On March 29, 2023 The Janssen Pharmaceutical Companies of Johnson & Johnson reported new long-term data from the CHRYSALIS study evaluating RYBREVANT (amivantamab-vmjw) in patients with advanced non-small cell lung cancer (NSCLC) and epidermal growth factor receptor (EGFR) exon 20 insertion mutations whose disease progressed on prior platinum-based chemotherapy (Press release, Janssen Pharmaceuticals, MAR 29, 2023, View Source [SID1234629515]). Data from the study showed long-term response and safety in this population and were presented in an oral presentation at the 2023 European Lung Cancer Congress (ELCC) (Abstract #779).1
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In the analysis of the CHRYSALIS study, investigators assessed the efficacy and safety of RYBREVANT in patients (n=114) with NSCLC and EGFR exon 20 insertion mutations, who had progressed on prior platinum-based chemotherapy, and were treated at the approved Phase 2 dose of 1050 mg (1400 mg for a patient weight of at least 80 kg).1 The primary endpoint was overall response rate (ORR) per Response Evaluation Criteria in Solid Tumors Version 1.1* (RECIST v1.1).1 Additional endpoints included duration of response (DOR), clinical benefit rate, progression-free survival (PFS) and overall survival (OS).1
After a median follow-up of 19.2 months, the median OS with RYBREVANT treatment was 23 months (95 percent Confidence Interval [CI], 18.5–29.5) with a two-year OS rate of 47 percent.1 The investigator-assessed ORR was 37 percent (95 percent CI, 28–46) with a median DOR of 12.5 months (95 percent CI, 6.9–19.3), and median PFS of 6.9 months (95 percent CI, 5.6-8.8).1 Across subgroups, treatment with RYBREVANT resulted in consistent efficacy across post-platinum patients with EGFR exon 20 insertion mutations, including the elderly, regardless of prior therapies or response to prior platinum chemotherapy.1 Forty-eight patients (42 percent) had sustained clinical response measured by ORR on RYBREVANT for at least 12 cycles.1 The median duration of treatment was 7.5 months and treatment is ongoing in 15 patients (13 percent) who have received RYBREVANT for a median of 2.6 years.1 Of these patients, seven are progression-free and eight are receiving treatment beyond progression.1
No new safety signals were identified and rash (all group, 89 percent), infusion-related reactions (IRR; 67 percent) and paronychia (58 percent) remained the most common treatment emergent adverse events (AEs).1 The incidence of treatment-related AEs leading to dose interruption, reduction and discontinuation was 29 percent, 18 percent and seven percent, respectively.1
"With these new data, amivantamab showed long-term consistent efficacy regardless of prior therapies or response to prior platinum chemotherapy," said Pilar Garrido♦, M.D., Associate Professor of Medical Oncology at Universidad de Alcalá, Head of Medical Oncology Department at the University Hospital Ramón y Cajal in Madrid, Spain and principal investigator. "Due to the aggressive nature of NSCLC with EGFR exon 20 insertion mutations, treatment with targeted therapies is an important consideration when identifying a treatment option for patients."
NSCLC driven by EGFR exon 20 insertion mutations carries a worse prognosis and shorter survival rates compared with lung cancer driven by more common EGFR mutations, such as exon 19 deletions and L858R substitutions.2 The standard of care for common EGFR mutations, such as EGFR tyrosine kinase inhibitor (TKIs), are generally inactive against exon 20 insertion mutations and are not FDA-approved for these patients.2
"The long-term CHRYSALIS data presented at ELCC support RYBREVANT as an important treatment option for patients with EGFR exon 20 insertion mutation-positive NSCLC, providing valuable clinical insights that may help inform treatment decisions," said Kiran Patel, M.D., Vice President, Clinical Development, Solid Tumors, Janssen Research & Development, LLC. "We’re committed to transforming the treatment of lung cancer through continued research and the development of targeted therapies for gene-mutated disease where high unmet needs continue to exist."
