PAPILLON Final Analysis: RYBREVANT Plus Chemotherapy Delivers Longest Reported Median Overall Survival in EGFR Exon 20 Insertion NSCLC
核心洞察
Final Phase 3 PAPILLON data show first-line RYBREVANT plus carboplatin-pemetrexed achieved median overall survival of 34.3 months versus 27.9 months with chemotherapy alone in EGFR (搜索) exon 20 insertion NSCLC.
A prespecified crossover-adjusted analysis showed a significant survival benefit, reducing the risk of death by 43 percent (HR 0.57; 95% CI 0.39-0.82; nominal P=0.003).
The combination extended progression-free survival through second disease progression by more than 10 months (28.3 vs 17.5 months; HR 0.59; nominal P<0.0001).
Johnson & Johnson reported final overall survival (OS) results from the Phase 3 PAPILLON study showing that first-line intravenous RYBREVANT (amivantamab-vmjw) plus carboplatin-pemetrexed chemotherapy extended median OS to nearly three years (34.3 months) in patients with advanced non-small cell lung cancer (搜索) (NSCLC) harboring epidermal growth factor receptor (EGFR (搜索)) exon 20 insertion (Ex20ins) mutations, compared with 27.9 months for chemotherapy alone. The data were presented during the Presidential Symposium at the International Association for the Study of Lung Cancer (IASLC) 2026 World Conference on Lung Cancer (WCLC) as late-breaking abstract #PL.03.03.
The company stated that this represents the longest reported median OS in this patient population, which is nearly twice the historical median. The combination extended median OS by more than six months despite 76 percent of eligible patients in the chemotherapy arm crossing over to second-line RYBREVANT after disease progression.
Survival Results and Statistical Analysis
In the protocol-specified final analysis, RYBREVANT plus chemotherapy demonstrated a median OS of 34.3 months versus 27.9 months for chemotherapy alone (hazard ratio [HR], 0.87; 95 percent confidence interval [CI], 0.66-1.14; P=0.307). A prespecified analysis accounting for crossover to RYBREVANT in the chemotherapy arm showed a significant overall survival benefit with the combination, reducing the risk of death by 43 percent (HR, 0.57; 95 percent CI, 0.39-0.82; nominal P=0.003).
Long-term follow-up provided further evidence of durable benefit, with RYBREVANT plus chemotherapy extending progression-free survival through second disease progression (PFS2) by more than 10 months compared with chemotherapy alone (28.3 vs. 17.5 months; HR, 0.59; 95 percent CI, 0.45-0.77; nominal P<0.0001). Twelve percent of patients remained on first-line treatment at the clinical cutoff, compared with no patients in the chemotherapy arm. Patient-reported outcomes also favored the combination, delaying the worsening of several key lung cancer symptoms compared with chemotherapy alone.
The safety profile of IV RYBREVANT plus chemotherapy was consistent with previous reports from studies conducted before prophylactic strategies were introduced, with no new safety signals observed with longer follow-up. The most common treatment-related adverse events occurring in at least 30 percent of patients included paronychia (60 percent), neutropenia (60 percent) and rash (58 percent).
Expert Perspectives on Durability
"We've come a long way in treating EGFR (搜索) exon 20 insertion-positive lung cancer, and these results demonstrate the lasting impact RYBREVANT plus chemotherapy can have in helping patients live longer," said Dr. Chul Kim, M.D., M.P.H., Director of Thoracic Oncology, MedStar Georgetown University Hospital. "Patients are continuing treatment years after they started, which speaks to the durability of this approach and its value as a first-line treatment for this disease." Dr. Kim has served as a consultant to Johnson & Johnson and has not been paid for any media work.
"We have long believed RYBREVANT could transform the outlook for patients with EGFR (搜索)-mutated lung cancer by addressing key drivers of disease progression and treatment resistance," said Yusri Elsayed, M.D., M.H.Sc., Ph.D., Global Therapeutic Area Head, Oncology, Johnson & Johnson. "With the longest survival seen in this patient population, these results add to the growing body of evidence across common, atypical and exon 20 insertion EGFR mutations and further establish the regimen as a backbone therapy."
Disease Burden and Unmet Need
EGFR exon 20 insertion mutations (搜索) account for approximately 12 percent of all EGFR (搜索) mutations and are the third-most prevalent activating EGFR mutation. Unlike more common EGFR mutations (exon 19 deletions and L858R), exon 20 insertion mutations have been difficult to treat with targeted medicines, leaving patients with few treatment options, challenging side effects and poorer outcomes. Historically, median overall survival has ranged from approximately 16 to 24 months, with five-year survival reported at just eight percent. Patients with EGFR exon 20 insertion mutations have a real-world five-year OS of eight percent in the frontline setting, which is worse than patients with EGFR ex19del or L858R mutations, who have a real-world five-year OS of 19 percent.
