Browsing by Author "Durm, Greg"

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    Association of Immune-Related Adverse Events and Efficacy Outcomes With Consolidation Pembrolizumab After Chemoradiation in Patients With Inoperable Stage III Non–Small-Cell Lung Cancer
    (ScienceDirect, 2021-07-01) Shukla, Nikhil Atul; Althouse, Sandra; Meyer, Zachary; Hanna, Nasser; Durm, Greg; Medicine, School of Medicine
    Background Many patients with non–small-cell lung cancer (NSCLC) treated with immunotherapy experience immune-related adverse events (irAEs). Patients with metastatic NSCLC who receive checkpoint inhibitors (CPI) and experience irAEs generally receive fewer cycles of CPI without decreased efficacy. However, the association between irAEs and efficacy outcomes in patients with locally advanced NSCLC treated with curative intent with CPI after chemoradiation has never been reported. Here we report a retrospective analysis of the association between irAEs and efficacy outcomes from the Hoosier Cancer Research Network (HCRN) LUN 14-179 single-arm phase 2 trial of consolidation pembrolizumab after chemoradiation in patients with stage III NSCLC. Patients and Methods A total of 92 eligible patients were enrolled from March 2015 to November 2016. Demographics, disease characteristics, and number of pembrolizumab cycles received were reported in patients with and without irAEs. Chi-square test was used for comparisons for categorical variables and Wilcoxon test for continuous variables. The Kaplan-Meier method was used to analyze time to metastatic disease or death (TMDD), progression-free survival (PFS), and overall survival (OS). A log-rank test was used to compare groups. Results Any grade irAEs occurred in 55.4% of patients. There was no significant difference in number of pembrolizumab cycles received, TMDD, OS, or PFS in patients with and without irAEs. Patients who discontinued pembrolizumab early because of irAEs received significantly fewer cycles of pembrolizumab (5 vs 15, P = .0016) without a significant difference in TMDD, PFS, or OS. Similarly, patients who received immunosuppressive therapy received fewer numbers of cycles of pembrolizumab (4 vs 16, P < .001) without significantly reduced TMDD, PFS, or OS. Conclusion irAEs due to pembrolizumab, regardless of grade or number of irAEs, were not associated with decreased efficacy outcomes. Furthermore, early discontinuation of pembrolizumab because of irAEs and/or treatment of irAEs with immunosuppressive therapy was not associated with a decrease in treatment efficacy.
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    CX-072 (pacmilimab), a Probody ® PD-L1 inhibitor, in advanced or recurrent solid tumors (PROCLAIM-CX-072): an open-label dose-finding and first-in-human study
    (BMJ, 2021) Naing, Aung; Thistlethwaite, Fiona; De Vries, Elisabeth G. E.; Eskens, Ferry A. L. M.; Uboha, Nataliya; Ott, Patrick A.; LoRusso, Patricia; Garcia-Corbacho, Javier; Boni, Valentina; Bendell, Johanna; Autio, Karen A.; Randhawa, Manreet; Durm, Greg; Gil-Martin, Marta; Stroh, Mark; Hannah, Alison L.; Arkenau, Hendrik-Tobias; Spira, Alexander; Medicine, School of Medicine
