Faculty Bibliography

Substantial therapeutic advancements have been made in identifying and treating activating mutations in advanced non-small cell lung cancer (NSCLC); however, resistance to epidermal growth factor receptor (EGFR) and mesenchymal-epithelial transition factor (MET) inhibitors remains common with current targeted therapies. Amivantamab, a fully human bispecific antibody targeting EGFR and MET, is approved in the United States and other countries for the treatment of patients with advanced NSCLC with EGFR exon 20 insertion mutations, for whom disease has progressed on or after platinum-based chemotherapy. Preliminary efficacy and safety have also been demonstrated in patients with common EGFR- or MET-mutated NSCLC. Amivantamab employs 3 distinct potential mechanisms of action (MOAs) including ligand blocking, receptor degradation, and immune cell-directing activity, such as antibody-dependent cellular cytotoxicity and trogocytosis. Notably, efficacy with amivantamab does not require all 3 MOAs to occur simultaneously, broadening applicability by using diverse antitumor mechanisms. This review focuses on the molecular characteristics of amivantamab and its unique MOAs leading to in vitro and in vivo efficacy and safety in preclinical and clinical studies.

Background: Amivantamab, an epidermal growth factor receptor (EGFR)-MET bispecific antibody, is approved for the treatment of patients with advanced EGFR ex20ins NSCLC that progressed on or after platinum-based chemotherapy. We present updated data on the real-world experience with amivantamab acquired through the global PAA program on a larger patient population with the inclusion of 4 additional countries and a longer follow-up period. The initial results were presented at the 2022 European Lung Cancer Congress on 210 patients.
Method(s): Patients who were eligible for PAA (NCT04599712) had EGFR ex20ins NSCLC that progressed after platinum-based chemotherapy. Amivantamab (1050 mg; 1400 mg for bodyweight >=80 kg) was administered intravenously once weekly for the first 4-week cycle, then every 2 weeks thereafter. Investigator assessment of response, based on radiologic and clinical judgement, was provided at the time of drug re-supply and was optional. Time to treatment discontinuation was analyzed using a Kaplan-Meier approach. Patients who did not request drug within 45 days from last supply were considered to have stopped treatment. Patients who transitioned to commercial amivantamab drug supply were censored at time of commercial supply.
Result(s): As of 10 June 2022, 380 patients had initiated treatment with amivantamab in the PAA program across 215 sites in 23 countries; 57.9% from Asia, 26.8% from Europe, 11.6% from North America, and 3.7% from South America. The median age was 63 years (range, 24-86), and the median number of prior lines was 2 (range, 1-9), with 60.5% of patients heavily pretreated with >=2 prior lines. Median time to treatment discontinuation was 5.13 months (95% CI, 4.2-7.0), with 28% of patients still on treatment at 12 months. Among 205 patients (53.9%) with response information available, 64 (31.2%) achieved partial responses. Frequency and response by site of exon 20 insertion will be reported at the time of the meeting.
Conclusion(s): The real-world experience of amivantamab from the PAA program was consistent with that observed from the registrational clinical trial (NCT02609776). Patients who entered the amivantamab PAA program were heavily pretreated, underscoring the high unmet need for patients with EGFR ex20ins NSCLC.
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BACKGROUND:Amivantamab, a fully humanized EGFR-MET bispecific antibody, has antitumor activity in diverse EGFR- and MET-driven non-small cell lung cancer (NSCLC) and a safety profile consistent with associated on-target activities. Infusion-related reaction(s) (IRR[s]) are reported commonly with amivantamab. We review IRR and subsequent management in amivantamab-treated patients. METHODS:Patients treated with the approved dose of intravenous amivantamab (1050 mg, <80 kg; 1400 mg, ≥80 kg) in CHRYSALIS-an ongoing, phase 1 study in advanced EGFR-mutated NSCLC-were included in this analysis. IRR mitigations included split first dose (350 mg, day 1 [D1]; remainder, D2), reduced initial infusion rates with proactive infusion interruption, and steroid premedication before initial dose. For all doses, pre-infusion antihistamines and antipyretics were required. Steroids were optional after the initial dose. RESULTS:As of 3/30/2021, 380 patients received amivantamab. IRRs were reported in 256 (67%) patients. Signs/symptoms of IRR included chills, dyspnea, flushing, nausea, chest discomfort, and vomiting. Most of the 279 IRRs were grade 1 or 2; grade 3 and 4 IRR occurred in 7 and 1 patients, respectively. Most (90%) IRRs occurred on cycle 1, D1 (C1D1); median time-to-first-IRR onset during C1D1 was 60 min; and first-infusion IRRs did not compromise subsequent infusions. Per protocol, IRR was mitigated on C1D1 with holding of infusion (56% [214/380]), reinitiating at reduced rate (53% [202/380]), and aborting infusion (14% [53/380]). C1D2 infusions were completed in 85% (45/53) of patients who had C1D1 infusions aborted. Four patients (1% [4/380]) discontinued treatment due to IRR. In studies aimed at elucidating the underlying mechanism(s) of IRR, no pattern was observed between patients with versus without IRR. CONCLUSION/CONCLUSIONS:IRRs with amivantamab were predominantly low grade and limited to first infusion, and rarely occurred with subsequent dosing. Close monitoring for IRR with the initial amivantamab dose and early intervention at first IRR signs/symptoms should be part of routine amivantamab administration.

