Background

A mechanistic basis for non-small cell lung cancer (NSCLC) initiation in never smokers, a disease with a high frequency of EGFR mutations (EGFRm), is unknown. The air pollutant, particulate matter (PM), is known to be associated with the risk of NSCLC, however a direct cause and mechanism remain elusive.

Methods

We analysed 463,679 individuals to address the associations of increasing 2.5um PM (PM2.5) concentrations with cancer risk. We performed ultra-deep profiling of 247 normal lung tissue samples, analysed normal lung tissue from humans and mice following exposures to PM, and investigated the consequences of PM on tumour promotion in mouse lung cancer models.

Results

Increasing PM2.5 levels were associated with increased risk of EGFRm NSCLC in England, S.Korea and Taiwan and with increased risk of mesothelioma (HR=1.19), lung (HR=1.16), anal (HR=1.23), small intestine (HR=1.30), GBM (HR=1.19), lip, oral cavity and pharynx (HR: 1.15) and laryngeal carcinomas (HR=1.26) in UK Biobank; HR for each 1ug/m³ PM2.5 increment. 18-33% of normal lung tissue samples harbour driver mutations in EGFR and KRAS in the absence of malignancy. PM promotes a macrophage response and a progenitor-like state in lung epithelium harbouring mutant EGFR. Consistent with PM promoting NSCLC in at-risk epithelium harbouring driver mutations, PM increased tumour burden in three EGFR or KRAS driven lung cancer models in a dose-dependent manner. Finally, we uncover an actionable inflammatory axis driven by IL1B in response to PM, with anti-IL1B therapy preventing PM-induced mouse tumour formation, consistent with reductions in human lung cancer incidence with anti-IL1B therapy.

Conclusions

These results shed light on the aetiology of EGFRm lung cancer, particularly in never-smokers, and suggest that oncogenic mutations may be necessary but insufficient for tumour formation. These data reveal a mechanistic basis for PM driven lung cancer in the absence of classical carcinogen-driven mutagenesis, reminiscent of models of tumour initiation and promotion proposed 70 years ago, providing evidence to limit air pollution and opportunities for molecular targeted cancer prevention.

Clinical trial identification

TRAcking Non-small Cell Lung Cancer Evolution Through Therapy (Rx) (TRACERx) (NCT01888601); The PEACE (Posthumous Evaluation of Advanced Cancer Environment) Study (PEACE) (NCT03004755); Biomarkers and Dysplastic Respiratory Epithelium (NCT00900419).

Legal entity responsible for the study

Francis Crick Institute and UCL Hospitals NHS Trust.

Funding

This work has been supported by the MarkFoundation ASPIRE I Award (Grant 21-029-ASP), Lung Cancer Research Foundation Grant on Disparities in Lung Cancer, ERC Advanced Grant (PROTEUS, Grant Agreement no. 835297), CRUK EDD (EDDPMA-Nov21100034), CRUK lung cancer centre of excellence infrastructure award, CRUK TRACERx grant and Rosetrees Out-of-round Award (OoR2020100009).

