstraZeneca; travel, accommodations, or expenses paid by Roche; and research funding from Roche, AstraZeneca, Bristol Myers Squibb, and MSD Avenir.


  1. Girard N, Park K, Tang K, et al. Amivantamab plus chemotherapy vs chemotherapy as first-line treatment in EGFR exon 20 insertion–mutated advanced non-small cell lung cancer (NSCLC). Ann Oncol. 2023;34(suppl 2):S1304. doi:10.1016/j.annonc.2023.10.060
  2. Zhou C, Tang KJ, Chul B, et al. Amivantamab plus chemotherapy in NSCLC with EGFR exon 20 insertions. N Engl J Med. Published online October 21, 2023. doi:10.1056/NEJMoa2306441
  3. Janssen submits supplemental biologics license application to the US Food and Drug Administration seeking approval of Rybrevant (amivantamab-vmjw) in combination with chemotherapy for the first-line treatment of patients with locally advanced or metastatic EGFR exon 20 insertion mutation-positive non-small cell lung cancer. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. August 25, 2023. Accessed October 21, 2023.
  4. Janssen submits application to the European Medicines Agency for Rybrevant (amivantamab) in combination with chemotherapy for the first-line treatment of adult patients with advanced non-small cell lung cancer with activating EGFR exon 20 insertion mutations. News release. The Janssen Pharmaceutical Companies of Johnson & Johnson. October 6, 2023. Accessed October 21, 2023.
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