Table of Contents
- Key Points
- Background: Why This Research Matters
- What Is EGFR Exon 20 Insertion NSCLC?
- What Is Amivantamab?
- How the Study Was Conducted
- Who Participated in the Study
- How Treatment Was Given
- Key Findings: Progression-Free Survival
- Tumor Response Results
- Overall Survival: Early Results
- Results Across Patient Subgroups
- Crossover: What Happened to Chemotherapy-Only Patients
- Side Effects and Safety
- What This Means for Patients
- Limitations of the Study
- Recommendations and Next Steps
- Frequently Asked Questions
- Source Information
Key Points
- In the PAPILLON trial of 308 patients with advanced NSCLC and EGFR exon 20 insertions, amivantamab plus chemotherapy nearly doubled median progression-free survival compared with chemotherapy alone (11.4 vs 6.7 months).
- The combination reduced the risk of disease progression or death by 60% (hazard ratio 0.40; P<0.001) in this trial.
- At 18 months, 31% of patients on the combination were progression-free versus 3% on chemotherapy alone.
- The main side effects were reversible blood-related and EGFR-related toxic effects; 7% of patients stopped amivantamab due to adverse reactions.
- Overall survival data are not yet mature; longer follow-up is needed to confirm a definitive survival benefit.
Background: Why This Research Matters
Lung cancer remains one of the most common cancers worldwide, and non-small-cell lung cancer (NSCLC) is its most frequent form. Within NSCLC, changes in a gene called epidermal growth factor receptor (EGFR) are among the most common driving mutations. These mutations cause the cancer to grow and spread.
Among EGFR mutations, insertions in a specific region called exon 20 are the third most common type. They account for up to 12% of all EGFR-mutated NSCLC cases. This is a meaningful proportion of patients who need effective treatment options.
The challenge with EGFR exon 20 insertions is that they respond poorly to the standard targeted drugs (tyrosine kinase inhibitors) that work well for other EGFR mutations. The shape of the mutated protein blocks these drugs from binding effectively. As a result, patients with this specific mutation have had limited targeted treatment options.
For years, the first-line standard treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertions has been platinum-based chemotherapy. This type of chemotherapy produces an objective response (tumor shrinkage) in only 23% to 29% of patients. The median progression-free survival (time before the cancer worsens) with platinum-based chemotherapy is just 3.4 to 6.9 months.
By contrast, patients with more common EGFR mutations have a median overall survival of up to 38.6 months. Real-world data for patients with EGFR exon 20 insertions show a median overall survival ranging from 16.2 to 24.3 months, with a 5-year overall survival of only 8%. This stark difference highlights the urgent need for better treatments for this patient group.
What Is EGFR Exon 20 Insertion NSCLC?
EGFR is a gene that provides instructions for a protein on the surface of cells. This protein helps cells grow and divide. When the EGFR gene has certain mutations, the protein becomes overactive, causing cancer cells to grow uncontrollably.
An exon 20 insertion is a specific type of mutation where extra genetic material is inserted into the EGFR gene at a particular location. This changes the shape of the EGFR protein in a way that makes it resistant to most approved EGFR-targeted drugs.
Patients with EGFR exon 20 insertion NSCLC tend to share certain characteristics. They are more likely to be female, of Asian descent, and to have never smoked. The study population reflected these patterns.
What Is Amivantamab?
Amivantamab is a type of drug called a bispecific antibody. This means it is designed to attach to two different targets at the same time: EGFR and another protein called MET (mesenchymal-epithelial transition factor).
Amivantamab works through several mechanisms. It blocks the signals that tell cancer cells to grow. It helps the immune system attack cancer cells by engaging macrophages, monocytes, and natural killer cells. It also causes the cancer cell to internalize and break down its EGFR and MET receptors.