Disclosure

C. Swanton: Financial Interests, Personal, Invited Speaker, Activity took place in 2016: Pfizer, Celgene; Financial Interests, Personal, Invited Speaker, October 26th 2020: Novartis; Financial Interests, Personal, Invited Speaker: Roche/Ventana, BMS, AstraZeneca, MSD, Illumina, GlaxoSmithKline; Financial Interests, Personal, Advisory Board, AdBoard - November 12th, 2020: Amgen; Financial Interests, Personal, Advisory Board: Genentech, Sarah Canon Research Institute, Medicxi; Financial Interests, Personal, Advisory Board, Joined October 2020. Also have stock options: Bicycle Therapeutics; Financial Interests, Personal, Advisory Board, Member of the Science Management Committee. Also have stock options: GRAIL; Financial Interests, Personal, Other, Consultancy agreement: Roche Innovation Centre Shanghai; Financial Interests, Personal, Full or part-time Employment, Chief Clinician since October 2017: Cancer Research UK; Financial Interests, Personal, Ownership Interest, Co-Founder of Achilles Therapeutics. Also, have stock options in this company: Achilles Therapeutics; Financial Interests, Personal, Stocks/Shares, Stocks owned until June 2021: GRAIL, Apogen Biotechnologies; Financial Interests, Personal, Stocks/Shares: Epic Biosciences, Bicycle Therapeutics; Financial Interests, Institutional, Research Grant, Funded RUBICON grant - October 2018 - April 2021.: Bristol Myers Squibb; Financial Interests, Institutional, Research Grant, Collaboration in minimal residual disease sequencing technologies.: Archer Dx Inc; Financial Interests, Institutional, Research Grant: Pfizer, Ono Pharmaceutical, Boehringer Ingelheim; Financial Interests, Institutional, Invited Speaker, Chief Investigator for the MeRmaiD1 clinical trial and chair of the steering committee: AstraZeneca; Financial Interests, Institutional, Research Grant, Research Grants from 2015-2019: Roche-Ventana; Financial Interests, Personal, Other, Co-chief investigator: NHS-Galleri Clinical Trial; Non-Financial Interests, Principal Investigator, Chief Investigator for MeRmaiD1 clinical trial: AstraZeneca; Non-Financial Interests, Invited Speaker, From 2019: AACR; Non-Financial Interests, Other, Board of Directors: AACR; Non-Financial Interests, Advisory Role, EACR Advisory Council member: EACR. T. Jacks: Financial Interests, Personal, Member of the Board of Directors: Amgen, Thermo Fisher Scientific; Financial Interests, Personal, Advisory Board, co-Founder: Dragonfly Therapeutics; Financial Interests, Personal, Other, co-Founder: T2 Biosystems; Financial Interests, Personal, Advisory Board: SQZ Biotech, Skyhawk Therapeutics; Financial Interests, Personal, Leadership Role: Break Through Cancer; Financial Interests, Institutional, Funding: Johnson & Johnson. J. Downward: Financial Interests, Personal, Other, consultant: AstraZeneca, Bayer, Jubilant, Theras, Vividion, Novartis; Financial Interests, Institutional, Research Grant: BMS, Revolution Medicines, Boehringer Ingelheim. K.R. Litchfield: Financial Interests, Personal, Invited Speaker: Roche Tissue Diagnostics; Financial Interests, Personal, Other, Consulting work: Monopteros Therapeutics; Financial Interests, Institutional, Research Grant: Ono/LifeArc; Financial Interests, Institutional, Research Grant, Research funding: Genesis Therapeutics; Non-Financial Interests, Institutional, Proprietary Information, Collaboration on data analysis: Bms. M. Jamal-Hanjani: Financial Interests, Personal, Invited Speaker, Invited speaker honorarium: Oslo Cancer Cluster, Astex Pharmaceutical; Non-Financial Interests, Advisory Role, Scientific Advisory Board and Steering Committee member: Achilles Therapeutics; Other, I am named as co-inventor on patent PCT/US2017/028013 relating to methods for lung cancer detection: Patent. All other authors have declared no conflicts of interest.

Background

DT are rare, locally aggressive soft-tissue tumors without approved systemic therapy. Nirogacestat (niro), a novel oral gamma secretase inhibitor (GSI) has shown antitumor activity in patients with DT.

Methods

DeFi is a global, Phase III, randomized, double-blind, placebo (pbo)-controlled trial in adults with progressing DT per RECIST v1.1 (NCT03785964). 142 participants were stratified by target tumor location (intra-/extra-abdominal) and randomized 1:1 to niro (n=70) 150 mg or pbo (n=72) BID. The primary endpoint was progression-free survival (PFS) per blinded independent central review. Prespecified secondary endpoints were safety, objective response rate (ORR), and patient-reported outcomes (PROs).

Results

Niro demonstrated significant PFS improvement compared with pbo (hazard ratio [HR], 0.29 [95% CI, 0.15, 0.55; P<0.001]). ORR was significantly improved with niro versus pbo (41% vs 8%; P<0.001), with a median time to response of 5.6 versus 11.1 months. The complete response rate was 7% with niro versus 0% with pbo. Statistically and clinically significant improvements in all prespecified PROs were observed early and sustained on treatment with niro compared with pbo (table). Of AEs with niro, 95% were grade 1/2, the most frequently reported being diarrhea (84%), nausea (54%), fatigue (51%), hypophosphatemia (42%), and maculopapular rash (32%). Ovarian dysfunction occurred in 75% (27/36) of women of childbearing potential treated with niro and resolved in 20 (74%), including 11/11 who discontinued niro for any reason.

Conclusions

Niro demonstrated statistically and clinically significant improvements in PFS, ORR, symptom burden, physical/role functioning, and health-related quality of life and had a manageable safety profile in adults with progressing DT. DeFi is the most rigorous randomized controlled trial performed to date in DT and the first positive Phase III trial of a GSI in any indication. Table: LBA2

Primary and secondary efficacy endpoints

Clinical trial identification

NCT03785964.

Editorial acknowledgement

Editorial assistance was provided under the direction of the authors by MedThink SciCom and funded by SpringWorks Therapeutics, Inc.

