Faculty Bibliography

PURPOSE/OBJECTIVE:fusion-positive lung cancers in the largest and most diverse series to date. METHODS:fusion-positive lung cancers. Profiling included DNA-based and/or RNA-based next-generation sequencing and fluorescence in situ hybridization. Anonymized clinical, pathologic, molecular, and response (RECIST v1.1) data were centrally curated and analyzed. RESULTS:fusion-positive lung cancer, further diversity, including in smoking history (43%) and histology (43% nonmucinous and 6% nonadenocarcinoma), was elucidated. RNA-based testing identified most fusions (74%). Molecularly, six (of 18) novel 5' partners, 20 unique epidermal growth factor domain-inclusive chimeric events, and heterogeneous 5'/3' breakpoints were found. Platinum-doublet and taxane-based (post-platinum-doublet) chemotherapy achieved low objective response rates (ORRs 13% and 14%, respectively) and modest progression-free survival medians (PFS 5.8 and 4.0 months, respectively). Consistent with a low programmed death ligand-1 expressing (28%) and low tumor mutational burden (median: 0.9 mutations/megabase) immunophenotype, the activity of chemoimmunotherapy and single-agent immunotherapy was poor (ORR 0%/PFS 3.3 months and ORR 20%/PFS 3.6 months, respectively). Afatinib achieved an ORR of 25%, not contingent on fusion type, and a 2.8-month median PFS. CONCLUSION/CONCLUSIONS:-rearranged tumor biology is needed to develop new therapeutic strategies.

BACKGROUND:Recent literature has identified significant benefit of consolidation durvalumab following chemoradiotherapy in patients with unresectable non-small cell lung cancer (NSCLC). However, immunotherapy has demonstrated modest benefit in patients harboring oncogene driver mutations. While standard of care in metastatic oncogenic driven tumors is targeted tyrosine kinase inhibitors (TKIs), there is little data to guide treatment for patients who present with earlier stage unresectable disease, receiving chemoradiotherapy and have both high PD-L1 expression as well as concomitant actionable driver mutations. CLINICAL PRESENTATION/METHODS:We report a patient who presented with stage IIIB lung adenocarcinoma with high PD-L1 expression (80%) for which she received definitive concurrent chemoradiotherapy with consolidation durvalumab. The patient quickly progressed and was found to harbor a MET exon 14 splice site alteration for which she received crizotinib and had a good response. DISCUSSION/CONCLUSIONS:This case highlights the possibility that patients with non-metastatic, unresectable NSCLC with high PD-L1 expression and a concomitant driver mutation may benefit from targeted tyrosine kinase inhibitors rather than immune checkpoint inhibitor therapy.

Background: KRAS, the most frequently mutated oncogene in cancer, is a key mediator of the RAS/MAPK signaling cascade that promotes cellular growth and proliferation. KRAS^G12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRAS^G12C that irreversibly and selectively binds to KRAS^G12C, locking it in its inactive state and was optimized for favorable PK properties, including oral bioavailability, long half-life (~24 h), and extensive tissue distribution.
Method(s): KRYSTAL-1 (NCT03785249) is a multi-cohort phase I/II study evaluating adagrasib in pts with advanced or metastatic solid tumors, including NSCLC, harboring a KRAS^G12C mutation previously treated with chemotherapy and an anti-PD-(L)1. Exploratory endpoints include correlative analysis of co-occurring genetic alterations in tumor tissue at baseline and evaluation of the modulation of PD markers, including transcriptomics, in pretreatment and on-study biopsies.
Result(s): As of 30 August 2020, 79 pts with pretreated NSCLC were treated with adagrasib 600 mg BID (phase I/Ib and phase II). Most commonly reported (>20%) TRAEs included: nausea (54%), diarrhea (48%), vomiting (34%), fatigue (28%), and increased ALT (23%). Among the 51 pts evaluable for clinical activity, 45% (23/51) had a partial response (PR) and 26 pts had stable disease (SD). In a subpopulation of pts with STK11-comutations, ORR was 64% (9/14). Preliminary PD and mechanistic biomarker analyses on pre- and post-treatment tumor NSCLC biopsies (n = 3) demonstrate downregulation of KRAS/MAPK pathway genes including DUSP6 and SPRY4. In pts with tumors harboring STK11-comutations, there was minimal expression of immune transcripts (eg, CD4 and CD8) at baseline and these transcripts were increased after treatment with adagrasib suggesting a potential immune response to therapy.
Conclusion(s): Adagrasib is tolerable and has demonstrated clinical activity in pts with previously treated KRAS^G12C-mutant NSCLC. Additional PD and mechanistic data will be presented. Clinical trial identification: NCT03785249. Editorial acknowledgement: Editorial support was provided by Robin Serody of Axiom Healthcare Strategies. Legal entity responsible for the study: Mirati Therapeutics, Inc.