These combined actions allow amivantamab to bypass the resistance that makes EGFR exon 20 insertions unresponsive to standard tyrosine kinase inhibitors. Amivantamab was already approved for treating patients with advanced NSCLC with EGFR exon 20 insertions whose disease had progressed during or after platinum-based chemotherapy.
The approval was based on the phase 1 CHRYSALIS trial. In that trial, amivantamab produced an objective response of 40% and a median response duration of 11.1 months. Patients had a median progression-free survival of 8.3 months and a median overall survival of 22.8 months. Indirect comparisons with real-world data suggested that amivantamab produced better outcomes than other real-world therapies.
Amivantamab plus carboplatin-pemetrexed (a common chemotherapy combination) was previously studied in 20 patients in the CHRYSALIS trial. The safety profile was consistent with that of each drug individually, and amivantamab levels in the body were not adversely affected by combining it with chemotherapy. Among 5 patients who had not received previous treatment, 4 had a partial response to the combination. These findings suggested the potential for the combination to work better together than either treatment alone.
How the Study Was Conducted
The PAPILLON trial was a phase 3, international, randomized study. Phase 3 means it was a large, late-stage trial designed to confirm whether a treatment works. Randomized means patients were assigned to treatment groups by chance, which helps ensure fair comparisons.
The trial enrolled patients from December 2020 to November 2022. A total of 542 patients were screened, and 308 patients underwent randomization. Of these, 153 patients were assigned to receive amivantamab plus chemotherapy, and 155 patients were assigned to receive chemotherapy alone.
The primary outcome measured was progression-free survival as determined by blinded independent central review. This means that a group of experts who did not know which treatment each patient received reviewed the imaging scans to determine when the cancer worsened. This approach reduces the risk of bias in the results.
The trial was conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. The trial was funded by Janssen Research and Development. The trial was designed by representatives of the sponsor in collaboration with the authors.
Patients were randomly assigned in a 1:1 ratio. Randomization was stratified (balanced) according to three factors:
- ECOG performance-status score (0 or 1), which measures how well patients can carry out daily activities
- History of brain metastases (yes or no)
- Previous receipt of an EGFR tyrosine kinase inhibitor (yes or no)
The study was designed to detect a hazard ratio of 0.625 with 90% power. This corresponded to an expected extension of at least 3 months in median progression-free survival. The expected median was 8 months in the amivantamab-chemotherapy group and 5 months in the chemotherapy-only group.
A hierarchical testing approach was used. This means the researchers tested progression-free survival first, then objective response, and then overall survival in a specific order. An interim overall survival analysis was planned at the time of the primary progression-free survival analysis.
All data reported were based on the primary analysis and were reported before the data cutoff date of May 3, 2023.
Who Participated in the Study
Eligible patients were 18 years of age or older. They had received no previous treatment for locally advanced or metastatic NSCLC with EGFR exon 20 insertions. Brief treatment with an approved EGFR tyrosine kinase inhibitor was allowed if a lack of response had been documented.
Patients with treated brain metastases were eligible if they were asymptomatic, clinically stable, and had received no glucocorticoid treatment for at least 2 weeks before randomization.
The demographic characteristics were well balanced between the two groups. The median age was 61 years in the amivantamab-chemotherapy group (range, 27 to 86) and 62 years in the chemotherapy group (range, 30 to 92).
In the amivantamab-chemotherapy group, 56% of patients were female, and in the chemotherapy group, 60% were female. Most patients were Asian (64% and 59%, respectively), followed by White (32% and 39%).
Most patients had never smoked: 58% in the amivantamab-chemotherapy group and 59% in the chemotherapy group. Nearly all patients had adenocarcinoma histology (99% in both groups).
History of brain metastases was present in 23% of patients in both groups. The median time from initial diagnosis was 1.8 months in both groups. The median time from metastatic diagnosis was 1.5 months in the amivantamab-chemotherapy group and 1.6 months in the chemotherapy group.
Patients were enrolled from multiple regions: Asia (63% in both groups), Europe (23% in both groups), North America (9% and 8%), South America (4% and 3%), and Oceania (1% and 3%).
