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Patrick M Forde
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MA04 - Novel Approaches with IO (ID 900)
- Event: WCLC 2018
- Type: Mini Oral Abstract Session
- Track: Immunooncology
- Presentations: 2
- Moderators:
- Coordinates: 9/24/2018, 13:30 - 15:00, Room 107
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MA04.08 - Discussant - MA 04.05, MA 04.06, MA 04.07 (ID 14589)
14:15 - 14:30 | Presenting Author(s): Patrick M Forde
- Abstract
- Presentation
Abstract not provided
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MA04.11 - Neoantigen Targeting and T Cell Reshaping in Resectable NSCLC Patients Treated with Neoadjuvant PD-1 Blockade (ID 12605)
14:40 - 14:45 | Author(s): Patrick M Forde
- Abstract
- Presentation
Background
PD-1 blockade is now standard treatment for advanced non-small cell lung cancer (NSCLC) and has recently shown impressive efficacy in promoting major pathologic response (MPR) and delaying relapse in the neoadjuvant setting. The role of tumor mutational burden, and specifically T cells targeting neoantigens derived from these mutations, in facilitating tumor clearance has been demonstrated in advanced NSCLC. However, it is unknown how neoadjuvant PD-1 blockade impacts the frequency and function of tumor specific T cells and their ability to promote major pathologic response, or how these factors may synergize to prevent or delay relapse after surgical resection.
a9ded1e5ce5d75814730bb4caaf49419 Method
Whole exome sequencing and neoantigen prediction was performed on pre-treatment tumor biopsies and matched normal tissue from 11 patients with resectable NSCLC treated with neoadjuvant nivolumab as part of a clinical trial (NCT02259621). T cell recognition of peptides representing candidate neoantigens was evaluated using the MANAFEST assay, which identifies T cell receptor clonotypes corresponding to antigen specificities. T cell receptor sequencing was additionally performed on serial peripheral blood T cells, pre-treatment tumor biopsies, and resected post-treatment tissues. A bioinformatic platform was developed to evaluate the dynamics of intratumoral T cell clonotypes, and more specifically neoantigen-specific clonotypes detected before, during, and after treatment and during long-term follow-up.
4c3880bb027f159e801041b1021e88e8 Result
High-magnitude, polyclonal neoantigen-specific T cell responses were detected in the peripheral blood and persisted for many months after surgical resection and cessation of treatment. Binding to and stability with cognate HLA I molecules was validated for reactive neoantigens. Significant treatment-induced systemic perturbations in the tumor-specific T cell repertoire and an influx of peripheral T cell clonotypes into tumor tissue and lymph nodes was observed in patients regardless of pathologic response, whereas peripheral clonotypic reshaping of the anti-tumor repertoire and intratumoral T cell clonality were associated with MPR status.
8eea62084ca7e541d918e823422bd82e Conclusion
We show significant and systemic alterations in the peripheral anti-tumor T cell repertoire in NSCLC patients treated with neoadjuvant anti-PD-1 regardless of MPR status. Notwithstanding, the impaired restructuring of the anti-tumor T cell repertoire in patients without MPR highlights a potential immunological deficiency to overcome in future therapeutic approaches aiming to increase the MPR rate in NSCLC patients treated with neoadjuvant PD-1 blockade.
6f8b794f3246b0c1e1780bb4d4d5dc53Only Members that have purchased this event or have registered via an access code will be able to view this content. To view this presentation, please login, select "Add to Cart" and proceed to checkout. If you would like to become a member of IASLC, please click here.
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P2.01 - Advanced NSCLC (Not CME Accredited Session) (ID 950)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.01-33 - Open-Label, Biomarker-Directed Platform Study in NSCLC Patients Who Progressed on an Anti-PD-(L)1 Containing Therapy (HUDSON) (ID 13743)
16:45 - 18:00 | Presenting Author(s): Patrick M Forde
- Abstract
Background
Immune checkpoint inhibitor (ICI)-containing regimens have significantly improved survival outcomes in first- and second-line NSCLC. However, the majority of patients do not respond or have non-durable responses to anti-programmed cell death-1/programmed cell death-ligand 1 (anti-PD-1/PD-L1) containing therapy (primary resistance) or progress during anti-PD-1/PD-L1 containing therapy (acquired resistance). HUDSON addresses the urgent need to identify treatments and understand ICI resistance for this emerging ICI-resistant population.
