Background

Patients diagnosed with rare cancers (RC, incidence < 6/100,000 person-years) face challenges in accessing RC care and clinical trials. Clinicians are often uncertain how to seek expert guidance. RC trials and research programs have difficulty recruiting patients. These complexities are compounded in Australia where vast geographic distance is a major barrier to accessing sub-specialist expertise. The Australian Rare Cancer (ARC) Portal (www.arcportal.org.au) was established in 2019 to address these challenges.

Methods

ARC Portal is an online service that provides clinicians with expert guidance, advice on molecular testing/interpretation and identification of drug access options and trials. Under the supervision of senior oncologists, fellows perform a literature review and search for drug access options. In complex cases, (inter)national experts are contacted for commentary. Clinicians receive reports within 2-3 weeks of referral and are connected directly to relevant trial investigators and drug access program managers. Patients are also invited to participate in research.

Results

From April 2019 to June 2023, 1463 patients were referred. 45% lived outside major metropolitan areas. 73.8% had metastatic/advanced disease. 151 unique tumour types were referred, of which >30 were ultra-rare (incidence ≤1/1,000,000). 84.2% consented to clinical history and biospecimen collection for research, which, together with ARC Portal reports, creates a valuable knowledge base and virtual biobank. Treating specialists have been networked to the national RC expert most appropriate for that case, and where needed, patients have been provided with supporting evidence for treatment with non-approved/non-reimbursed therapies, resulting in compassionate drug access. To date, six fellows have graduated from ARC Portal, contributing to national RC expertise. Collaborations with national expert tumour groups, consumer organisations (e.g. Rare Cancers Australia) and regional trial alliances are ongoing.

Conclusions

Through a unique, multi-faceted approach linking patients, clinicians, clinical trials, industry and professional bodies, the ARC Portal addresses disparities inherent in RC care and contributes to research.

Legal entity responsible for the study

Australian Rare Cancer Portal.

Funding

The ARC Portal is funded by an Australian Federal Government grant through the Australian Genomic Cancer Medicine Centre, now known as Omico.

Disclosure

All authors have declared no conflicts of interest.

Background

The long-term impact of tyrosine kinase inhibitor (TKI) interruption on resistance and survival in patients with advanced GIST is unclear. We report here on the long-term outcome of patients with advanced GIST stopping imatinib in the BFR14 randomized study.

Methods

Patients with advanced GIST (any mutation) aged >=18 with a PS 0-3, adequate renal and hepatic function were eligible in the BFR14 study. Patients in complete or partial response, or stable disease at 3 time periods (1 year, 3 years, 5 years) were proposed for randomisation between treatment discontinuation and restart at progression (STOP arm) or continuation of the treatment until progression (CONT arm). Randomization at 1, 3 and 5 years took place from Feb 2003 to Mar 2004, May 2005 to May 2007, and Nov 2007 to Jul 2010 respectively. The primary objective was to compare progression free survival (PFS) in the two groups. Secondary endpoints included overall survival (OS) and time to imatinib resistance (TTIR), defined as the time between randomisation and progression on imatinib (i.e., after restart in the stop arm). Median follow-up after 1, 3, and 5 years randomisations were 234, 200 and 164 months respectively.

Results

Among the 434 patients included in the BFR14 trial, respectively 58 were randomized in the STOP and CONT arms after 1 year, 50 after 3 years, and 27 after 5 years. Two were lost for follow-up. PFS was significantly improved in the CONT vs STOP arms in the three randomization periods. (p<0.001). The TTIR was significantly shorter for patients randomized in the STOP vs CONT arms after 3-years (66 vs 127 months, p=0.009), and after 5-years of imatinib (58.6 vs NR, p=0.03), while no significant difference was found for those randomised after 1 year. Survival after the randomization at 1 year was not significantly different but median OS were 66 vs 127 months in the STOP and CONT arms. Survival after randomization at 3 years was significantly shorter in the STOP arm after 10 year (logrank p=0.005, 15 year survival 5% vs 42%). Survival after randomization at 5 years was not significantly different.

