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Amy Roshak
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OA04 - New Data from Rare EGFR Alterations (ID 223)
- Event: WCLC 2020
- Type: Oral
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/29/2021, 11:45 - 12:45, Scientific Program Auditorium
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OA04.04 - Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer (ID 3031)
11:45 - 12:45 | Author(s): Amy Roshak
- Abstract
- Presentation
Introduction
Despite sharing similar tumor biology to other epidermal growth factor receptor (EGFR) mutant non-small cell lung cancer (NSCLC) tumors, no targeted therapies have been approved for NSCLC harboring EGFR Exon 20 insertion mutations (Exon20ins). The standard of care remains platinum-based chemotherapy for the front-line, with no clear subsequent options available. Amivantamab (JNJ-61186372) is a novel, fully human EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations, as well as MET mutations and amplifications, and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC after platinum-based chemotherapy. Here we present updated results on the Exon20ins cohort from the CHRYSALIS study (NCT02609776).
Methods
The dose escalation phase enrolled patients with advanced NSCLC to determine the recommended phase 2 dose (RP2D) of 1050 mg (1400 mg for ≥80 kg) amivantamab. The dose expansion phase assessed the safety and efficacy of amivantamab in patients with EGFR- and MET-mutant NSCLC treated at the RP2D. Disease response was assessed by the investigator per RECIST v1.1 and is presented for those patients with Exon20ins NSCLC who had progressed on prior platinum-based chemotherapy, were treated at the RP2D, and had at least 3 post-baseline disease assessments (18 weeks) or discontinued, progressed, or died prior to the 3rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Results
In the Post-Platinum Cohort (n=81), median age was 62 (42 – 84), 59% were women, 49% were Asian, median prior lines of therapy was 2 (1 – 7), and 53% were never-smokers. At a median follow-up of 6.5 months (1.1 – 29.3), investigator-assessed overall response rate (ORR) was 36% (29/81; 95% CI, 25 – 47), with all responders achieving partial response (PR). The clinical benefit rate (≥PR or stable disease ≥11 weeks) was 73% (59/81; 95% CI, 62 – 82). Responses were durable at a median of 6.8 months (95% CI, 5.0 – not reached) with ongoing responses in 18/29 (longest at 16+ months). Median progression-free survival was 8.3 months (95% CI, 5.5 – 12.7) and median overall survival was 22.8 months (95% CI, 14.0 – not reached).
Among all phase 1 patients, across a variety of EGFR genomic alterations and lines of therapy, treated with amivantamab monotherapy at the RP2D (n=258), the most common adverse events (AEs) were rash (78%), infusion related reaction (IRR; 65%), and paronychia (40%). Additional EGFR-related AEs were stomatitis (19%), pruritus (19%), and diarrhea (11%). Grade ≥3 AEs were reported in 39% of patients; 14% were considered treatment-related, with rash (3%) and IRR (2%) being most frequent. No treatment-related deaths were reported. The incidence of treatment-related AEs leading to dose reduction and discontinuation was 10% and 3%, respectively.
Conclusion
Amivantamab treatment led to promising efficacy with durable responses in patients with EGFR Exon20ins NSCLC post-platinum doublet and continues to demonstrate a manageable safety profile in over 250 patients treated at the RP2D. A phase 3 study, PAPILLON, evaluating amivantamab in combination with chemotherapy in the front-line setting is in planning stages.
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P15 - Immuno-biology and Novel Immunotherapeutics (Phase I and Translational) - Novel Immunotherapeutics (Phase I) (ID 154)
- Event: WCLC 2020
- Type: Posters
- Track: Immuno-biology and Novel Immunotherapeutics (Phase I and Translational)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P15.03 - A Phase 1/1b Study of Lazertinib as Monotherapy and in Combination with Amivantamab in Advanced EGFR-Mutated NSCLC (ID 1405)
00:00 - 00:00 | Author(s): Amy Roshak
- Abstract
Introduction
The use of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) has improved clinical outcomes for patients with EGFR-mutated non-small cell lung cancer (NSCLC); however, patients will inevitably progress due to acquired resistance mutations. Lazertinib is an oral, highly potent, mutant-selective, and irreversible EGFR TKI targeting both T790M and activating EGFR mutations while sparing wild type EGFR. Lazertinib has demonstrated efficacy against EGFR-mutated NSCLC in both systemic and central nervous system lesions due to its ability to cross the blood-brain barrier. Amivantamab (JNJ-61186372) is an EGFR-MET bispecific antibody with immune cell-directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. The synergistic mechanisms of action of amivantamab, which targets the extracellular ligand binding domain, combined with lazertinib, which targets the intracellular active site, have the potential to more potently inhibit the EGFR pathway than either agent alone.