a9ded1e5ce5d75814730bb4caaf49419 Method
HUDSON is a multi-centre, international multi-arm umbrella study that will 1) evaluate therapies to reverse ICI resistance and 2) define mechanisms of ICI resistance in NSCLC patients who have progressed following standard-of-care platinum and ICI-based therapies. HUDSON is a platform study that consists of two groups; a biomarker matched and a biomarker non-matched group. Within the biomarker matched group, different cohorts will test 1) homologous recombination repair (HRR) defects and 2) LKB1 aberration for response to durvalumab and olaparib (PARP inhibitor), 3) ATM deficiency for response to durvalumab and AZD6738 (ATR inhibitor) and 4) RICTOR amplification for response to durvalumab and vistusertib (mTORC1/2 inhibitor). In the biomarker non-matched group, cohorts will test durvalumab in combination with either i) olaparib, ii) AZD9150 (STAT3 inhibitor) or iii) AZD6738, in patients with primary and acquired resistance to a prior ICI. Allocation to a cohort is informed by the tumour molecular profile according to a pre-specified assignment algorithm. New cohorts will be added as new translational hypotheses are established. Translational research will be performed on serial peripheral blood samples (including ctDNA) and tumour biopsies. HUDSON enrols ICI-resistant patients in a signal searching manner. Biomarker matched and non-matched groups will be opened simultaneously, and all eligible patients can be allocated a treatment option irrespective of their tumour profile. Enrolment is ongoing, clinical trial information: NCT03334617.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
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P2.16 - Treatment of Early Stage/Localized Disease (Not CME Accredited Session) (ID 965)
- Event: WCLC 2018
- Type: Poster Viewing in the Exhibit Hall
- Track:
- Presentations: 1
- Moderators:
- Coordinates: 9/25/2018, 16:45 - 18:00, Exhibit Hall
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P2.16-03 - CheckMate 816: A Phase 3 Trial of Neoadjuvant Nivolumab Plus Ipilimumab or Chemotherapy vs Chemotherapy in Early-Stage NSCLC (ID 12599)
16:45 - 18:00 | Author(s): Patrick M Forde
- Abstract
Background
Approximately 20–25% of patients with NSCLC are diagnosed with early or localized disease, which has a relapse rate of 30–80% with surgery. Although neoadjuvant chemotherapy can reduce the risk of relapse, it only provides a pathological complete response (pCR; no viable tumor cells) rate of 4%. The neoadjuvant setting presents abundant tumor-associated neoantigens derived from the primary tumor that may allow immunotherapy to prime a long-lasting immune response. Clinical trial results support the use of immuno-oncology agents as neoadjuvant treatment for early-stage NSCLC. In a pilot study in patients with untreated, surgically resectable early-stage (stage I–IIIA) NSCLC, nivolumab (a fully human PD-1 immune checkpoint inhibitor antibody) administered as neoadjuvant treatment (3 mg/kg for 2 cycles during the 4 weeks prior to surgery) induced a pCR in 10% of patients and a major pathological response (MPR; ≤10% residual viable tumor cells in resected primary tumor) in 45% of patients, did not delay surgery, and was associated with an acceptable safety profile. Combining immuno-oncology agents with distinct mechanisms of action, such as PD-1 and CTLA-4 inhibitors, offers the possibility of a synergistic response and may improve antitumor activity compared with either agent alone. The combination of an immuno-oncology agent and chemotherapy may also offer synergistic activity, given that chemotherapy results in tumor cell death and subsequent antigen release that can activate an immune response. Promising results have been noted with nivolumab plus ipilimumab (a CTLA-4 immune checkpoint inhibitor antibody) and nivolumab plus chemotherapy in patients with treatment-naïve stage IIIB/IV NSCLC in the multicohort phase 1 CheckMate 012 study. CheckMate 816 (NCT02998528) is a phase 3 study evaluating nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, and platinum-doublet chemotherapy as neoadjuvant treatment for early-stage NSCLC.
a9ded1e5ce5d75814730bb4caaf49419 Method
Approximately 642 patients aged ≥18 years with early-stage (stages IB–IIIA) resectable NSCLC, ECOG performance status 0–1, pulmonary function capable of tolerating lung resection, and available lung tumor tissue will be enrolled in North America, South America, Europe, Asia, and Africa. Patients are ineligible if they have active autoimmune disease or had received prior treatment with immune checkpoint inhibitors. Patients will be randomized (1:1:1) to receive neoadjuvant nivolumab plus ipilimumab, nivolumab plus platinum-doublet chemotherapy, or platinum-doublet chemotherapy. Primary endpoints are event-free survival and pCR. Key secondary endpoints are overall survival and MPR (<10% residual tumor in lung and lymph nodes). The start date was January 2017. The estimated primary completion date is May 2023.
4c3880bb027f159e801041b1021e88e8 Result
Section not applicable
8eea62084ca7e541d918e823422bd82e Conclusion
Section not applicable
6f8b794f3246b0c1e1780bb4d4d5dc53