Conclusions

In this randomized study, matinib interruption in non-progressing GIST patients was associated with faster resistance to imatinib and shorter OS in the long-term.

Clinical trial identification

NCT00367861.

Editorial acknowledgement

none

Legal entity responsible for the study

Centre Léon Bérard.

Funding

Novartis, Ligue contre le Cancer, Fondation ARC, NOT PHRC.

Disclosure

J-Y. Blay: Financial Interests, Institutional, Invited Speaker: MSD, MSD, PharmaMar; Financial Interests, Institutional, Advisory Board: Bayer, GSK, Roche; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, member of the supervisory board. No remunerations in 2021 and 2022: Innate Pharma; Financial Interests, Personal, Member of Board of Directors: Transgene; Financial Interests, Institutional, Funding: MSD, BMS, Deciphera; Financial Interests, Institutional, Research Grant: AstraZeneca, Roche, Bayer, GSK, Novartis, OSE pharma. F. Duffaud, M. Toulmonde, N. Firmin, E. Bompas, S. Salas, C. Honoré, M. Pracht, D. Perol, S. Chabaud, A. Le Cesne: Financial Interests, Personal and Institutional, Research Grant: Novartis. I.L. Ray-Coquard: Financial Interests, Personal, Advisory Board: Roche, GSK, AstraZeneca, Mersana, Deciphera, Amgen, Oxnea, Merck Sereno, Agenus, Novartis, Macrogenics, Clovis, EQRX, Adaptimmun, Eisai, Sutro, BMS, Adaptimmune, Daiichi Sankyo; Financial Interests, Institutional, Other, COLIBRI translational research: BMS; Financial Interests, Institutional, Advisory Board, translational research NEOPREMBROV trial: MSD; Non-Financial Interests, Personal, Principal Investigator: PAOLA1; Non-Financial Interests, Personal, Other, President: GINECO. M. Brahmi: Financial Interests, Personal, Advisory Board: Bayer; Financial Interests, Personal, Invited Speaker: Amgen, PharmaMar, Deciphera. A. Dufresne: Non-Financial Interests, Personal, Project Lead, Translational research project: GSK, Adaptimmune; Non-Financial Interests, Personal, Project Lead, Translational research program: Bayer. N. Penel: Financial Interests, Institutional, Research Grant, Research grant for clinical trials in sarcoma filed: Bayer HealthCare. A. Italiano: Financial Interests, Personal, Advisory Board: Bayer, Roche, Philips, Chugai, GSK; Financial Interests, Institutional, Invited Speaker: Bayer, AstraZeneca, Roche, MSD, Ipsen, Merck. All other authors have declared no conflicts of interest.

Background

AXL is a cell-surface receptor tyrosine kinase highly expressed in several sarcoma subtypes that has been associated with tumor resistance to chemotherapy. Mecbotamab vedotin (BA3011) is a conditionally active biologic anti-AXL antibody-drug conjugate (CAB-AXL-ADC) that conditionally and reversibly binds AXL under tumor-specific, low-pH conditions, which reduces off-tumor toxicity and immunogenicity, avoids tissue-mediated drug deposition, and improves pharmacokinetics.

Methods

This phase 2 part 1 open-label study evaluated BA3011 in adult and adolescent patients (pts) with AXL-expressing (tumor membrane percent score ≥50%) advanced refractory sarcoma who received either BA3011 monotherapy 1.8 mg/kg every 2 weeks (Q2W) or BA3011 1.8 mg/kg Q2W + nivolumab. Efficacy endpoints were disease control rate (DCR; objective response or stable disease for ≥12 weeks), number of responders (complete or partial), and progression-free survival (PFS) rate at week 12, while safety was assessed via treatment-emergent adverse events (TEAEs).

