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Sanjay Popat
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ES18 - The Future of Immunotherapy in Unresectable Mesothelioma (ID 244)
- Event: WCLC 2020
- Type: Educational Session
- Track: Mesothelioma, Thymoma and Other Thoracic Malignancies
- Presentations: 1
- Moderators:
- Coordinates: 1/30/2021, 16:45 - 17:45, Scientific Program Auditorium
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ES18.01 - Immunotherapy – Current State of Play (Concentrating on Current Data for First Line and Salvage Strategies) (ID 4112)
16:45 - 17:45 | Presenting Author(s): Sanjay Popat
- Abstract
- Presentation
Abstract
Immune checkpoint inhibitor therapy can be highly effective for some patients with malignant pleural mesothelioma (MPM), with resolution of bulky tumours with few adverse events and durable clinical benefit. However, for many patients there is no appreciable benefit with primary progression.
Checkpoint inhibitors were initially evaluated in the salvage setting where targeting CTLA4 with tremelimumab was evaluated in the randomized Phase 2b DETERMINE trial following two single arm phase 2 trials. In DETERMINTE, overall survival was disappointingly no different versus placebo. With the development of anti-PD1 agents, pembrolizumab was evaluated in the KEYNOTE-028 multi-cohort study. Here, fit PD-L1 positive relapsed MPM patients (using a prototype assay) demonstrated an objective response rate (ORR) of 20% and a median overall survival (OS) of 18 months. Since then, several cohort trials of either anti-PD1, or anti-PD1 in combination with CTLA4 inhibitors have evaluated activity mostly in relapsed patients. Two randomized trials of anti-PD1 (pembrolizumab and nivolumab are ongoing). PROMISE-Meso reported in 2019 demonstrating no OS or PFS advantage for pembrolizumab over vinorelbine or gemcitabine chemotherapy, although the ORR was significantly improved. Results from the CONFIRM trial of nivolumab versus placebo in relapsed MPM are eagerly anticipated.
In the front-line setting, the CHECKMATE743 trial randomized unresectable fit MPM patients to either cisplatin-pemetrexed or nivolumab-ipilimumab (nivo-ipi). A significant OS benefit for nivo-ipi was observed, with robust similar clinical effect in both epithelioid and non-epithelioid subtypes, whereas chemotherapy was markedly inferior in non-epithelioid subtypes. Nevertheless, PFS curve analysis demonstrates a likely bimodal distribution of patients with an initial inferior PFS versus chemotherapy for the first 7 months, after which PFS is markedly superior. A number of other front line trials are ongoing evaluating immune checkpoint inhibitor therapy in combination with chemotherapy. The BEAT-Meso trial is evaluating the addition of atezolizumab to combination carboplatin-pemetrexed-bevacizumab, DREAM3R will evaluate the benefit of durvalumab to cisplatin-pemetrexed, and a Canadian-led trial is evaluating the benefit of pembrolizumab to cisplatin-pemetrexed.
Several other novel strategies are being evaluated to immunomodulate MPM. A cell therapy programme at the Memorial Sloan Kettering Institution is evaluating an academically developed CAR-T cell directed against mesothelin administered intrapleurally, in conjunction with immune-checkpoint inhibitor therapy, with initial signal of efficacy and safety demonstrated. The Zurich group have evaluated an academic CAR-T cell directed against FAP again administered intrapleurally, with initial safety demonstrated. Finally, colleagues in the Netherlands are evaluating the role of dendritic cell therapy, with in vitro culture and maturation of autologous dendritic cells with allogeneic whole tumour lysate and intravenous/intradermal return, in a randomized phase 2/3 maintenance trial.
In summary, in the salvage setting, immune checkpoint inhibitors have modest activity overall, although not superior to chemotherapy; nevertheless, some patients do have spectacular benefit and considerable work is required to identify those that benefit the most. For the first line setting, nivolumab-ipilimumab improves OS over chemotherapy, markedly so in non-epithelioid subtypes. Many trials are ongoing investigating first line checkpoint inhibitor-chemo combinations and in parallel novel approaches such as cellular therapies are in development.
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P01 - Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics (ID 227)
- Event: WCLC 2020
- Type: Posters
- Track: Antibody Drug Conjugates, Novel Therapeutics and Cytotoxics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P01.02 - Trastuzumab Deruxtecan Plus Pembrolizumab in Advanced/Metastatic Breast or Non-Small Cell Lung Cancer: A Phase 1b Study (ID 1829)
00:00 - 00:00 | Author(s): Sanjay Popat
- Abstract
Introduction
Trastuzumab deruxtecan (T-DXd) is an antibody-drug conjugate composed of an anti-HER2 antibody, cleavable tetrapeptide-based linker, and potent topoisomerase I inhibitor. In a phase 2 trial in patients with heavily pretreated, metastatic HER2+ breast cancer, T-DXd had a confirmed objective response rate (cORR) of 60.9% (112/184) and median progression-free survival (PFS) of 16.4 mo (Modi N Engl J Med 2019); these results led to the recent FDA approval for HER2+ unresectable or metastatic breast cancer after ≥ 2 prior anti-HER2 based regimens. For HER2-low breast cancer and HER2-expressing/mutated NSCLC, no HER2-directed therapies have been approved. In a phase 1 trial of T-DXd in patients with HER2-low breast cancer or HER2-expressing/mutated NSCLC, cORR was 44.2% (19/43) (Modi SABCS 2018), and 55.6% (10/18) (Tsurutani Thorac Oncol 2018), respectively. In preclinical models, T-DXd combined with an anti–PD-1 antibody was more effective than monotherapy with either agent (Iwata Mol Cancer Ther 2018). Here we describe a phase 1b study of T-DXd in combination with pembrolizumab in patients with locally advanced/metastatic HER2-expressing breast cancer or HER2-expressing/mutated NSCLC (DS8201-A-U106; NCT04042701). This abstract was previously submitted to ASCO 2020.