Methods
This is a phase 1/1b open-label, multicenter study in patients with advanced EGFR-mutated NSCLC (NCT04077463). The study was initially opened in 3 sites in Japan. Phase 1 dose escalation cohorts enrolled Japanese patients with metastatic or unresectable EGFR-mutated NSCLC who had progressed after available targeted therapies. Phase 1b combination cohorts assessed the safety and tolerability of lazertinib and amivantamab in increasing doses in Japanese patients. The phase 1b expansion cohort A will enroll patients who have progressed on prior treatment with both osimertinib and platinum-doublet chemotherapy, for treatment with the combination of lazertinib and amivantamab. The objective of phase 1 dose escalation cohorts is to confirm the recommended phase 2 dose (RP2D) and to evaluate the safety, tolerability, and pharmacokinetics of lazertinib as monotherapy (phase 1 dose escalation cohorts) and in combination with amivantamab (phase 1b combination cohorts) in Japanese patients. Phase 1b dose expansion cohort A is enrolling patients globally to further characterize the safety, tolerability, and preliminary antitumor activity of the combination of lazertinib with amivantamab at the global recommended phase 2 combination dose of 240 mg lazertinib orally daily and 1050 mg (1400 mg for patients ≥80 kg) amivantamab intravenously weekly for the first 28-day cycle and biweekly thereafter. The primary endpoints are frequency of dose limiting toxicity, overall response rate, duration of response, and clinical benefit rate based on investigator-assessed efficacy according to RECIST 1.1 criteria. Key secondary endpoints include adverse events as graded by NCI CTCAE criteria v4.03, pharmacokinetic parameters of lazertinib and amivantamab, progression-free survival, and overall survival.
Results
Fourteen Japanese patients have been enrolled in phase 1 dose escalation (n=11) and phase 1b combination (n=3) cohorts. No dose limiting toxicity has been observed, and the safety and tolerability of lazertinib monotherapy at the RP2D was confirmed in Japanese patients. Enrollment into phase 1b expansion cohort A is ongoing.
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P76 - Targeted Therapy - Clinically Focused - EGFR (ID 253)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 2
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P76.73 - MARIPOSA: Randomized Phase 3 Study of First-line Amivantamab + Lazertinib vs Osimertinib vs Lazertinib in EGFR-mutant NSCLC (ID 3374)
00:00 - 00:00 | Author(s): Amy Roshak
- Abstract
Introduction
Amivantamab (JNJ-61186372) is an epidermal growth factor receptor (EGFR)-MET bispecific antibody with immune-cell directing activity that targets activating and resistance EGFR and MET aberrations. Lazertinib is a 3rd-generation tyrosine kinase inhibitor (TKI) with efficacy against activating EGFR mutations, T790M, and central nervous system lesions (Ahn Lancet Oncol 20(12):P1681; Kim JTO 38;no.15_suppl:9571). The low rates of EGFR-related toxicities observed with lazertinib support combination approaches with other anti-EGFR molecules. Preclinical studies with the combination of amivantamab and lazertinib have shown synergistic inhibition of tumor growth. In the ongoing CHRYSALIS phase 1 study (NCT02609776), amivantamab demonstrated antitumor activity both as monotherapy, and in combination with lazertinib, in patients with diverse EGFR-mutant non-small cell lung cancer (NSCLC), and in both treatment-naïve and osimertinib-relapsed disease, with a tolerable safety profile. The objective of this phase 3 randomized study is to assess the efficacy of the combination of amivantamab and lazertinib, as compared with single-agent osimertinib, as first-line therapy in patients with advanced EGFR-mutant NSCLC.