Results

Eighty-seven pts received BA3011 monotherapy and 26 received BA3011 + nivolumab. The median (range) duration of BA3011 treatment was 56.0 (11-315) and 56.5 (9-476) days in the monotherapy and combination therapy cohorts, respectively. The most common TEAEs of special interest among monotherapy pts were peripheral neuropathy (32.2%), neutropenia (25.3%), and abnormal liver function tests (20.7%). Grade 3+ TEAEs occurring in ≥5% of monotherapy pts included neutropenia (18.4%), decreased lymphocyte count (9.2%), and abdominal pain (5.7%). BA3011, with or without nivolumab, achieved a PFS rate of 39.9% and DCR of 41.1%, and 5 pts responded (Table).

Table: 53O

Efficacy of BA3011 monotherapy and BA3011 + nivolumab in patients with advanced refractory sarcoma

Conclusions

Promising disease control with acceptable tolerability justifies further evaluation of BA3011 ± nivolumab in a randomized controlled trial among pts with heavily pretreated metastatic bone and soft tissue sarcomas.

Clinical trial identification

NCT03425279; EudraCT 2022-001111-10.

Editorial acknowledgement

Alec Jacobson, MD (MedLogix Communications, LLC).

Legal entity responsible for the study

BioAtla, Inc.

Funding

BioAtla, Inc.

