A phase 1a/1b trial of CSF-1R inhibitor LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid tumors
Background LY3022855 is a recombinant, immunoglobulin, human monoclonal antibody targeting the colony-stimulating factor-1 receptor. This phase 1 trial determined the safety, pharmacokinetics, and antitumor activity of LY3022855 in combination with durvalumab or tremelimumab in patients with advanced solid cancers who had received standard anti-cancer treatments. Methods In Part A (dose-escalation), patients received intravenous (IV) LY3022855 25/50/75/100Â mg once weekly (QW) combined with durvalumab 750Â mg once every two weeks (Q2W) IV or LY3022855 50 or 100Â mg QW IV with tremelimumab 75/225/750Â mg once every four weeks. In Part B (dose-expansion), patients with non-small cell lung cancer (NSCLC) or ovarian cancer (OC) received recommended phase 2 dose (RP2D) of LY3022855 from Part A and durvalumab 750Â mg Q2W. Results Seventy-two patients were enrolled (median age 61Â years): Part Aâ€‰=â€‰33, Part Bâ€‰=â€‰39. In Part A, maximum tolerated dose was not reached, and LY3022855 100Â mg QW and durvalumab 750Â mg Q2W was the RP2D. Four dose-limiting equivalent toxicities occurred in two patients from OC cohort. In Part A, maximum concentration, area under the concentration-time curve, and serum concentration showed dose-dependent increase over two cycles of therapy. Overall rates of complete response, partial response, and disease control were 1.4%, 2.8%, and 33.3%. Treatment-emergent anti-drug antibodies were observed in 21.2% of patients. Conclusions LY3022855 combined with durvalumab or tremelimumab in patients with advanced NSCLC or OC had limited clinical activity, was well tolerated. The RP2D was LY3022855 100Â mg QW with durvalumab 750Â mg Q2W. ClinicalTrials.gov ID: NCT02718911 (Registration Date: May 3, 2011).
Comparison of solid tissue sequencing and liquid biopsy accuracy in identification of clinically relevant gene mutations and rearrangements in lung adenocarcinomas
Screening for therapeutic targets is standard of care in the management of advanced non-small cell lung cancer. However, most molecular assays utilize tumor tissue, which may not always be available. "Liquid biopsies" are plasma-based next generation sequencing (NGS) assays that use circulating tumor DNA to identify relevant targets. To compare the sensitivity, specificity, and accuracy of a plasma-based NGS assay to solid-tumor-based NGS we retrospectively analyzed sequencing results of 100 sequential patients with lung adenocarcinoma at our institution who had received concurrent testing with both a solid-tissue-based NGS assay and a commercially available plasma-based NGS assay. Patients represented both new diagnoses (79%) and disease progression on treatment (21%); the majority (83%) had stage IV disease. Tissue-NGS identified 74 clinically relevant mutations, including 52 therapeutic targets, a sensitivity of 94.8%, while plasma-NGS identified 41 clinically relevant mutations, a sensitivity of 52.6% (pâ€‰<â€‰0.001). Tissue-NGS showed significantly higher sensitivity and accuracy across multiple patient subgroups, both in newly diagnosed and treated patients, as well as in metastatic and nonmetastatic disease. Discrepant cases involved hotspot mutations and actionable fusions including those in EGFR, ALK, and NTRK1. In summary, tissue-NGS detects significantly more clinically relevant alterations and therapeutic targets compared to plasma-NGS, suggesting that tissue-NGS should be the preferred method for molecular testing of lung adenocarcinoma when tissue is available. Plasma-NGS can still play an important role when tissue testing is not possible. However, given its low sensitivity, a negative result should be confirmed with a tissue-based assay.