Methods
The multicenter, global MARIPOSA study (NCT04487080) will open in 262 sites in 27 countries. Eligible patients will have locally advanced or metastatic EGFR-mutant NSCLC not amenable to curative therapy, Exon19del or L858R mutation, measurable disease, and be treatment-naïve for advanced disease. Patients with asymptomatic or previously treated and stable brain metastases are eligible. Key exclusion criteria include prior systemic treatment for locally advanced or metastatic disease, history of leptomeningeal disease, interstitial lung disease, and prior treatment with an EGFR TKI. Approximately 1000 patients will be randomly assigned 2:2:1 to receive amivantamab + lazertinib (n~400), osimertinib (n~400), or lazertinib (n~200). Randomization will be stratified by mutation type (Exon19del vs L858R), race (Asian vs non-Asian), and history of brain metastases (present vs absent).
Patients in the combination arm will receive open-label treatment with amivantamab (1050 mg [1400 mg, patients ≥80 kg] intravenously once weekly for the first 4 weeks, every 2 weeks thereafter) + lazertinib (240 mg oral daily). Patients in the single-agent osimertinib and lazertinib arms will receive double-blind treatment (80 mg or 240 mg oral daily, respectively).
The primary endpoint of the study is progression-free survival (PFS) based on blinded independent central review according to RECIST v1.1. To assess the contribution of amivantamab to the efficacy of the combination, comparison of the combination and monotherapy lazertinib arms will also be performed. Secondary endpoints include overall survival, objective response rate, duration of response, PFS after first subsequent therapy, time to symptomatic progression, and intracranial PFS. Safety assessments will include monitoring adverse events and laboratory abnormalities.
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P76.74 - PAPILLON: Randomized Phase 3 Study of Amivantamab Plus Chemotherapy vs Chemotherapy Alone in EGFR Exon20ins NSCLC (ID 3380)
00:00 - 00:00 | Author(s): Amy Roshak
- Abstract
Introduction
Epidermal growth factor receptor (EGFR) Exon 20 insertions (Exon20ins) account for approximately 10% of all EGFR-mutant non-small cell lung cancers (NSCLCs). Currently approved EGFR tyrosine kinase inhibitors (TKIs) are considered ineffective against Exon20ins NSCLC, and the standard of care for patients with Exon20ins disease remains platinum-based doublet chemotherapy. Amivantamab (JNJ-61186372) is an EGFR-MET bispecific antibody with immune-cell directing activity that targets activating and resistance EGFR mutations and MET mutations and amplifications. Amivantamab has shown monotherapy activity, with a tolerable safety profile, in the ongoing phase 1 CHRYSALIS study (NCT02609776) in patients with diverse EGFR-mutant NSCLC and has received FDA Breakthrough Therapy Designation for the treatment of patients with EGFR Exon20ins NSCLC, after prior platinum-based chemotherapy (Haura JCO 37;no.15_suppl:9009; Park JTO 38;no. 15_suppl:9512). The primary objective of this phase 3 randomized, open-label study is to compare the efficacy of amivantamab in combination with chemotherapy (amivantamab/carboplatin/pemetrexed) versus carboplatin/pemetrexed alone as a first-line treatment for patients with EGFR Exon20ins disease.
Methods
The multicenter, global PAPILLON study is planned to open in 200 sites in 25 countries and enroll patients with EGFR Exon20ins-mutant NSCLC who are treatment-naive for metastatic disease, although limited prior EGFR TKI exposure may be allowed. Eligible patients also have measurable disease according to RECIST v1.1, Eastern Cooperative Oncology Group performance status (ECOG PS) of 0 – 1, and adequate bone marrow and organ function. Additionally, patients with history of brain metastases are eligible provided they have been definitively treated, are asymptomatic, and clinically stable.