Disclosure

S. Pollack: Financial Interests, Personal, Other, Advisory and consulting fees: Adaptimmune, Bayer, Boehringer Ingelheim, Deciphera, Rain Therapeutics, SpringWorks. A.P. Conley: Financial Interests, Personal, Funding, Research: Chordoma Foundation, Eli Lilly, EpicentRx, Inhbrx, Kronos, NCI, Roche; Financial Interests, Personal, Other, Consulting: Aadi Biosciences, Deciphera. W.D. Tap: Financial Interests, Personal, Funding, Research: BioAtla; Financial Interests, Personal, Advisory Board: Bayer, C4 Therapeutics, Certis Oncology Solutions, Daiichi Sankyo, Deciphera, Eli Lilly, Epizyme, MedPacto; Financial Interests, Personal, Other, Consulting: Abbisko, Adcendo, Amgen, Ayala Pharmaceuticals, Boehringer Ingelheim, BioAtla, C4 Therapeutics, Cogent Biosciences, Curadev, Daiichi Sankyo, Eli Lilly, Foghorn Therapeutics, Inhibrx, Innova Therapeutics, Ipsen, Kowa, Nuvation Bio, Osteosarcoma Institute, PharmaEssentia, Servier, Sonata; Financial Interests, Personal, Other, Travel expenses: Eli Lilly; Financial Interests, Personal, Stocks/Shares: Atropos Therapeutics, Certis Oncology Solutions; Financial Interests, Personal, Leadership Role, Co-founder: Atropos Therapeutics. C. Yen: Financial Interests, Personal, Funding, Research: BioAtla, Boehringer Ingelheim, Cogent Biosciences, Deciphera, Napo Pharmaceuticals, Ono Pharmaceutical, PharmaEssentia, Rain Therapeutics, Taiho, TDW Pharmaceuticals; Financial Interests, Personal, Advisory Role: Boehringer Ingelheim, CStone Pharmaceuticals, Daiichi Sankyo, Novartis, TDW Pharmaceuticals, TTY, ZiaLab. J. Charlson: Financial Interests, Personal, Advisory Role: Adaptimmune, Deciphera; Financial Interests, Personal, Other, Consulting: Adaptimmune, Deciphera. L. Davis: Financial Interests, Personal, Funding, Research: Adaptimmune, BioAtla, BTG, Epizyme, GSK, Inhbrx, Novartis, Salarius, SpringWorks; Financial Interests, Personal, Advisory Role: Daiichi Sankyo, Inhbrx, Regeneron, SpringWorks. A. Chalmers: Financial Interests, Personal, Other, Research support: BioAtla, Boehringer Ingelheim, GSK, Tracon; Financial Interests, Personal, Other, Consulting: Boehringer Ingelheim; Financial Interests, Personal, Speaker’s Bureau: SpringWorks. M. Druta: Financial Interests, Personal, Advisory Role: Aadi Biosciences, AdaptImmune, Deciphera; Financial Interests, Personal, Other, Consulting: Aadi, AdaptImmune, Deciphera. E. Loggers: Financial Interests, Institutional, Funding, Research: Abbisko, Ayala Pharmaceuticals, BioAtla, Cogent, Dicephera, SpringWorks. G. Falchook: Financial Interests, Personal, Royalties: Wolters Kluwer; Financial Interests, Institutional, Advisory Role: AbbVie, BostonGene, BridgeBio, Fujifilm, Inspirna, Jubilant, Merck, Navire, Predicine, Regeneron, Sanofi, Silicon, Teon, Turning Point; Financial Interests, Personal, Advisory Role: EMD Serono; Financial Interests, Personal, Other, Speakers' honorarium: CME from Rocky Mountain Oncology Society and Total Health Conferencing; Financial Interests, Personal, Other, Travel fees: Amgen, Bristol Myers Squibb, EMD Serono, Fujifilm, Millennium, Sarah Cannon Research Institute, Synthorx/Sanofi; Financial Interests, Institutional, Funding, Research: 3-V Biosciences, Abbisko, AbbVie, ABL Bio, Accutar, ADC Therapeutics, Agenus, Aileron, American Society of Clinical Oncology, Amgen, ARMO/Eli Lilly, Artios, AstraZeneca, Bayer, BeiGene, Bicycle, BioAtla, BioInvent, Bio-Thera, Black Diamond, Boehringer Ingelheim, Celgene, Celldex, Ciclomed, Curegenix, Curis, Cyteir, Daiichi Sankyo, DelMar, eFFECTOR, Eli Lilly, EMD Serono, Epizyme, Erasca, Exelixis, Freenome, Fujifilm, Genmab, GSK, Hutchison MediPharma, IGM Biosciences, Ignyta, Immunitas, ImmunoGen/MacroGenics, Incyte, Jacobio, Jazz, Jounce, Jubilant, Kineta, Kolltan, Loxo/Bayer, MedImmune, Merck, Metabomed, Millennium, Mirati, miRNA Therapeutics, Molecular Templates, National Institutes of Health, Navire/BridgeBio, NGM Bio, NiKang, Novartis, OncoMed, Oncorus, Oncothyreon, Poseida, Precision Oncology, Prelude, PureTech, Pyramid, Pyxis, RasCal, Regeneron, Relay, Rgenix, Ribon, Roche, Samumed, Sapience, Seagen, Silicon, Simcha, Sirnaomics, Strategia, Syndax, Synthorx/Sanofi, Taiho, Takeda, Tallac, Tarus, Tarveda, Teneobio, Tesaro, Tocagen, Turning Point, University of Texas MD Anderson Cancer Center, Vegenics, Xencor, Zhuhai Yufan. T. Yau: Financial Interests, Personal, Advisory Role, Honoraria and Consulting: AstraZeneca, Bristol Myers Squibb, MSD, Exelixis, Ipsen, Eisai, Bayer, Novartis, EMD Sereon, AbbVie, Pfizer, Ei Lilly, Sirtex, Sillajen, Taiho, OrigiMed, New B Innovation, Sirtex, H3 Biomedicine. H.H.F. Loong: Financial Interests, Personal, Advisory Role: AstraZeneca, Boehringer Ingelheim, Celgene, Eli Lilly, George Clinical, Illumina, Janssen, Merck Serono, Novartis, Takeda; Financial Interests, Personal, Speaker’s Bureau: Bayer, Eisai, Eli Lilly, Guardant Health, Novartis; Financial Interests, Institutional, Funding, Research: MSD, Mundipharma, Novartis. S. George: Financial Interests, Institutional, Funding, Research: BioAtla, Daiichi Sankyo, Deciphera, Eisai, IDRx, Merck, NewBay, Theseus, TRACON; Financial Interests, Personal, Advisory Board: Kayothera; Financial Interests, Personal, Other, Consulting: BioAtla, Blueprint, Deciphera, IDRx, Immunicum, NewBay; Financial Interests, Personal, Stocks/Shares: Abbott Labs, Pfizer. L. Mascarenhas: Financial Interests, Personal, Funding, Research: Amgen, AstraZeneca/MedImmune, Bayer, E.R. Squibb & Sons, Incyte, Jazz, Eli Lilly, Merck, Pfizer, Salarius, Turning Point; Financial Interests, Personal, Advisory Role: Gilead, Novartis. G.M. Cote: Financial Interests, Personal, Other, Honorarium: BioAtla, Gilead; Financial Interests, Personal, Other, Consultant: Chordoma Foundation, Sonata; Financial Interests, Personal, Advisory Board: C4 Therapeutics, Daiichi Sankyo, Eisai, Foghorn Therapeutics, Ikena Oncology; Financial Interests, Personal, Funding, Research: Bavarian Nordic, BioAtla, C4 Therapeutics, Eisai, Foghorn Therapeutics, Ikena Oncology, Inhibrx, Jazz, Kronos, MacroGenics, Merck KGaA/EMD Serono Research and Development Institute, PharmaMar, Pyxis, Rain Oncology, Repare Therapeutics, Servier, SMP Oncology, SpringWorks. B. Wilky: Financial Interests, Personal, Advisory Board: AADi, Adcendo, Boehringer Ingelheim, Deciphera, Epizyme, Polaris, Springworks; Financial Interests, Personal, Funding, Research Funding: Exelixis; Financial Interests, Personal, Other, Travel, Accommodations, Expenses: Agenus Bio. All other authors have declared no conflicts of interest.