Funding(s): Mirati Therapeutics, Inc. Disclosure: G.J. Riely: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: Takeda; Advisory/Consultancy: Mirati Therapeutics. S-H.I. Ou: Advisory/Consultancy: Pfizer; Advisory/Consultancy: Roche; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: TP Therapeutics; Speaker Bureau/Expert testimony: Genentech; Speaker Bureau/Expert testimony: AstraZeneca; Speaker Bureau/Expert testimony: Takeda; Shareholder/Stockholder/Stock options: Turning Point Therapeutics. I. Rybkin: Advisory/Consultancy: AstraZeneca. A. Spira: Shareholder/Stockholder/Stock options: Lilly; Advisory/Consultancy: Incyte; Advisory/Consultancy: Amgen; Advisory/Consultancy: Novartis; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Gritstone; Advisory/Consultancy: Jazz Pharmaceuticals; Honoraria (self): CytomX Therapeutics; Honoraria (self): AstraZeneca/MedImmune; Honoraria (self): Merck; Honoraria (self): Takeda; Honoraria (self): Amgen; Honoraria (self): Janssen Oncology; Honoraria (self): Novartis; Honoraria (self): Bristol Myers Squibb; Honoraria (self): Bayer. K. Papadopoulos: Advisory/Consultancy: Bayer; Advisory/Consultancy: ArQule; Advisory/Consultancy: Basilea. M. Johnson: Spouse/Financial dependant: Otsuka; Travel/Accommodation/Expenses: AbbVie; Travel/Accommodation/Expenses: AstraZeneca; Travel/Accommodation/Expenses: Genentech; Travel/Accommodation/Expenses: Incyte; Travel/Accommodation/Expenses: Merck; Travel/Accommodation/Expenses: Pfizer; Travel/Accommodation/Expenses: Sanofi. R.S. Heist: Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Tarveda; Advisory/Consultancy: Apollonia; Honoraria (self): Chugai/Roche. L. Bazhenova: Shareholder/Stockholder/Stock options: Epic Sciences; Advisory/Consultancy, Research grant/Funding (self): Beyond Spring Pharmaceuticals; Advisory/Consultancy: AstraZeneca; Advisory/Consultancy: Takeda; Advisory/Consultancy: Roche; Advisory/Consultancy: Blueprint Medicines; Advisory/Consultancy: G1; Advisory/Consultancy: Bayer; Advisory/Consultancy: Boehringer Ingelheim; Advisory/Consultancy: Novartis; Advisory/Consultancy: Regeneron; Advisory/Consultancy: Merck; Advisory/Consultancy: Johnson & Johnson; Advisory/Consultancy: BMSi; Advisory/Consultancy: Daichi Sankyo; Advisory/Consultancy: Neuvogen. J.M. Pacheco: Advisory/Consultancy, Travel/Accommodation/Expenses: AstraZeneca; Advisory/Consultancy, Travel/Accommodation/Expenses: Novartis; Advisory/Consultancy: Hengrui; Advisory/Consultancy: Gerson Lehrman; Advisory/Consultancy, Travel/Accommodation/Expenses: Pfizer; Honoraria (self), Travel/Accommodation/Expenses: Takeda. K. Velastegui: Full/Part-time employment: Mirati Therapeutics, Inc. C. Cilliers: Full/Part-time employment: Mirati Therapeutics, Inc. P. Olson: Full/Part-time employment: Mirati Therapeutics, Inc. J.G. Christensen: Leadership role, Shareholder/Stockholder/Stock options, Officer/Board of Directors: Mirati Therapeutics, Inc; Advisory/Consultancy: BridgeBio; Leadership role, Shareholder/Stockholder/Stock options: BCTG Acquisition; Shareholder/Stockholder/Stock options: Bluebird Bio. T. Kheoh: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc; Shareholder/Stockholder/Stock options: Tocagen. R.C. Chao: Shareholder/Stockholder/Stock options, Full/Part-time employment: Mirati Therapeutics, Inc. P.A. Janne: Shareholder/Stockholder/Stock options: Gatekeeper Pharmaceuticals; Advisory/Consultancy, Shareholder/Stockholder/Stock options: Loxo; Research grant/Funding (self): Revolution Medicines; Advisory/Consultancy, Research grant/Funding (self): Takeda; Research grant/Funding (self): Puma Biotechnology; Advisory/Consultancy, Research grant/Funding (self): Boehringer Ingelheim; Advisory/Consultancy, Research grant/Funding (self): Lilly; Advisory/Consultancy, Research grant/Funding (self): Daichi Sankyo; Research grant/Funding (self): Astellas; Advisory/Consultancy, Research grant/Funding (self): AstraZeneca; Advisory/Consultancy: Pfizer; Advisory/Consultancy: Merrimack; Advisory/Consultancy: Roche/Genentech; Advisory/Consultancy: Chugai; Advisory/Consultancy: Mirati Therapeutics, Inc; Advisory/Consultancy: Araxes; Advisory/Consultancy: Ignyta; Advisory/Consultancy: Novartis; Advisory/Consultancy: Biocartis; Advisory/Consultancy: Voronoi; Advisory/Consultancy: SFJ Pharmaceuticals; Advisory/Consultancy: Silicon Therapeutics. All other authors have declared no conflicts of interest.