About the CHRYSALIS Study
CHRYSALIS (NCT02609776) is a Phase 1 open-label, multicenter, first-in-human study to evaluate the safety, pharmacokinetics and preliminary efficacy of RYBREVANT as a monotherapy and in combinations including with lazertinib*, a novel third-generation EGFR TKI3, in adults with advanced NSCLC.4 The study consists of two parts: RYBREVANT monotherapy and combination-dose escalations (Part 1) and RYBREVANT monotherapy and combination-dose expansions (Part 2). The study enrolled 780 patients with advanced NSCLC.5
In the ongoing CHRYSALIS study, patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations weighing less than 80 kg received RYBREVANT 1050 mg and patients weighing at least 80 kg or more received RYBREVANT 1400 mg weekly for four weeks, with the initial dose as a split infusion in week 1 on day 1 and day 2, then administered every two weeks thereafter until disease progression or unacceptable toxicity.5 Disease response using ORR, per Response Evaluation Criteria in Solid Tumors Version 1.1** (RECIST v1.1) as evaluated by Blinded Independent Central Review (BICR), was the primary endpoint.
About RYBREVANT
RYBREVANT (amivantamab-vmjw) received accelerated approval by the U.S. Food and Drug Administration (FDA) in May 2021 for the treatment of adult patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy.6 This indication is approved under accelerated approval based on overall response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in the confirmatory trials. RYBREVANT has also received approval from health authorities in Europe, as well as other markets around the world.
The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Non-Small Cell Lung Cancer◊ prefer NGS-based strategies over PCR-based approaches for the detection of EGFR exon 20 insertion variants and include amivantamab-vmjw (RYBREVANT) as a subsequent therapy option with a Category 2A recommendation for patients that have progressed on or after platinum-based chemotherapy with or without immunotherapy and have EGFR exon 20 insertion mutation-positive advanced NSCLC.7†^
RYBREVANT is being studied in multiple clinical trials in NSCLC, including:
As first-line therapy in the Phase 3 MARIPOSA (NCT04487080) study assessing amivantamab in combination with lazertinib, a novel third generation EGFR TKI, against osimertinib and against lazertinib alone in untreated advanced EGFR-mutated NSCLC.8
The Phase 3 MARIPOSA-2 (NCT04988295) study assessing the efficacy of lazertinib, amivantamab and carboplatin-pemetrexed versus carboplatin-pemetrexed in patients with locally advanced or metastatic EGFR exon 19 deletion or exon 21 L858R substitution NSCLC after osimertinib failure.9
The Phase 1/1b CHRYSALIS-2 (NCT04077463) study evaluating amivantamab in combination with lazertinib and lazertinib as a monotherapy in patients with advanced NSCLC with EGFR mutations.10
The Phase 3 PAPILLON (NCT04538664) study assessing amivantamab in combination with carboplatin-pemetrexed versus chemotherapy alone in patients with advanced or metastatic EGFR-mutated NSCLC and exon 20 insertion mutations.11
The Phase 1 PALOMA (NCT04606381) study assessing the feasibility of subcutaneous (SC) administration of amivantamab based on safety and pharmacokinetics and to determine a dose, dose regimen and formulation for amivantamab SC delivery.12
The Phase 2 PALOMA-2 (NCT05498428) study assessing amivantamab in participants with advanced or metastatic solid tumors including EGFR-mutated NSCLC.13
The Phase 3 PALOMA-3 (NCT05388669) study assessing lazertinib with subcutaneous amivantamab as compared to intravenous amivantamab in participants with EGFR-mutated advanced or metastatic NSCLC.14
The Phase 1/2 METalmark (NCT05488314) study assessing amivantamab and capmatinib combination therapy in unresectable metastatic NSCLC.15
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About Non-Small Cell Lung Cancer
Worldwide, lung cancer is one of the most common cancers, and NSCLC makes up 80 to 85 percent of all lung cancers.3 The main subtypes of NSCLC are adenocarcinoma, squamous cell carcinoma and large cell carcinoma.3 Among the most common driver mutations in NSCLC are alterations in EGFR, which is a receptor tyrosine kinase supporting cell growth and division.3 EGFR mutations are present in 10 to 15 percent of people with NSCLC adenocarcinoma and occur in 40 to 50 percent of Asians.3 The five-year survival rate for all people with advanced NSCLC and EGFR mutations treated with EGFR TKIs is less than 20 percent.3 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 exon 19 deletions or L858R mutations, who have a real-world five-year OS of 19 percent.3
RYBREVANT IMPORTANT SAFETY INFORMATION5
WARNINGS AND PRECAUTIONS
Infusion Related Reactions
RYBREVANT can cause infusion related reactions (IRR); signs and symptoms of IRR include dyspnea, flushing, fever, chills, nausea, chest discomfort, hypotension, and vomiting.