The patients' mutational status was determined by local testing of tissue samples in 92% of cases or plasma samples in 8% of cases.
How Treatment Was Given
Treatment was given in 21-day cycles. Patients in the amivantamab-chemotherapy group received intravenous amivantamab at a dose of 1400 mg (1750 mg for patients weighing 80 kg or more).
Amivantamab was given weekly for the first 4 weeks. The first infusion was split over 2 days: 350 mg on cycle 1, day 1, and the remainder on cycle 1, day 2. Starting at cycle 3 (week 7), the dose was increased to 1750 mg (2100 mg for patients weighing 80 kg or more) given every 3 weeks until disease progression.
Carboplatin was given at a dose based on kidney function (area under the concentration-time curve of 5 mg per milliliter per minute) for up to 4 cycles. Pemetrexed was given at 500 mg per square meter of body-surface area until disease progression.
Treatment blinding was not feasible because of differences in how the drugs were given, premedication requirements, and safety profiles. Patients in the chemotherapy-only group could cross over to receive amivantamab monotherapy after documented disease progression.
Disease assessments using computed tomography (CT) or magnetic resonance imaging (MRI) were performed within 28 days after randomization. They were then performed at 6 weeks after randomization and every 6 weeks for the first 18 months. After 18 months, assessments were performed every 12 weeks until disease progression.
All patients were required to undergo brain imaging at baseline. Subsequent imaging was performed according to local standards. Adverse events, vital signs, and laboratory tests were assessed at each visit.
Key Findings: Progression-Free Survival
The study met its primary goal. Progression-free survival was significantly longer in the amivantamab-chemotherapy group than in the chemotherapy group.
The median progression-free survival by blinded independent central review was 11.4 months (95% confidence interval [CI], 9.8 to 13.7) in the amivantamab-chemotherapy group. In the chemotherapy group, it was 6.7 months (95% CI, 5.6 to 7.3).
The hazard ratio for disease progression or death was 0.40 (95% CI, 0.30 to 0.53; P<0.001). A hazard ratio of 0.40 means the combination reduced the risk of disease progression or death by 60% compared with chemotherapy alone. The P value of less than 0.001 means there is less than a 0.1% probability that this result occurred by chance.
At 18 months, progression-free survival was reported in 31% of patients in the amivantamab-chemotherapy group and in 3% of patients in the chemotherapy group. This means that nearly one-third of patients on the combination were still progression-free at 18 months, compared with only 3% on chemotherapy alone.
Investigator-assessed progression-free survival showed similar results. It was 12.9 months (95% CI, 11.4 to 16.7) with amivantamab-chemotherapy and 6.9 months (95% CI, 6.2 to 8.3) with chemotherapy. The hazard ratio for disease progression or death was 0.38 (95% CI, 0.29 to 0.51).
At a median follow-up of 14.9 months, the median treatment duration was 9.7 months (range, 0.1 to 26.9) with amivantamab-chemotherapy and 6.7 months (range, 0 to 25.3) with chemotherapy.
At the data cutoff, the assigned treatment was still being administered in 70 patients (46%) in the amivantamab-chemotherapy group and in 24 patients (15%) in the chemotherapy group.
The most common reason for treatment discontinuation was progressive disease. This occurred in 50 of 151 patients (33%) in the amivantamab-chemotherapy group and in 107 of 155 patients (69%) in the chemotherapy group.
Tumor Response Results
A complete or partial response at data cutoff was reported in 73% of patients in the amivantamab-chemotherapy group and 47% of patients in the chemotherapy group. The rate ratio was 1.50 (95% CI, 1.32 to 1.68; P<0.001).
The mean percent decrease in tumor size was 53% with amivantamab-chemotherapy and 34% with chemotherapy.