Approximately 300 patients will be randomly assigned 1:1 to receive amivantamab/carboplatin/pemetrexed (Arm A) or carboplatin/pemetrexed (Arm B). Randomization will be stratified by ECOG PS (0 or 1), history of brain metastases (yes or no), and prior EGFR TKI (yes or no). Patients in Arm A will be treated with amivantamab/carboplatin/pemetrexed in a 21-day cycle for 4 cycles followed by maintenance with amivantamab and pemetrexed until disease progression or any of the treatment discontinuation criterion is met. Similarly, patients in Arm B will receive treatment with carboplatin/pemetrexed in a 21-day cycle for 4 cycles followed by maintenance therapy with pemetrexed alone. Crossover from the chemotherapy arm to monotherapy amivantamab may be allowed.
The primary endpoint of the study is progression-free survival (PFS) as assessed by blinded independent central review according to RECIST v1.1. Key secondary endpoints include objective response rate and overall survival. Safety assessments will include monitoring adverse events and laboratory abnormalities.
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P86 - Targeted Therapy - Clinically Focused - New Target (ID 263)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P86.12 - Cardiac Safety Assessment of Lazertinib in Patients with EGFR Mutation-Positive Advanced Non-Small Cell Lung Cancer (ID 1247)
00:00 - 00:00 | Author(s): Amy Roshak
- Abstract
Introduction
Lazertinib (YH25448, JNJ-73841937) is a highly mutant-selective, irreversible 3rd-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor that targets the activating EGFR mutations (Del19 and L858R), as well as the T790M mutation, while sparing wild type. The recommended phase 2 dose was determined to be 240 mg once daily (QD) in Korean patients based on the results of a first-in-human study in patients with advanced, EGFR-mutated non-small cell lung cancer at doses of 20-320 mg QD. The objective of this evaluation was to assess lazertinib cardiac safety in these patients.
Methods
The electrocardiogram (ECG) assessments (absolute and change from baseline QTcF) were performed in an ongoing phase 1/2 lazertinib pharmacokinetics, safety and efficacy study. A total of 224 patients [1st (n=43) and 2nd (n=181) line therapy, 20-320 mg QD dose] with baseline and postdose ECG assessments (in triplicates) along with time-matched plasma concentration data were included in exposure-QTcF analysis using linear regression. The left ventricular ejection fraction (LVEF) was assessed using an echocardiogram or multiple gated acquisition (MUGA) scan at baseline and every 12 weeks.
Results
Of 224 evaluable patients, no post-treatment QTcF values >500 ms were reported during the study; 26 (11.6%) patients had a post-baseline QTcF >450 ms including 3 (1.3%) patients with QTcF >480 ms. Of the 221 patients with baseline QTcF confirmed by central assessment, 22 (10.0%) patients had >30 to 60 ms increase and 1 (0.5%) had >60 ms increase in QTcF from baseline. Of the 121 patients at 240 mg, 10 (8.3%) patients had a post-baseline QTcF >450 ms including 1 (0.8%) patient with QTcF >480 ms. There were no clinical symptoms of QTc prolongation observed in any of the patients. At clinically relevant (240 mg QD dosing) plasma steady state Cmax (maximum plasma concentration) of 517.15 (43% coefficient of variation) ng/mL, the upper bound of the two-sided 90% confidence interval for change from baseline QTcF was estimated to 3.9 ms (low concern category). The exposure-QTcF assessment-based prediction suggests that a 2.5-fold and 4.8-fold higher than 517.15 ng/ml plasma concentration would be required to cause the upper bound of two-sided 90% confidence interval for the change from baseline in QTcF of ~10 ms (increasing concern category) and QTcF of ~20 ms (definite concern category), respectively. These results are in line with in vitro (hERG assay), ex-vivo (isolated perfused rabbit heart) and in vivo (instrumented male beagle dogs) preclinical findings. Of 224 patients, no treatment emergent adverse event related with heart failure or clinically meaningful decrease of LVEF was reported.
Conclusion
Taken together, preclinical and clinical cardiac safety assessment findings suggest that lazertinib has no clinically relevant effect on QT interval and LVEF. Time-matched plasma concentration and QTcF read-outs as well as LVEF assessments will continue to be collected in all ongoing as well as future lazertinib clinical studies to further confirm that lazertinib has no/minimal cardiac safety risk.