Amivantamab in EGFR Exon 20 Insertion-Mutated Non-Small-Cell Lung Cancer Progressing on Platinum Chemotherapy: Initial Results From the CHRYSALIS Phase I Study
PURPOSE/OBJECTIVE:) exon 20 insertion (Exon20ins) mutations exhibits inherent resistance to approved tyrosine kinase inhibitors. Amivantamab, an EGFR-MET bispecific antibody with immune cell-directing activity, binds to each receptor's extracellular domain, bypassing resistance at the tyrosine kinase inhibitor binding site. METHODS:Exon20ins NSCLC population treated at the recommended phase II dose of 1,050 mg amivantamab (1,400 mg, â‰¥ 80 kg) given once weekly for the first 4 weeks and then once every 2 weeks starting at week 5. RESULTS:In the efficacy population (n = 81), the median age was 62 years (range, 42-84 years); 40 patients (49%) were Asian, and the median number of previous lines of therapy was two (range, 1-7). The overall response rate was 40% (95% CI, 29 to 51), including three complete responses, with a median duration of response of 11.1 months (95% CI, 6.9 to not reached). The median progression-free survival was 8.3 months (95% CI, 6.5 to 10.9). In the safety population (n = 114), the most common adverse events were rash in 98 patients (86%), infusion-related reactions in 75 (66%), and paronychia in 51 (45%). The most common grade 3-4 adverse events were hypokalemia in six patients (5%) and rash, pulmonary embolism, diarrhea, and neutropenia in four (4%) each. Treatment-related dose reductions and discontinuations were reported in 13% and 4% of patients, respectively. CONCLUSION/CONCLUSIONS:Exon20ins mutations after progression on platinum-based chemotherapy.
Comprehensive Molecular and Clinicopathologic Analysis of 200 Pulmonary Invasive Mucinous Adenocarcinomas Identifies Distinct Characteristics of Molecular Subtypes
PURPOSE/OBJECTIVE:Comprehensive analysis of a large series of IMAs utilizing broad DNA and RNA sequencing methods is still lacking, and it remains unclear whether molecular subtypes of IMA differ clinicopathologically. DESIGN/METHODS:A total of 200 IMAs were analyzed by 410-gene DNA next-generation sequencing (MSK-IMPACT; n=136) or hotspot 8-oncogene genotyping (n=64). Driver-negative cases were further analyzed by 62-gene RNA sequencing (MSK-Fusion) and those lacking fusions were further tested by whole-exome and whole-transcriptome sequencing. RESULTS:-rearranged tumors exhibited several more aggressive characteristics including worse recurrence-free survival (p<0.0001). CONCLUSIONS:wild-type IMAs that includes fusion testing is essential given the high prevalence of alterations with established and investigational targeted therapies in this subset.
The Common Thread: A Case of Synchronous Lung Cancers and a Germline CHEK2 Mutation [Case Report]
Patients with one form of cancer are at increased risk for another, and this is true for lung cancer, where synchronous primary lung cancers are an increasing multifaceted challenge.1,2 Here, we present the case of a middle age woman who was found to have bilateral lung masses. Biopsy and subsequent testing revealed unique synchronous lung adenocarcinomas, each with unique genetic signatures. Despite having two unique tumors, she was found to have CHEK2 mutations in both tumors and in germline testing. Because of this extensive testing that showed unique tumors, she was ultimately diagnosed with stage IIIb and IA2 lung cancers, and this changed her treatment options. Consideration of unique primary tumors leads to thorough diagnostics, which changed this patient's diagnosis, prognosis, and treatment. We hope this case raises awareness for multiple primary tumors, as well as CHEK2 as an important oncogene.
Clinicopathologic Features and Response to Therapy of NRG1 Fusion-Driven Lung Cancers: The eNRGy1 Global Multicenter Registry
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.
Durvalumab consolidation therapy in a patient with stage IIIB unresectable NSCLC harboring a MET exon 14 splice site alteration
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.
99O_PR KRYSTAL-1: Activity and preliminary pharmacodynamic (PD) analysis of adagrasib (MRTX849) in patients (Pts) with advanced non-small cell lung cancer (NSCLC) harboring KRASG12C mutation [Meeting Abstract]
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. KRASG12C mutations occur in approximately 14% of NSCLC (adenocarcinoma). Adagrasib, an investigational agent, is a potent, covalent inhibitor of KRASG12C that irreversibly and selectively binds to KRASG12C, 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 KRASG12C 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 KRASG12C-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.
OA04.04 Amivantamab in Post-platinum EGFR Exon 20 Insertion Mutant Non-small Cell Lung Cancer [Meeting Abstract]
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 3rd 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
Dynamic Management of Lung Cancer Care During Surging COVID-19
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.