The median duration of objective response was 9.7 months (95% CI, 8.2 to 13.5) with amivantamab-chemotherapy and 4.4 months (95% CI, 4.1 to 5.6) with chemotherapy. This means that when tumors did shrink, the response lasted more than twice as long with the combination.
At the time of the primary analysis, treatment was ongoing in 49% of patients with a response in the amivantamab-chemotherapy group and in 17% of those in the chemotherapy group.
The median time until response was 6.7 weeks (range, 5.1 to 72.5) with amivantamab-chemotherapy and 11.4 weeks (range, 5.1 to 60.2) with chemotherapy. This means the combination produced responses nearly twice as fast.
Overall Survival: Early Results
At the time of the interim survival analysis, 70 deaths had been reported. This represented a calculated 33% data maturity, meaning that only about one-third of the expected deaths had occurred. A total of 210 deaths were anticipated for the final analysis.
The hazard ratio for death for amivantamab-chemotherapy compared with chemotherapy was 0.67 (95% CI, 0.42 to 1.09; P=0.11). This means there was a trend toward improved overall survival with the combination, but the result did not reach statistical significance at this early time point.
The wide confidence interval (0.42 to 1.09) and the P value of 0.11 indicate that the overall survival data are not yet mature. More follow-up time is needed to determine whether the combination provides a definitive overall survival benefit.
Results Across Patient Subgroups
The progression-free survival benefit was consistent across all prespecified subgroups. This means the combination worked better than chemotherapy alone regardless of patient age, sex, race, weight, ECOG performance status, smoking history, or history of brain metastases.
For patients under 65 years of age, the hazard ratio was 0.37 (95% CI, 0.26 to 0.53). For patients 65 years or older, the hazard ratio was 0.44 (95% CI, 0.27 to 0.70).
For female patients, the hazard ratio was 0.31 (95% CI, 0.21 to 0.46). For male patients, the hazard ratio was 0.47 (95% CI, 0.30 to 0.72).
For Asian patients, the hazard ratio was 0.36 (95% CI, 0.25 to 0.52). For non-Asian patients, the hazard ratio was 0.45 (95% CI, 0.28 to 0.72).
For patients with a history of brain metastases, the hazard ratio was 0.47 (95% CI, 0.28 to 0.80). For patients without a history of brain metastases, the hazard ratio was 0.34 (95% CI, 0.24 to 0.48).
These subgroup analyses were not part of the formal hypothesis testing. The results are reported as point estimates and 95% confidence intervals without adjustment for multiple comparisons. They should be interpreted with caution.
Crossover: What Happened to Chemotherapy-Only Patients
A total of 65 patients crossed over from the chemotherapy group to receive amivantamab monotherapy as part of the trial. An additional 6 patients received amivantamab monotherapy as their first subsequent therapy off protocol.
Together, this represented 66% (71 of 107) of patients in the chemotherapy group who had disease progression. The results of the efficacy and safety analyses among the crossover patients were provided in supplementary tables.
The crossover design means that many patients who initially received chemotherapy alone were later able to receive amivantamab. This may affect the overall survival comparison between the two groups, because patients in the chemotherapy group had access to amivantamab after their disease progressed.
Side Effects and Safety
The predominant adverse events associated with amivantamab-chemotherapy were reversible hematologic (blood-related) and EGFR-related toxic effects. Reversible means these side effects improved after treatment was adjusted or stopped.
Hematologic side effects are those affecting blood cells, such as low red blood cell counts, low white blood cell counts, or low platelet counts. EGFR-related toxic effects are those caused by blocking the EGFR protein, which can include skin rash, dry skin, and nail changes.
A total of 7% of patients discontinued amivantamab owing to adverse reactions. This means that the vast majority of patients were able to continue treatment.
The safety profile of the combination was consistent with the known safety profiles of each individual drug. The addition of amivantamab to chemotherapy did not produce unexpected safety concerns.
Adverse events were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 5.0. Electrocardiograms were assessed at baseline and at cycle 3, day 1.