Based on the safety population, IRR occurred in 66% of patients treated with RYBREVANT. Among patients receiving treatment on Week 1 Day 1, 65% experienced an IRR, while the incidence of IRR was 3.4% with the Day 2 infusion, 0.4% with the Week 2 infusion, and cumulatively 1.1% with subsequent infusions. Of the reported IRRs, 97% were Grade 1-2, 2.2% were Grade 3, and 0.4% were Grade 4. The median time to onset was 1 hour (range 0.1 to 18 hours) after start of infusion. The incidence of infusion modifications due to IRR was 62% and 1.3% of patients permanently discontinued RYBREVANT due to IRR.
Premedicate with antihistamines, antipyretics, and glucocorticoids and infuse RYBREVANT as recommended. Administer RYBREVANT via a peripheral line on Week 1 and Week 2. Monitor patients for any signs and symptoms of infusion reactions during RYBREVANT infusion in a setting where cardiopulmonary resuscitation medication and equipment are available. Interrupt infusion if IRR is suspected. Reduce the infusion rate or permanently discontinue RYBREVANT based on severity.
Interstitial Lung Disease/Pneumonitis
RYBREVANT can cause interstitial lung disease (ILD)/pneumonitis. Based on the safety population, ILD/pneumonitis occurred in 3.3% of patients treated with RYBREVANT, with 0.7% of patients experiencing Grade 3 ILD/pneumonitis. Three patients (1%) discontinued RYBREVANT due to ILD/pneumonitis.
Monitor patients for new or worsening symptoms indicative of ILD/pneumonitis (e.g., dyspnea, cough, fever). Immediately withhold RYBREVANT in patients with suspected ILD/pneumonitis and permanently discontinue if ILD/pneumonitis is confirmed.
Dermatologic Adverse Reactions
RYBREVANT can cause rash (including dermatitis acneiform), pruritus and dry skin. Based on the safety population, rash occurred in 74% of patients treated with RYBREVANT, including Grade 3 rash in 3.3% of patients. The median time to onset of rash was 14 days (range: 1 to 276 days). Rash leading to dose reduction occurred in 5% of patients, and RYBREVANT was permanently discontinued due to rash in 0.7% of patients.
Toxic epidermal necrolysis occurred in one patient (0.3%) treated with RYBREVANT.
Instruct patients to limit sun exposure during and for 2 months after treatment with RYBREVANT. Advise patients to wear protective clothing and use broad spectrum UVA/UVB sunscreen. Alcohol free emollient cream is recommended for dry skin.
If skin reactions develop, start topical corticosteroids and topical and/or oral antibiotics. For Grade 3 reactions, add oral steroids and consider dermatologic consultation. Promptly refer patients presenting with severe rash, atypical appearance or distribution, or lack of improvement within 2 weeks to a dermatologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.
Ocular Toxicity
RYBREVANT can cause ocular toxicity including keratitis, dry eye symptoms, conjunctival redness, blurred vision, visual impairment, ocular itching, and uveitis. Based on the safety population, keratitis occurred in 0.7% and uveitis occurred in 0.3% of patients treated with RYBREVANT. All events were Grade 1-2. Promptly refer patients presenting with eye symptoms to an ophthalmologist. Withhold, dose reduce or permanently discontinue RYBREVANT based on severity.
Embryo Fetal Toxicity
Based on its mechanism of action and findings from animal models, RYBREVANT can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential of the potential risk to the fetus. Advise female patients of reproductive potential to use effective contraception during treatment and for 3 months after the final dose of RYBREVANT.
Adverse Reactions
The most common adverse reactions (≥20%) were rash, IRR, paronychia, musculoskeletal pain, dyspnea, nausea, fatigue, edema, stomatitis, cough, constipation, and vomiting. The most common Grade 3 or 4 laboratory abnormalities (≥2%) were decreased lymphocytes, decreased albumin, decreased phosphate, decreased potassium, increased alkaline phosphatase, increased glucose, increased gamma-glutamyl transferase, and decreased sodium.