Legal entity responsible for the study

SpringWorks Therapeutics, Inc.

Funding

SpringWorks Therapeutics, Inc.

Disclosure

B. Kasper: Financial Interests, Personal, Advisory Board: Bayer, Blueprint, Boehringer Ingelheim, Springworks, GSK, PharmaMar, Ayala; Financial Interests, Institutional, Invited Speaker: PharmaMar, Springworks, Ayala; Non-Financial Interests, Leadership Role, Chair of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG): European Organisation for Research and Treatment of Cancer (EORTC). R. Ratan: Financial Interests, Personal, Advisory Board: Epizyme; Financial Interests, Personal, Invited Speaker: Epizyme; Financial Interests, Institutional, Invited Speaker: Ayala Pharmaceuticals, Springworks Therapeutics, C4 Therapeutics. T. Alcindor: Financial Interests, Personal, Advisory Board: Merck, Taiho, Eisai, Pfizer, Roche, BMS, AstraZeneca, Bayer; Financial Interests, Institutional, Funding, For investigator-initiated trial: EMD Serono; Financial Interests, Personal and Institutional, Invited Speaker: Astellas; Financial Interests, Institutional, Invited Speaker: Deciphera, Epizyme, Isofol, SpringWorks; Non-Financial Interests, Leadership Role, Co-chair of Esophago-Gastric Disease Site-Oriented Group: Canadian Cancer Trials Group; Non-Financial Interests, Advisory Role, Member, Committee for immunotherapy in upper GI cancers: American Society of Clinical Oncology; Non-Financial Interests, Advisory Role: Colorectal Cancer Canada. P. Schoeffski: Financial Interests, Personal, Advisory Board: Deciphera, BluePrint Medicines, Boehringer Ingelheim, Ellipses Pharma, Transgene, Exelixis, Medscape, Guided Clarity, Ysios, Modus Outcomes, Studiecentrum voor Kernenergie, Curio Science; Financial Interests, Institutional, Advisory Board: Blueprint Medicines, Ellipses Pharma, Intellisphere; Financial Interests, Institutional, Expert Testimony: Advance Medical/Teladoc Health; Financial Interests, Institutional, Funding: CoBioRes NV, Eisai, G1 Therapeutics, Novartis, PharmaMar. W.T.A. Van Der Graaf: Financial Interests, Institutional, Advisory Board, One advisory board: Bayer; Financial Interests, Institutional, Invited Speaker: Springworks, Ayala; Financial Interests, Institutional, Research Grant, IIS grant: Novartis; Financial Interests, Institutional, Research Grant, IIS: Lilly; Financial Interests, Institutional, Other, consultancy work: Springworks; Non-Financial Interests, Invited Speaker, President: EORTC; Non-Financial Interests, Invited Speaker: European Cancer Organisation, Connective Tissue Oncology Society (CTOS); Non-Financial Interests, Invited Speaker, Chair: Dutch Sarcoma Group, Dutch AYA 'Young and Cancer' Care Network. B.A. Wilky: Financial Interests, Personal, Other, Consulting for curriculum development: Springworks; Financial Interests, Personal, Advisory Board: Deciphera, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker: Agenus. R.F. Riedel: Financial Interests, Personal and Institutional, Grants or contracts from any entity; Consulting fees: Aadi, Daiichi-Sankyo, Deciphera, Ignyta, Lilly, NanoCarrier, SpringWorks; Financial Interests, Institutional, Grants or contracts from any entity: AROG, Ayala, BioAtla, GlaxoSmithKline, Inhibrx, Immune Design, Karyopharm, Novartis, Oncternal, Philogen, Plexxikon, Rain Therapeutics, Roche, Threshold, Tracon, Trillium; Financial Interests, Personal, Consulting fees: Bayer, Blueprint, Eisai, EMD Serono, Janssen; Financial Interests, Personal, Patents planned, issued or pending: Limbguard, LLC; Personal, Leadership or fiduciary role in other board, society, committee or advocacy group, paid or unpaid: ECOG-ACRIN Sarcoma Working Group. A. Lim: Financial Interests, Personal, Stocks/Shares: SpringWorks; Financial Interests, Personal, Full or part-time Employment: SpringWorks. L..M. Smith: Financial Interests, Institutional, Stocks/Shares: SpringWorks; Financial Interests, Institutional, Full or part-time Employment, Support for attending meetings and/or travel: SpringWorks. S. Attia: Financial