    Background: Probody® therapeutics are antibody prodrugs that are activated in the tumor microenvironment by tumor-associated proteases, thereby restricting the activity to the tumor microenvironment and minimizing 'off-tumor' toxicity. We report dose-escalation and single-agent expansion phase data from the first-in-human study of CX-072 (pacmilimab), a Probody checkpoint inhibitor directed against programmed death-ligand 1 (PD-L1). Methods: In the dose-escalation phase of this multicenter, open-label study (NCT03013491), adults with advanced solid tumors (naive to programmed-death-1/PD-L1 or cytotoxic T-lymphocyte-associated antigen 4 inhibitors) were enrolled into one of seven dose-escalation cohorts, with pacmilimab administered intravenously every 14 days. The primary endpoints were safety and determination of the maximum tolerated dose (MTD). In the expansion phase, patients with one of six prespecified malignancies (triple-negative breast cancer [TNBC]; anal squamous cell carcinoma [aSCC]; cutaneous SCC [cSCC]; undifferentiated pleomorphic sarcoma [UPS]; small bowel adenocarcinoma [SBA]; and thymic epithelial tumor [TET]); or high tumor mutational burden (hTMB) tumors were enrolled. The primary endpoint was objective response (Response Evaluation Criteria In Solid Tumors v.1.1). Results: An MTD was not reached with doses up to 30 mg/kg. A recommended phase 2 dose (RP2D) of 10 mg/kg was chosen based on pharmacokinetic and pharmacodynamic findings in the expansion phase. Ninety-eight patients enrolled in the expansion phase: TNBC (n=14), aSCC (n=14), cSCC (n=14), UPS (n=20), SBA (n=14), TET (n=8), and hTMB tumors (n=14). Of 114 patients receiving pacmilimab at the RP2D, grade ≥3 treatment-related adverse events (TRAEs) were reported in 10 patients (9%), serious TRAEs in six patients (5%), and treatment discontinuation due to TRAEs in two patients (2%). Grade ≥3 immune-related AEs occurred in two patients (rash, myocarditis). High PD-L1 expression (ie, >50% Tumor Proportion Score) was observed in 22/144 (19%) patients. Confirmed objective responses were observed in patients with cSCC (n=5, including one complete response), hTMB (n=4, including one complete response), aSCC (n=2), TNBC (n=1), UPS (n=1), and anaplastic thyroid cancer (n=1). Conclusions: Pacmilimab can be administered safely at the RP2D of 10 mg/kg every 14 days. At this dose, pacmilimab had a low rate of immune-mediated toxicity and showed signs of antitumor activity in patients not selected for high PD-L1 expression.
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    Multicancer Early Detection Tests: A State-of-the-Art Review for Otolaryngologists
    (Wiley, 2024-10-26) Kennedy, Elena; Durm, Greg; Farlow, Janice L.; Otolaryngology -- Head and Neck Surgery, School of Medicine
    Objective: To provide a review of the science and applicability of current multi-cancer early detection (MCED) tests for otolaryngologists. Data sources: PubMed, clinicaltrials.gov, company websites. Review methods: Using PRISMA methodology, primary literature regarding MCED tests was queried from April 26 to May 12, 2024 using MCED search terms. Ongoing clinical trials incorporating MCED screens were identified via the National Institutes of Health clinicaltrials.gov website. Company websites for available or upcoming MCED tests were reviewed. Conclusion: Long-term robust data regarding the performance characteristics, effects on clinical outcomes, and cost-utility of MCED tests for head and neck cancer are currently lacking. Otolaryngologists should be aware of the implications of MCED tests as these assays become more widely used. Implications for practice: Although not FDA-approved or covered by insurances at the time of writing of this manuscript, MCED testing is rapidly gaining interest, and patients with positive tests are presenting to otolaryngologists for evaluation. While MCED technologies hold great promise for early detection of disease and potential reduction of morbidity and mortality, more study is needed about their utility for head and neck cancer and optimal diagnostic workflows.