Immune checkpoint blockade with pembrolizumab has demonstrated both progression-free survival and overall survival benefit for patients with NSCLC regardless of PD-L1 expression. However, immune-related adverse events, and in particular checkpoint inhibitor pneumonitis (CIP), are common and can complicate the treatment course, duration of response, as well as overall survival. Here we present a patient with stage IV lung adenocarcinoma who experienced a dramatic response following treatment with pembrolizumab, followed by the development of biopsy-proven organizing pneumonia and immune-mediated pneumonitis requiring early treatment discontinuation. The patient has now achieved a near-complete response over 13 months after treatment discontinuation, highlighting the importance of early recognition and management of immune-related adverse events as well as the possibility of durable response despite treatment discontinuation.

Purpose/Objective(s): Standard therapy for unresectable locally advanced non-small cell lung cancer (LA-NSCLC) is concurrent chemoradiotherapy (chemoRT), which is usually followed by adjuvant durvalumab. We performed a prospective trial testing sequential pembrolizumab and risk-adapted radiotherapy without chemotherapy for biomarker-selected LA-NSCLC patients. Materials/Methods: Patients with AJCC version 8 stage III NSCLC or unresectable stage II NSCLC and ECOG performance status 0-1 were eligible for this trial. Subjects with PD-L1 tumor proportion score (TPS) >= 50% received three cycles of induction pembrolizumab (200 mg, every 21 days), underwent restaging FDG-PET/CT, received risk-adapted thoracic radiotherapy (55 Gy delivered to tumors or lymph nodes with metabolic tumor volume exceeding 20 cc and 48 Gy delivered to smaller lesions, all in 20 daily fractions), and then received up to 13 cycles of additional pembrolizumab. Subjects with PD-L1 TPS < 50% received concurrent chemoRT, and adjuvant durvalumab was recommended for patients without disease progression. The primary study endpoint was one-year progression-free survival (PFS) for subjects treated with pembrolizumab and radiotherapy (pembroRT), which we hypothesized would exceed 65%. Other study endpoints included 1-year overall survival (OS) and rates of clinician-scored (CTCAE v. 4.03) and patient-reported (PRO-CTCAE) adverse events observed over one year.
Result(s): Twenty-five subjects with PD-L1 TPS >= 50% and 12 subjects with PD-L1 TPS < 50% from three institutions were enrolled between August 2018 and November 2021. Median age was 70. Twenty-four subjects had stage II-IIIA disease, and 13 had stage IIIB-IIIC disease. Except for PD-L1 TPS, subject characteristics did not differ significantly across treatment groups. Ten out of the 12 subjects with ChemoRT received adjuvant durvalumab, and one received adjuvant osimertinib for EGFR mutation. The median follow-up duration is 15 months. Compared to patients treated with chemoRT, treatment with pembroRT has yielded numerically higher 1-year PFS (72% v. 46%, log rank p=0.232) and OS (91% v. 73%, log rank p=0.213) rates. Similar rates of grade 3 physician-scored adverse events have been observed with pembroRT (24%) and chemoRT (25%). Less severe patient-reported adverse events occurred with pembroRT compared to chemoRT (See Table).
Conclusion(s): Treatment with pembrolizumab and risk-adapted radiotherapy without chemotherapy is a promising approach for LA-NSCLC patients with PD-L1 TPS >= 50%. In addition to yielding high disease control rates, this strategy appears to reduce patient-reported adverse events compared to standard chemoRT and adjuvant therapy.
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An 83-year-old woman presents with two synchronous primary lung adenocarcinomas each harboring unique EGFR mutations, one classical and the other rare. She was treated with adjuvant Osimertinib following surgical lobectomy and remains well 44 months from the time of her diagnosis. Her case demonstrates the potential value in using EGFR third generation TKI monotherapy in patients with early-stage disease, harboring rare mutations and in patients with multiple primary cancers harboring targetable mutations. Further research into the use of targeted therapy in these areas is needed.