Background

Afamitresgene autoleucel (afami-cel) is an autologous engineered T-cell receptor T-cell therapy targeting tumors expressing melanoma-associated antigen A4 (MAGE-A4). Cohort 1 of the phase 2 SPEARHEAD-1 trial showed a response rate of 38.6% and 25.0% and a median duration of response of 11.6 months and 4.2 months in advanced synovial sarcoma (SyS) and myxoid/round cell liposarcoma (MRCLS), respectively. We analyzed the effects of treatment on pts’ health state and quality of life.

Methods

Afami-cel was infused into pts following lymphodepletion chemotherapy. ECOG performance status (PS) at baseline; Days 8, 15, 22, 29; Weeks 6, 8, 12, 16, 24; and Months 8, 10, 12, and 14, and EQ-5D-3L at baseline and Weeks 8, 16, and 24 post infusion were recorded. EQ-5D-3L visual analogue scores (VAS) and domain changes, Paretian Classification of Health Change (PCHC), and correlations with clinical response (assessed by RECIST v1.1 by investigators) were analyzed.

Results

Baseline PS was recorded for 52 pts (PS 0, n=27; PS 1, n=25). As of August 30, 2023, at Days 8 and 15 post infusion, 63% (30 of 48 recorded) and 75% (39 of 52 recorded) maintained or improved their PS, respectively, and 38% (18 of 48) and 25% (13 of 52) had a deterioration in PS from baseline. At Days 22 and 29, 78% (40 of 51 recorded) and 78% (38 of 49 recorded), respectively, maintained or improved their PS. From Week 6 to Month 14, 87–100% of pts with reported PS had an improved or maintained PS compared with baseline. Median VAS EQ-5D-3L health score at baseline was 61 in 45 pts, improving to 80 at Week 24 (n=19). Median time to next treatment or death was 10.0 months in the 27 pts with stable/improving VAS and 5.7 months in the 7 pts with worsening VAS. At baseline, of the 45 pts completing EQ-5D-3L domain analysis, 76% had pain/discomfort and 58% had anxiety/depression. 74% (25 of 34) of pts with baseline and ≥1 subsequent time point had a better/no change best PCHC assessment vs baseline. PCHC correlated with disease control.

Conclusions

These pt-reported outcomes suggest that clinical responses to afami-cel in pts with advanced SyS/MRCLS were associated with maintenance or improvement in overall health and quality of life.

Clinical trial identification

NCT04044768.