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    A phase 2 trial of consolidation pembrolizumab following concurrent chemoradiation for patients with unresectable stage III non–small cell lung cancer: Hoosier Cancer Research Network LUN 14-179
    (Wiley, 2020-10) Durm, Greg; Jabbour, Salma; Althouse, Sandra; Liu, Ziyue; Sadiq, Ahad; Zon, Robin; Jalal, Shadia; Kloecker, Goetz; Williamson, Michael; Reckamp, Karen; Langdon, Robert; Kio, Ebenezer; Gentzler, Ryan; Adesunloye, Bamidele; Harb, Wael; Walling, Radhika; Titzer, Michael; Hanna, Nasser; Medicine, School of Medicine
    Background Five-year overall survival (OS) for patients with unresectable stage III non–small cell lung cancer (NSCLC) is poor. Until recently, a standard of care was concurrent chemoradiation alone. Patients with metastatic NSCLC treated with anti–programmed death 1 antibodies have demonstrated improved OS. This trial evaluated pembrolizumab as consolidation therapy after concurrent chemoradiation in patients with unresectable stage III disease. Methods Patients with unresectable stage III NSCLC received concurrent chemoradiation with cisplatin and etoposide, cisplatin and pemetrexed, or carboplatin and paclitaxel and 59.4 to 66.6 Gy of radiation. Patients with nonprogression of disease were enrolled and received pembrolizumab (200 mg intravenously every 3 weeks for up to 12 months). The primary endpoint was the time to metastatic disease or death (TMDD). Secondary endpoints included progression-free survival (PFS) and OS. Results The median follow-up for 93 patients (92 for efficacy) was 32.2 months (range, 1.2-46.6 months). The median TMDD was 30.7 months (95% confidence interval [CI], 18.7 months to not reached), which was significantly longer than the historical control of 12 months (P < .0001). The median PFS was 18.7 months (95% CI, 12.4-33.8 months), and the median OS was 35.8 months (95% CI, 24.2 months to not reached). The 1-, 2-, and 3-year OS estimates were 81.2%, 62.0%, and 48.5%, respectively. Forty patients (43.5%) completed 12 months of treatment (median number of cycles, 13.5). Symptomatic pneumonitis (grade 2 or higher) was noted in 16 patients (17.2%); these cases included 4 grade 3 events (4.3%), 1 grade 4 event (1.1%), and 1 grade 5 event (1.1%). Conclusions Consolidation pembrolizumab after concurrent chemoradiation improves TMDD, PFS, and OS in comparison with historical controls of chemoradiation alone. Rates of grade 3 to 5 pneumonitis were similar to those reported with chemoradiation alone.
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    Prognostic variables associated with improved outcomes in patients with stage III NSCLC treated with chemoradiation followed by consolidation Pembrolizumab: a subset analysis of a phase II study from the Hoosier Cancer Research Network LUN 14-179
    (Elsevier, 2019) Anouti, Bilal; Althouse, Sandra; Durm, Greg; Hanna, Nasser; Medicine, School of Medicine
    Introduction HCRN LUN 14-179 is a phase II trial of consolidation pembrolizumab following concurrent chemoradiation for the treatment of patients with stage III NSCLC. Time to metastatic disease, progression free survival and overall survival appear superior to historical controls of chemoradiation alone. Unfortunately, not all patients benefit from consolidation immunotherapy. We performed a univariate analysis evaluating variables associated with PFS, metastatic disease, and OS. Methods We conducted a retrospective analysis from patients enrolled on HCRN LUN14-179. Data collected included age, sex, stage, smoking status, PD-L1 status, >G2 vs G3 pneumonitis, duration of pembrolizumab (<4 vs. >4 cycles), chemotherapy regimen, PS 0 vs 1, time to start pembrolizumab (4-6 vs. 6-8 weeks from radiation), V20 (<20% vs. >20%). Univariable Cox regression was performed to determine the variables associated with 3 endpoints: TMDD; PFS; and OS. Results From April 2015 to December 2016, 93 patients were enrolled and 92 were included in the efficacy analysis (1 patient was ineligible). For TMDD, improved outcomes may be associated (p<0.1) with stage IIIA, non-squamous cell, >4 cycles of pembrolizumab, and V20< 20%. For PFS, improved outcomes (p<0.1) may be seen for >4 cycles of pembrolizumab, and V20< 20%. For OS, improved outcomes (p<0.1) may be seen for non-squamous histology, >4 cycles of pembrolizumab. Conclusion Non-squamous NSCLC, longer duration of pembrolizumab, and V20< 20% may be associated with prolonged time to metastatic disease or death, PFS, and OS for patients with stage III NSCLC treated with chemoradiation followed by pembrolizumab.
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    Second Line Chemotherapy and Beyond for Non-Small Cell Lung Cancer (NSCLC)
    (Elsevier, 2017-02) Durm, Greg; Hanna, Nasser; Department of Medicine, School of Medicine