Worldwide, lung cancer is one of the most common cancers, with NSCLC making up 80 to 85 percent of all lung cancer cases. EGFR (搜索) mutations are present in 10 to 15 percent of Western patients with NSCLC with adenocarcinoma histology and occur in 40 to 50 percent of Asian patients. The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR tyrosine kinase inhibitors (TKIs) is less than 20 percent.
Mechanism and Prior Evidence
RYBREVANT is a first-in-class bispecific antibody designed to dual-target EGFR (搜索) and mesenchymal-epithelial transition (MET), two key drivers of tumor growth and treatment resistance, while also engaging the immune system. It is currently approved for use in patients with EGFR-mutated advanced NSCLC across common (exon 19 deletions and exon 21 L858R substitution mutations) and exon 20 insertion mutations, in the first- and second-line settings.
The final OS findings build on the primary PAPILLON analysis, which demonstrated a statistically significant and clinically meaningful 60 percent improvement in progression-free survival (primary endpoint) with first-line RYBREVANT plus chemotherapy versus chemotherapy alone. Clinical benefit in the primary analysis was consistent across key patient subgroups, including patients with brain metastases, EGFR (搜索) exon 20 insertion variants and TP53 co-mutations. Those results, which supported global approvals of the regimen in this setting, were simultaneously published in The New England Journal of Medicine.
Trial Design
PAPILLON (NCT04538664), which enrolled 308 patients, is a randomized, open-label Phase 3 study evaluating the efficacy and safety of RYBREVANT in combination with chemotherapy compared with chemotherapy alone in newly diagnosed patients with advanced or metastatic NSCLC characterized by EGFR exon 20 insertion mutations (搜索). The primary endpoint is progression-free survival (PFS) using RECIST v1.1 guidelines as assessed by blinded independent central review (BICR). Secondary endpoints include overall response rate (ORR), PFS after first subsequent therapy, time to symptomatic progression and overall survival. Patients randomized to chemotherapy alone were permitted to cross over to receive second-line RYBREVANT monotherapy after disease progression confirmed by BICR, reflecting the study's crossover design for patients in the control arm.
Subcutaneous Formulation and Additional Data
Additional data presented at WCLC 2026 highlight continued innovation across RYBREVANT and RYBREVANT FASPRO (搜索) (amivantamab and hyaluronidase-lpuj), with approaches aimed at improving the treatment experience and helping patients stay on treatment longer. This includes prophylactic strategies in the COPERNICUS study (Abstract #MO12.09) designed to reduce key treatment-related events and subcutaneous administration evaluated in the PALOMA-2 study (Abstract #PT2.03.06).
RYBREVANT FASPRO (搜索) received U.S. FDA approval in December 2025 and is approved in multiple markets worldwide for the treatment of adults with EGFR (搜索)-mutated NSCLC, including those with exon 19 deletions, exon 21 L858R substitution mutations, and exon 20 insertion mutations. It is the only subcutaneous therapy approved for these EGFR-mutated NSCLC populations and may be used as monotherapy or in combination with LAZCLUZE (lazertinib) or chemotherapy, depending on the specific mutation and treatment setting. For eligible patients, RYBREVANT FASPRO offers a once-monthly dosing option following initial weekly dosing. RYBREVANT FASPRO is co-formulated with recombinant human hyaluronidase PH20 (rHuPH20), Halozyme's ENHANZE drug delivery technology.
The effectiveness of RYBREVANT FASPRO (搜索) is supported by the established clinical profile of RYBREVANT, including data from multiple Phase 3 studies such as MARIPOSA, which demonstrated improvements in progression-free and overall survival when used in combination with LAZCLUZE in first-line advanced EGFR (搜索)-mutated NSCLC. The National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology include amivantamab-vmjw (RYBREVANT) across its FDA-approved treatment settings, including as a Category 1 preferred option in combination with lazertinib (LAZCLUZE) for first-line treatment of patients with locally advanced or metastatic NSCLC with EGFR exon 19 deletions or exon 21 L858R mutations. The NCCN Guidelines for Central Nervous System Cancers also include amivantamab (RYBREVANT)-based regimens, including in combination with lazertinib (LAZCLUZE), as the only NCCN-preferred combination options for patients with EGFR-mutated NSCLC and brain metastases.
Beyond NSCLC, RYBREVANT-based therapies are being investigated across other solid tumors, including head and neck and colorectal cancers. The legal manufacturer for RYBREVANT FASPRO (搜索) and RYBREVANT is Janssen Biotech, Inc.