Interests, Personal, Funding, Research Funding: Desmoid Tumor Research Foundation; Financial Interests, Institutional, Funding, Research Funding: AB Science, TRACON Pharma, Ayala Pharmaceuticals, Trillium Therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, InhibRx, Noxopharm, Rain Therapeutics, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics. S.P. Chawla: Financial Interests, Personal and Institutional, Funding: ADI, Amgen, GlaxoSmithKline, Ignyta, Immix Bopharma, Inhibrx, Janssen, Karyopharm Therapeutics, Roche, SARC, Tracon. N. Federman: Financial Interests, Personal, Advisory Board, Participation on a Data Safety Monitoring Board or Advisory Board: DSMB participation Ayala Pharmaceuticals; Financial Interests, Personal, Speaker’s Bureau, Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events: Speaker Bureau, Larotrectinib, Bayer AG. B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Invited Speaker, Also attended an Ad Board meeting. Travel was paid to present abstract at conference: GSK; Financial Interests, Personal, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise: ADRx; Financial Interests, Personal, Advisory Board, tenosynovial giant cell tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting/Advisor: Cytokinetics Inc; Financial Interests, Personal, Other, Consulting: Bayer; Financial Interests, Personal, Other, 60 minute interview regarding Synovial Sarcoma: Bionest Partners; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere LLC; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo, Deciphera Pharmaceuticals, Inc; Financial Interests, Personal, Advisory Board, Attended an advisory board meeting: Novartis; Financial Interests, Personal, Advisory Board: lilly, PTC Therapeutics; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Non-Financial Interests, Invited Speaker: Polaris. B. Vincenzi: Financial Interests, Personal, Consultant / Advisory: Eisai; Financial Interests, Personal and Institutional, Consultant / Advisory; Research funds: Eli Lilly; Financial Interests, Personal and Institutional, Other, Consultant / Advisory; Honoraria; Research funds: Novartis, PharmaMar; Financial Interests, Personal, Consultant / Advisory; Honoraria; Testimony: Abbott, GSK; Financial Interests, Personal, Honoraria; Testimony: Accord. S. Kummar: Financial Interests, Personal, Advisory Board: Bayer, Gilead, Mundibiopharma, Boehringer Ingelheim, Springworks Theraepeutics, HarbourBiomed, Boehringer Ingelheim; Financial Interests, Personal, Advisory Board, Spouse: Cadila Pharmaceuticals; Financial Interests, Personal, Ownership Interest: Pahtomiq; Financial Interests, Personal, Co-founder: Pathomiq; Financial Interests, Institutional, Invited Speaker: ADC Therapeutics, Pionyr Therapeutics, Eisai, Bristol Myers Squibb, Syndax, SeaGen, Oric, EMD Serono, Genome & Company, Moderna, Amgen, ASTX Therapeutics, PMV Pharmaceuticals, Elevation Oncology, VelosBio Inc, Gilead, Day One Biopharmaceuticals, Vincerx Pharma, Inc. M.M. Gounder: Financial Interests, Personal, Other, Honoraria: Flatiron Health, PER, Medscape, Guidepoint Global, touchIME, Med Learning Group, More Health; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role: Daiichi Sankyo, Bayer, Springworks, TYME, Ayala Pharmaceuticals, Rain Therapeutics; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Speakers' Bureau: Karyopharm Therapeutics, Boehringer Ingelheim; Financial Interests, Personal, Advisory Role, Consulting or Advisory Role; Travel, Accommodations, Expenses: Epizyme; Financial Interests, Personal, Speaker’s Bureau: Amgen; Financial Interests, Personal, Royalties, Patents, Royalties, Other Intellectual Property: UpToDate; Financial Interests, Institutional, Royalties, Patents, Royalties, Other Intellectual Property: Goddess Pro Desmoid Tumor; Financial Interests, Personal: Desmoid Tumor Research Foundation; Non-Financial Interests, Personal, Uncompensated Relationships: Foundation Medicine, Athenex. All other authors have declared no conflicts of interest.