What This Means for Patients
The PAPILLON trial demonstrated that amivantamab plus chemotherapy is superior to chemotherapy alone as first-line treatment for advanced NSCLC with EGFR exon 20 insertions. This is a significant advance for a patient group that has had limited targeted treatment options.
The combination nearly doubled median progression-free survival compared with chemotherapy alone (11.4 months versus 6.7 months). It also produced a 60% reduction in the risk of disease progression or death.
The 18-month progression-free survival rate of 31% with the combination compared with 3% with chemotherapy alone is particularly meaningful. It suggests that a substantial proportion of patients can achieve long-term disease control with this treatment.
The response rate was also significantly higher with the combination (73% versus 47%). Responses lasted more than twice as long (9.7 months versus 4.4 months) and occurred nearly twice as fast (6.7 weeks versus 11.4 weeks).
The overall survival data are not yet mature, but there is a trend toward improved survival with the combination. The hazard ratio of 0.67 suggests a 33% reduction in the risk of death, but this result did not reach statistical significance at the interim analysis.
The safety profile was manageable. The main side effects were reversible blood-related and EGFR-related toxic effects. Only 7% of patients discontinued amivantamab because of adverse reactions.
These results indicate that amivantamab plus chemotherapy was an effective first-line treatment for advanced NSCLC with EGFR exon 20 insertions in this clinical trial, though overall survival data were not yet mature enough for robust conclusions.
Limitations of the Study
The overall survival data are not yet mature. At the interim analysis, only 33% of the expected deaths had occurred. The overall survival benefit did not reach statistical significance (P=0.11). Longer follow-up is needed to determine whether the combination provides a definitive survival benefit.
The crossover design may affect the overall survival comparison. A total of 66% of patients in the chemotherapy group who had disease progression went on to receive amivantamab. This means the chemotherapy group had access to amivantamab after progression, which could narrow the overall survival difference between the two groups.
Treatment blinding was not feasible because of differences in how the drugs were given, premedication requirements, and safety profiles. However, the primary outcome was assessed by blinded independent central review, which reduces the risk of bias.
The subgroup analyses were not part of the formal hypothesis testing. The results are reported as point estimates and 95% confidence intervals without adjustment for multiple comparisons. They should be interpreted with caution.
The study enrolled patients with good performance status (ECOG 0 or 1). The results may not apply to patients with poorer performance status.
The median follow-up was 14.9 months. Longer follow-up is needed to assess long-term outcomes.
Recommendations and Next Steps
Patients with newly diagnosed advanced NSCLC with EGFR exon 20 insertions should discuss amivantamab plus chemotherapy with their oncology team. This combination is now supported by phase 3 evidence as a first-line treatment option.
Patients should be aware of the potential side effects of the combination. The main side effects are blood-related and EGFR-related toxic effects. These are typically reversible with appropriate management.
Patients should report any new or worsening symptoms to their healthcare team promptly. Early recognition and management of side effects can help patients stay on treatment.
Patients should ask their healthcare team about the following:
- Whether their tumor has been tested for EGFR exon 20 insertions
- Whether amivantamab plus chemotherapy is an appropriate treatment option for them
- What side effects to watch for and how to manage them
- What the treatment schedule involves and how it may affect their daily life
- Whether they are eligible for clinical trials of other new treatments
Longer follow-up from the PAPILLON trial will provide more information about overall survival. Additional studies may explore amivantamab in other treatment settings or in combination with other therapies.
The PAPILLON trial was funded by Janssen Research and Development. The trial is registered on ClinicalTrials.gov with the number NCT04538664.
Frequently Asked Questions
What is an EGFR exon 20 insertion mutation?
An EGFR exon 20 insertion is a specific change in the EGFR gene where extra genetic material is inserted at a particular location. This alters the shape of the EGFR protein, making it resistant to most approved EGFR-targeted drugs. These mutations account for up to 12% of all EGFR-mutated non-small-cell lung cancer cases and are the third most common type of EGFR mutation.