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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).
Method(s): 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 3^rd assessment (the Post-Platinum Cohort). The data cutoff date was 8 Jun 2020.
Result(s): 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(s): 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. Keywords: amivantamab, Exon20ins, Bispecific antibody
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Management of patients with lung cancer continues to be challenging during the COVID-19 pandemic, due to the increased risk of complications in this subset of patients. During the COVID-19 surge in New York City, New York University Langone Health adopted triage strategies to help with care for lung cancer patients, with good surgical outcomes and no transmission of COVID-19 to patients or healthcare workers. Here, we will review current recommendations regarding screening and management of lung cancer patients during both a non-surge phase and surge phase of COVID-19.

Background: In preclinical studies, the combination of amivantamab (EGFR-MET bispecific antibody) with lazertinib demonstrates synergistic inhibition of tumor growth. We present the safety and early efficacy results of patients receiving amivantamab in combination with lazertinib in the phase 1 CHRYSALIS study (NCT02609776).
Method(s): Patients with EGFR Exon 19 deletion or L858R mutation non-small cell lung cancer (NSCLC) were enrolled in this 2-part study. To identify the recommended phase 2 combination dose (RP2CD), Part 1 enrolled patients without restriction on prior therapy to evaluate escalating dose cohorts of amivantamab (700-1050 mg, iv once weekly for 28 days; biweekly thereafter) in combination with standard monotherapy dosing of lazertinib (240 mg oral daily). The ongoing Part 2 dose expansion Cohort E is evaluating preliminary efficacy, without biomarker selection, in patients progressing on osimertinib. Response was assessed by investigator per RECIST v1.1.
Result(s): As of 17 March 2020, 71 patients received the combination: median age was 61 y (36-79), median prior lines was 1 (0-9). In Part 1, the RP2CD was the maximally assessed doses of 1050 mg (1400 mg, >=80 kg) amivantamab + 240 mg lazertinib. Interim safety profile includes rash (78%), infusion related reaction (61%), paronychia (42%), stomatitis (31%), pruritus (24%), and diarrhea (14%). Majority of treatment-related AEs were grade 1-2, with grade >=3 reported in 7%. As of 30 April 2020, in 23 Part 1 patients with measurable disease, the overall response rate (ORR) was 43.5% (95% CI, 23.2-65.5) with 10 partial responses (PRs), and 9 patients with stable disease (SD); median treatment duration was 8.2 months (0.5-10.7), with 13 patients still ongoing. In the post-osimertinib expansion Cohort E, early antitumor activity is being observed in 14/20 response-evaluable patients with 1 complete response, 7 PRs (2 pending confirmation), and 6 SD with tumor shrinkage.
Conclusion(s): Amivantamab can be combined safely with lazertinib at their respective full monotherapy doses. Encouraging preliminary activity was observed in osimertinib-relapsed disease: updated data will be presented. Clinical trial identification: NCT02609776; submitted November 18, 2015. Editorial acknowledgement: Medical writing support was provided by Tracy T. Cao, PhD (Janssen Global Services, LLC) and funded by Janssen Global Services, LLC. Legal entity responsible for the study: Janssen R&D.