Background

Immune checkpoint inhibitors and targeted therapies have greatly improved the outcome of patients (pts) with advanced melanoma. However, as approximately half will not derive durable benefit, a large unmet need for additional treatment options remains. Adoptive cell therapy with TIL is a treatment modality with promising response rates (RR) of 36-70% in pts with advanced melanoma, observed in multiple phase 1/2 trials. To date, no data from phase 3 trials is available to determine the role of TIL in the current treatment landscape.

Methods

In this multicenter, open-label phase 3 trial, pts with unresectable stage IIIC-IV melanoma (7^th edition), ≥18 ≤ 75 years, were randomized 1:1 to TIL or ipilimumab (3mg/kg q3wks, max 4 doses). Pts were stratified for BRAF^V600 mutation status, treatment line and center. Pts randomized to TIL underwent resection of a melanoma lesion (2-3cm) for the ex vivo outgrowth and expansion of tumor resident T cells. Infusion of ≥5x10⁹ TIL was preceded by non-myeloablative, lymphodepleting chemotherapy with cyclophosphamide + fludarabine and followed by high-dose interleukin-2. The primary endpoint was progression-free survival (PFS) per RECIST 1.1. Secondary endpoints were (overall and complete) RR, overall survival (OS) and safety.

Results

In total, 168 pts, the majority (86%) refractory to anti-PD-1 treatment, were randomized to TIL (n=84) or ipilimumab (n=84). With a median follow-up of 33.0 months, median PFS was 7.2 months for TIL (95% CI, 4.2 - 13.1), compared to 3.1 months (95% CI, 3.0 - 4.3) for ipilimumab (HR: 0.50 [95% CI, 0.35 - 0.72]; P<0.001). Overall RR was 49% (95% CI, 38% - 60%) for TIL and 21% (95% CI, 13% - 32%) for ipilimumab, with 20% (95% CI, 12% - 30%) and 7% (95% CI, 3% - 15%) complete responses, respectively. Median OS for TIL was 25.8 months (95% CI, 18.2 - not reached) and 18.9 months (95% CI, 13.8 - 32.6) for ipilimumab (HR: 0.83 [95% CI, 0.54 - 1.27]; P=0.39). Grade ≥3 treatment-related adverse events occurred in all TIL and 57% of ipilimumab pts.

Conclusions

TIL therapy significantly improved PFS compared to ipilimumab in pts with advanced melanoma, the vast majority being anti-PD-1 refractory, making it a possible new treatment option in this pt population.

Clinical trial identification

NCT02278887.

Legal entity responsible for the study

Netherlands Cancer Institute.

Funding

The Dutch Cancer Society, the Netherlands Organization for Health Research and Development, the Dutch Ministry of Health, Stichting Avento, Copenhagen University Hospital, Herlev, the Danish Cancer Society and Capital Region of Denmark Research Foundation.

Disclosure

J.B.A.G. Haanen: Financial Interests, Institutional, Advisory Board: Bristol Myers Squipp, Achilles Therapeutics, Immunocore, Gadeta, Ipsen, Merck Sharpe & Dohme, Merck Serono, Pfizer, Molecular Partners, Novartis, Roche, Sanofi, Third Rock Venture, Iovance Biotherapeutics; Financial Interests, Institutional, Advisory Board, SAB member: BioNTech, Instil Bio, PokeAcel, T-Knife; Financial Interests, Personal, Advisory Board, SAB member: Neogene Therapeutics; Financial Interests, Personal, Stocks/Shares: Neogene Therapeutics; Financial Interests, Institutional, Research Grant: Bristol Myers Squibb, BioNTech US, Merck Sharpe & Dohme, Amgen, Novartis, Asher Bio; Non-Financial Interests, Member: ASCO, AACR, SITC; Editor-in-Chief IOTECH, ESMO; Editorial Board ESMO Open, Editorial Board: Kidney Cancer. J.H. van den Berg: Financial Interests, Institutional, Research Collaboration: NEON therapeutics, Bristol Myers Squibb, Medimmune. J.H. Beijnen: Financial Interests, Personal, Stocks/Shares, part time employee and (in)direct stock holder: Modra Pharmaceuticals. S. Wilgenhof: Financial Interests, Institutional, Advisory Board: Eisai, Bristol Myers Squibb. A.C.J. van Akkooi: Financial Interests, Institutional, Advisory Board: Amgen, Bristol Myers Squibb, Novartis, MSD - Merck, Merck-Pfizer, Pierre Fabre, Sanofi, Sirius Medical, 4SC, Provectus; Financial Interests, Institutional, Research Grant, NIVEC study: Amgen; Financial Interests, Institutional, Research Grant: Merck-Pfizer. I. Svane: Financial Interests, Personal, Advisory Board: BMS, Pierre Fabre, Novartis; Financial Interests, Personal, Invited Speaker: MSD, Pierre Fabre, Novartis, Roche, BMS, MSD; Financial Interests, Personal, Stocks/Shares, Cofounder and Founder warrents: IO Biotech; Financial Interests, Institutional, Research Grant: Adaptimmune, Enara Bio, Lytix Biopharma, TILT Biotherapeutics; Financial Interests, Institutional, Funding: Evaxion; Non-Financial Interests, Principal Investigator: BMS, Roche, TILT Biotherapeutics, Lytix Biopharma, Novartis. All other authors have declared no conflicts of interest.