Editorial acknowledgement

Christine Ingleby, Excel Scientific Solutions, funded by Adaptimmune.

Legal entity responsible for the study

Adaptimmune.

Funding

Adaptimmune.

Disclosure

M. Wagner: Financial Interests, Personal, Advisory Board: Adaptimmune, Deciphera, Aadi, Epizyme, PharmaEssentia. C. Lunt: Financial Interests, Personal, Full or part-time Employment, At the time of study: Adaptimmune; Financial Interests, Personal, Stocks/Shares: Adaptimmune. J-Y. Blay: Financial Interests, Personal and Institutional, Research Grant, and personal honoraria: Adaptimmune, GSK. M. Druta: Financial Interests, Personal and Institutional, Invited Speaker, research funding, and food/beverage: Deciphera; Financial Interests, Personal, Other, Honoraria and food/beverage: Aadi Biosciences; Financial Interests, Personal, Other, Consulting and Food/beverage: Daiichi Sankyo; Financial Interests, Institutional, Principal Investigator: GSK, Blueprint Medicines, Trillium Therapeutics. S. Attia: Financial Interests, Personal, Research Grant: Desmoid Tumor Research Foundation, Guardant; Financial Interests, Institutional, Research Grant: Tracon Pharma, Bayer, Novartis, Lilly, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GSK, Forma Therapeutics, Ayala Pharmaceuticals, Trilium therapeutics, Boehringer Ingelheim, Salarius Pharmaceuticals, Theseus Pharmaceuticals, Monopar Therapeutics, C4 Therapeutics, Inhibrix, Noxopharm, Rain Therapeutics, Cogent Biosciences, Jazz Pharmaceuticals, Shanghai Pharma, PharmaMar. C.M. Valverde Morales: Financial Interests, Institutional, Funding, Clinical trial performance: Adaptimmune; Financial Interests, Personal, Other, consulting fees: Deciphera; Financial Interests, Personal, Other, Honoraria: Bayer; Financial Interests, Personal, Other, travel/meeting support: PharmaMar; Financial Interests, Personal, Advisory Board: PharmaMar, Bayer, Boehringer Ingelheim. K. Ganjoo: Financial Interests, Personal, Advisory Board: Adaptimmune, Deciphera, Daiichi Sankyo, Boehringer Ingelheim. S.M. Schuetze: Financial Interests, Institutional, Research Grant: Adaptimmune, GSK, Tracon, Shanghai Pharma, Rain Oncology; Financial Interests, Institutional, Research Grant, and Principal Investigator: Boehringer Ingelheim; Financial Interests, Personal, Royalties: UpToDate; Financial Interests, Personal, Other, DSMB member: Bioatla. E. Van Winkle, J. Bai, D. Bestul, V. Desai, M. Yule, D. Williams, E. Norry: Financial Interests, Personal, Full or part-time Employment: Adaptimmune. P. Bayer: Financial Interests, Personal, Full or part-time Employment, at the time of study: Adaptimmune. B.A. Van Tine: Financial Interests, Personal, Research Grant, and travel: Polaris; Other, Personal, Other, Patent/licenses: Accuronix Therapeutics; Financial Interests, Personal, Other, Consulting: Deciphera, Putnam, Salarius Pharmaceuticals Inc, Boxer Capital LLC, Acuta Capital Partners, Aadi Biosciences, Race Oncology, Hinge Bio, Sonata Therapeutics; Financial Interests, Personal, Advisory Board: Daiichi Sankyo, EcoR1, Apexigen Inc, Epizyme, Bayer US Medical Affairs Oncology, PTC Therapeutics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals, Curis, Inhibrx; Financial Interests, Personal, Other, Consulting/travel: Advenchen, Kronos Bio; Financial Interests, Personal, Other, Honoraria: Iterion Therapeutics; Financial Interests, Personal, Other, Honoraria/travel: Total Health Conference; Financial Interests, Personal, Other, Travel: Adaptimmune. All other authors have declared no conflicts of interest.