What were the main results of the PAPILLON trial?
In the PAPILLON trial of 308 patients with advanced non-small-cell lung cancer and EGFR exon 20 insertions, those who received amivantamab plus chemotherapy had a median progression-free survival of 11.4 months versus 6.7 months with chemotherapy alone. This represented a 60% reduction in the risk of disease progression or death. The combination also produced a higher response rate (73% versus 47%).
What does a hazard ratio of 0.40 mean?
A hazard ratio of 0.40 means that the risk of disease progression or death was 60% lower in the amivantamab-chemotherapy group compared with the chemotherapy-alone group. In the PAPILLON trial, this result had a P value of less than 0.001, indicating that there is less than a 0.1% probability that the finding occurred by chance.
What are the side effects of amivantamab plus chemotherapy?
The main side effects in the PAPILLON trial were reversible blood-related and EGFR-related toxic effects. Blood-related effects include low red blood cell, white blood cell, or platelet counts. EGFR-related effects can include skin rash, dry skin, and nail changes. These side effects typically improve after treatment is adjusted or stopped. Only 7% of patients discontinued amivantamab because of adverse reactions.
Who was eligible for the PAPILLON trial?
Eligible patients were 18 years or older with locally advanced or metastatic non-small-cell lung cancer with EGFR exon 20 insertions and no previous treatment. Brief prior treatment with an EGFR tyrosine kinase inhibitor was allowed if lack of response was documented. Patients with treated brain metastases could join if they were asymptomatic, clinically stable, and had not received glucocorticoids for at least 2 weeks before randomization.
What does the 18-month progression-free survival rate mean?
At 18 months in the PAPILLON trial, 31% of patients receiving amivantamab plus chemotherapy were still progression-free, meaning their cancer had not worsened, compared with 3% of those receiving chemotherapy alone. This suggests that nearly one-third of patients on the combination achieved longer-term disease control, while very few on chemotherapy alone did.
What should patients discuss with their oncology team?
Patients with newly diagnosed advanced non-small-cell lung cancer with EGFR exon 20 insertions should ask their oncology team whether their tumor has been tested for this mutation, whether amivantamab plus chemotherapy is an appropriate option, what side effects to watch for and how to manage them, what the treatment schedule involves, and whether they are eligible for clinical trials of other new treatments.
I've just been diagnosed with advanced NSCLC with an EGFR exon 20 insertion — when should I seek a second opinion?
Because EGFR exon 20 insertions account for up to 12% of EGFR-mutated NSCLC and respond poorly to standard tyrosine kinase inhibitors, treatment decisions are nuanced. The PAPILLON trial found amivantamab plus chemotherapy extended median progression-free survival to 11.4 months versus 6.7 months with chemotherapy alone, with 73% versus 47% responding. Diagnostic Detectives Network provides independent expert second opinions.
Source Information
Original article title: Amivantamab plus Chemotherapy in NSCLC with EGFR Exon 20 Insertions NEJM 2023
Authors: C. Zhou, K.-J. Tang, B.C. Cho, B. Liu, L. Paz-Ares, S. Cheng, S. Kitazono, M. Thiagarajan, J.W. Goldman, J.K. Sabari, R.E. Sanborn, A.S. Mansfield, J.-Y. Hung, M. Boyer, S. Popat, J. Mourão Dias, E. Felip, M. Majem, M. Gumus, S. Kim, A. Ono, J. Xie, A. Bhattacharya, T. Agrawal, S.M. Shreeve, R.E. Knoblauch, K. Park, and N. Girard, for the PAPILLON Investigators
Publication: The New England Journal of Medicine, 2023;389:2039-51
DOI: 10.1056/NEJMoa2306441
Published online: October 21, 2023
ClinicalTrials.gov number: NCT04538664
Funding: Janssen Research and Development
This patient-friendly article is based on peer-reviewed research.