Funding(s): Janssen R&D. Disclosure: B.C. Cho: Advisory/Consultancy: Novartis, AstraZeneca, Boehringer Ingelheim, Roche, Bristol-Myers Squibb, Yuhan, Pfizer, Lilly, Janssen, Takeda, MSD, Ono Pharmaceuticals; Speaker Bureau/Expert testimony: Novartis; Licensing/Royalties: Champions Oncology; Shareholder/Stockholder/Stock options: Theravance, Gencurix, Bridgebio Therapeutics, Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD; Research grant/Funding (self): Novartis, Bayer, AstraZeneca, Mogam Biotechnology Research Institute, Dong-A ST, Champions Oncology, Janssen, Yuhan, Ono Pharmaceutical, Dizal Pharma, MSD. K.H. Lee: Advisory/Consultancy: Bristol-Myers Squibb, MSD, AstraZeneca; Honoraria (self): Bristol-Myers Squibb, MSD, AstraZeneca. D-W. Kim: Travel/Accommodation/Expenses: Daiichi Sankyo, Amgen; Research grant/Funding (institution): Alpha Biopharma, AstraZeneca/MedImmune, Hanmi, Janssen, Merus, Mirati Therapeutics, MSD, Novartis, Ono Pharmaceutical, Pfizer, Roche/Genentech, Takeda, TP Therapeutics, Xcovery, Yuhan, Boehringer Ingelheim. J-Y. Han: Advisory/Consultancy: MSD Oncology, AstraZeneca, Bristol-Myers Squibb, Lilly, Novartis, Takeda, Pfizer; Honoraria (self): Roche, AstraZeneca, Bristol-Myers Squibb, MSD, Takeda; Research grant/Funding (self): Roche, Pfizer, Ono Pharmaceutical, Takeda. A. Spira: Advisory/Consultancy, AstraZeneca/MedImmune consulting applies to my institution: Array BioPharma, Incyte, Amgen, Novartis, AstraZeneca/MedImmune; Shareholder/Stockholder/Stock options: Lilly; Honoraria (self): CytomX Therapeutics, AstraZeneca/MedImmune, Merck, Takeda, Amgen; Research grant/Funding (institution): Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, LAM Therapeutics, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol-Myers Squibb, Loxo, Arch Therap; Research grant/Funding (self): LAM Therapeutics. E.B. Haura: Advisory/Consultancy: Janssen; Travel/Accommodation/Expenses: Bristol-Myers Squibb, Roche, Janssen; Research grant/Funding (institution): Janssen, Novartis, Revolution Medicines, AstraZeneca, Genentech; Research grant/Funding (self): FORMA Therapeutics, Incyte. J.K. Sabari: Advisory/Consultancy: AstraZeneca. R.E. Sanborn: Advisory/Consultancy: Amgen, Seattle Genetics, Peregrine Pharmaceuticals, ARIAD, Genentech/Roche, AstraZeneca, Celldex, AbbVie, Takeda; Travel/Accommodation/Expenses: Five Prime Therapeutics, Janssen, AstraZeneca; Honoraria (self): AstraZeneca; Research grant/Funding (institution): Bristol-Myers Squibb, MedImmune; Research grant/Funding (self): Merck. J.M. Bauml: Advisory/Consultancy: Bristol-Myers Squibb, Merck, AstraZeneca, Genentech, Celgene, Boehringer Ingelheim, Guardant Health, Takeda, Novartis, Janssen, Ayala Pharmaceuticals, Regeneron; Research grant/Funding (institution): Merck, Carevive Systems, Novartis, Incyte, Bayer, Janssen, AstraZeneca, Takeda, Amgen. J.E. Gomez: Speaker Bureau/Expert testimony: Bristol-Myers Squibb, Atara, AstraZeneca. P. Lorenzini, J.R. Infante, J. Xie, N. Haddish-Berhane, M. Thayu, R.E. Knoblauch: Full/Part-time employment: Janssen; Shareholder/Stockholder/Stock options: Johnson & Johnson. K. Park: Advisory/Consultancy: AstraZeneca, Boehringer Ingelheim, Lilly, Hanmi, Novartis, Ono Pharmaceutical, Roche, Bristol-Myers Squibb, MSD, Blueprint Medicines, Amgen, Merck KGaA, Loxo, AbbVie, Daiichi Sankyo; Speaker Bureau/Expert testimony: Boehringer Ingelheim, AZD; Research grant/Funding (self): AstraZeneca, MSD Oncology. All other authors have declared no conflicts of interest.
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The development of effective therapies against brain metastasis is currently hindered by limitations in our understanding of the molecular mechanisms driving it. Here we define the contributions of tumour-secreted exosomes to brain metastatic colonization and demonstrate that pre-conditioning the brain microenvironment with exosomes from brain metastatic cells enhances cancer cell outgrowth. Proteomic analysis identified cell migration-inducing and hyaluronan-binding protein (CEMIP) as elevated in exosomes from brain metastatic but not lung or bone metastatic cells. CEMIP depletion in tumour cells impaired brain metastasis, disrupting invasion and tumour cell association with the brain vasculature, phenotypes rescued by pre-conditioning the brain microenvironment with CEMIP⁺ exosomes. Moreover, uptake of CEMIP⁺ exosomes by brain endothelial and microglial cells induced endothelial cell branching and inflammation in the perivascular niche by upregulating the pro-inflammatory cytokines encoded by Ptgs2, Tnf and Ccl/Cxcl, known to promote brain vascular remodelling and metastasis. CEMIP was elevated in tumour tissues and exosomes from patients with brain metastasis and predicted brain metastasis progression and patient survival. Collectively, our findings suggest that targeting exosomal CEMIP could constitute a future avenue for the prevention and treatment of brain metastasis.