PURPOSE/OBJECTIVE:Patients with KRAS-mutant non-small cell lung cancer (NSCLC) with brain metastases (BM) have a poor prognosis. Adagrasib (MRTX849), a potent oral small molecule KRASG12C inhibitor, irreversibly and selectively binds KRASG12C, locking it in its inactive state. Adagrasib has been optimized for favorable pharmacokinetic (PK) properties, including long half-life (~24 hours), extensive tissue distribution, dose-dependent PK, and central nervous system penetration, however BM-specific anti-tumor activity of KRASG12C inhibitors remains to be fully characterized. EXPERIMENTAL DESIGN/METHODS:A retrospective database query identified patients with KRAS-mutant NSCLC to understand their propensity to develop BM. Preclinical studies assessed physiochemical and PK properties of adagrasib. Mice bearing intracranial KRASG12C-mutant NSCLC xenografts (LU99-Luc/H23-Luc/LU65-Luc) were treated with clinically relevant adagrasib doses and levels of adagrasib in plasma, cerebrospinal fluid (CSF), and brain were determined along with anti-tumor activity. Preliminary clinical data were collected from 2 patients with NSCLC with untreated BM who had received adagrasib 600 mg BID in the Phase 1b cohort of the KRYSTAL-1 trial; CSF was collected, adagrasib concentrations measured, and anti-tumor activity in BM evaluated. RESULTS:Patients with KRAS-mutant NSCLC demonstrated high propensity to develop BM ({greater than or equal to}40%). Adagrasib penetrated into CSF and demonstrated tumor regression and extended survival in multiple preclinical BM models. In 2 patients with NSCLC and untreated BM, CSF concentrations of adagrasib measured above the target cellular IC50. Both patients demonstrated corresponding BM regression, supporting potential clinical activity of adagrasib in the brain. CONCLUSIONS:These data support further development of adagrasib in patients with KRASG12C-mutant NSCLC with untreated BM.

BACKGROUND:, locking it in its inactive state. Adagrasib showed clinical activity and had an acceptable adverse-event profile in the phase 1-1b part of the KRYSTAL-1 phase 1-2 study. METHODS: RESULTS: CONCLUSIONS:

Background: Amivantamab is an epidermal growth factor receptor (EGFR)-MET bispecific antibody approved in the US for the treatment of EGFR exon 20 insertion non-small cell lung cancer that progressed on or after platinum-based chemotherapy. We review infusion-related reactions (IRRs) and its management in patients (pts) treated with amivantamab.
Method(s): This analysis includes pts treated at the recommended phase 2 dose (RP2D) of amivantamab (1050 mg; 1400 for bodyweight 80 kg or greater) from the CHRYSALIS study (NCT02609776). Mitigation strategies for IRR included a split first dose (350 mg on day 1, remainder on day 2), reduced initial infusion rates with proactive infusion interruption, and required steroid premedication for the initial dose. Pre-infusion antihistamines and antipyretics were required for all doses; steroids were optional after the initial dose.
Result(s): As of 8 Jun 2020, 258 pts received the RP2D of amivantamab. IRR was reported in 167 pts (65%) and was characterized by dyspnea, flushing, chills, and nausea. Severity of IRRs was mostly grade 1-2; with grade 3 IRR in 5 pts and 1 grade 4 event. Onset of IRR was rapid at a median of 44 mins; 94% occurred on cycle 1, day 1 (C1D1), and only 1 event occurred after C2. Of the 167 pts with IRR, 134 completed the full split dose and continued treatment per schedule; 33 pts (13%) aborted C1D1 infusion due to IRR, of which 4 discontinued further therapy. IRRs were mitigated on C1D1 with holding of infusion (54%) and reinitiating at a reduced rate (50%). In a subset of pts, an analysis of 22 circulating analytes (eg, markers of cytokine release syndrome, mast cell degranulation, complement activation) did not distinguish a pattern between pts with and without IRR.
Conclusion(s): IRRs with amivantamab treatment were frequently observed but were mostly low grade and primarily limited to the first infusion. Close monitoring for IRR with the initial dose helps mitigate IRR through proactive rate modifications.
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