Methods
This is an open-label, multicenter, nonrandomized, multidose, 2-part study in adult (aged ≥18 y) patients in the United States and Europe. In part 1 (dose escalation), patients received T-DXd 3.2 or 5.4 mg/kg IV q3w and pembrolizumab 200 mg IV q3w to determine the recommended dose for expansion (RDE). The RDE will be given to 4 cohorts (part 2): 2 cohorts with breast cancer (HER2+ [IHC 3+ or IHC 2+/ISH+] with progression on prior T-DM1; and HER2-low [IHC 1+ or IHC2+/ISH-] with progression on prior standard treatments) and 2 cohorts with NSCLC (anti–PD-1, –PD-L1, and -HER2 treatment naive either HER2-expressing [IHC ≥ 1+] or HER2-mutated). Enrollment began in February 2020 with approximately 115 to 133 patients planned to be enrolled at 5 sites for part 1 and expanding to 25 sites for part 2. The primary endpoint in part 1 is dose-limiting toxicities. The part 2 primary efficacy endpoint is cORR by independent central review (ICR) per RECIST 1.1. Additional endpoints include duration of response, disease control rate, and progression-free survival by ICR, overall survival, safety, and pharmacokinetics.
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P09 - Health Services Research/Health Economics - Real World Outcomes (ID 121)
- Event: WCLC 2020
- Type: Posters
- Track: Health Services Research/Health Economics
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P09.18 - COVID-19 Outcomes in Patients With Thoracic Malignancies According to Gender and Ethnicity (TERAVOLT) (ID 3702)
00:00 - 00:00 | Author(s): Sanjay Popat
- Abstract
Introduction
Previously reported data on patients with thoracic malignancies who develop COVID-19 have suggested a higher mortality rate compared to the general population and to other cancer types, particularly in patients over 65 years of age or suffering from active or progressive disease. Preliminary data from other studies have suggested that gender and ethnicity may also impact patient outcomes.
Methods
TERAVOLT is a multi-center, international observational study composed of a cross-sectional component and a longitudinal cohort component. Eligibility criteria include the presence of any thoracic cancer and a COVID-19 diagnosis confirmed in the laboratory with RT-PCR/serology, highly suspicious radiological and clinical findings, or suspected with symptoms and known contact with a positive person. The overarching goals of this consortium are to provide data for guidance to oncology professionals on managing patients with thoracic malignancies while understanding the risk factors for morbidity and mortality from this novel virus. Clinical outcomes including hospitalization, ICU admission, oxygen requirement and mortality were collected. The association between demographic/clinical characteristics and outcomes were measured with odds ratio with 95% confidence intervals using a logistic regression model.
Results
As of August 20, 2020, a total of 1,053 patients with COVID-19 and thoracic cancers from 19 countries and 130 centers have been identified, including 42% females and 84% White, 9.3% African American, 25% Hispanic. The median age of male patients was 69 compared to 66 years of age for females. While ECOG PS was similar between treatment groups, 77% of males were admitted to hospital with a mortality rate of 37% compared to 66% of females with a mortality rate of 28%. The median age of African American patients was 66 years of age compared to 68 and 69 years of age for white and Hispanic patients, respectively; 26% of African American and 25% White patients had an ECOG PS ≥2 compared to 19% of Hispanics. A similar percentage of patients were admitted to the hospital and ICU, while the mortality rate for Hispanics was 36% compared to 34% for whites and 26% for African Americans.
Conclusion
Similar to the general population, the mortality rate of males with thoracic cancer is higher than females. Regarding ethnicity, there is a difference in the median age of African American patients compared to Whites and Hispanics. Although the severity of COVID-19 disease, as defined by hospital admission, is similar between ethnic groups, the mortality rate in Hispanics is higher. We will present a multivariate analysis of these data according to gender and ethnicity, including the impact of cancer stage, prior cancer therapy, and COVID-19 therapy on outcomes.
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P78 - Immunotherapy (Phase II/III Trials) - Immune Checkpoint Inhibitor Single Agent (ID 255)
- Event: WCLC 2020
- Type: Posters
- Track: Immunotherapy (Phase II/III Trials)
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P78.01 - Nivolumab in Second Line Non-Small Cell Lung Cancer – Comparing Real-World Outcomes in England to CheckMate (CM) 017 and 057 (ID 1125)
00:00 - 00:00 | Presenting Author(s): Sanjay Popat
- Abstract
Introduction
Nivolumab was licensed in Europe as monotherapy for second-line metastatic non-small cell lung cancer (NSCLC) in 2015. The National Institute for Health and Care Excellence (NICE) recommended reimbursement via the Cancer Drugs Fund (CDF) for all patients of squamous histology and non-squamous histology patients with PD-L1 expression ≥1%.
During this period, real-world evidence on patient characteristics and outcomes was collected by Public Health England using the Systemic Anti-Cancer Therapy (SACT) dataset.
We reviewed SACT data with the registrational CM017 and 057 trials, to assess the generalisability of these trial data to the real-world setting.
Methods
Data included all patients with a CDF application from September 2017 to December 2018 with follow-up until 31 January 2019. Baseline characteristics included sex, age, performance status and PD-L1 distribution. Endpoints included overall survival (OS) and treatment duration(DOT).
Results
In total, 448 new CDF applications were received; after appropriate exclusions there were 391 patients (348 squamous / 43 non-squamous) included in the SACT analysis. This compares to 135 patients from CM017 and 292 from CM057.
For squamous-NSCLC, median age was 70 years; 66% were male. 17% had an ECOG performance score(PS) of 0 and 71% of 1. Median OS was 8.4 months (95% CI, 7.2‑9.7 months) compared with a median OS of 9.2 months (95% CI: 7.3-12.6 months) in CM017 (Figure 1). The median DOT in SACT was 3.5 months.
For non-squamous, the median age was 65 years; 67% were male.21% had a PS of 0 and 67% of 1. Median OS was 9.2 months (CIs not available) compared with 12.21 months (95% CI: 9.7-15.1 months) in CM057 (Figure 2). Median DOT was 4.1 months
Figure 1: Kaplan-Meier for overall survival in the SACT database and CheckMate 017
Figure 2: Kaplan-Meier for overall survival in the SACT database and CheckMate 057
Conclusion
Median OS in SACT are similar to those in CM017 and CM057 suggesting the trial data are generalisable to the real-world setting.
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P87 - Targeted Therapy - Clinically Focused - RET (ID 264)
- Event: WCLC 2020
- Type: Posters
- Track: Targeted Therapy - Clinically Focused
- Presentations: 1
- Moderators:
- Coordinates: 1/28/2021, 00:00 - 00:00, ePoster Hall
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P87.02 - AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC (ID 1787)
00:00 - 00:00 | Author(s): Sanjay Popat
- Abstract
Introduction
RET gene fusions have been identified as oncogenic drivers in multiple tumor types, including 1–2% of non-small cell lung cancer (NSCLC). The investigational oral RET inhibitor, pralsetinib, potently and selectively targets oncogenic RET alterations, including those that confer resistance to multi-kinase inhibitors. In the registration-enabling phase 1/2 study (ARROW; NCT03037385), patients with RET-fusion+ NSCLC treated with pralsetinib 400 mg once daily (QD) after platinum-based chemotherapy (n=80) achieved an overall response rate (ORR) of 61% (95% CI 50, 72; two responses pending confirmation) per independent central review. In addition, an ORR of 73% (all centrally confirmed responses) was attained in the systemic treatment naïve cohort (n=26). Most treatment-related adverse events were grade 1–2 across the entire safety population treated with pralsetinib 400 mg QD (N=354). AcceleRET Lung, an international, open-label, randomized, phase 3 study, will evaluate the efficacy and safety of pralsetinib versus standard of care (SOC) in first-line treatment of advanced/metastatic RET fusion+ NSCLC (NCT04222972). This abstract was previously submitted to the American Society of Clinical Oncology 2020 annual meeting, May 29 to June 2, 2020, and to the IASLC 2020 North America Conference on Lung Cancer meeting in Chicago, Illinois, United States of America, October 16 to 17, 2020.
Methods
Approximately 250 patients with advanced/metastatic RET-fusion+ NSCLC will be randomized 1:1 to pralsetinib 400 mg QD or SOC (non-squamous histology: platinum/pemetrexed ± pembrolizumab followed by maintenance pemetrexed ± pembrolizumab; squamous histology: platinum/gemcitabine). Stratification factors include intended use of pembrolizumab, history of brain metastases, and Eastern Cooperative Oncology Group Performance Status 0 vs 1. Key eligibility criteria include no prior systemic treatment for advanced/metastatic NSCLC; RET-fusion+ tumor by local or central assessment, no additional actionable oncogenic drivers, no prior treatment with a selective RET inhibitor, and measurable disease per RECIST v1.1. Cross-over to receive pralsetinib upon disease progression will be permitted for patients randomized to SOC. The primary endpoint is progression-free survival (blinded independent central review; RECIST v1.1). Secondary endpoints include ORR, overall survival, duration of response, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety/tolerability, and quality of life. Recruitment has begun with sites (active or planned) in North America, Europe, Asia, and Australia.
