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Howard L. Kaufman - One of the best experts on this subject based on the ideXlab platform.
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Advancing oncolytic virus therapy by understanding the biology
Nature reviews. Clinical oncology, 2021Co-Authors: Howard L. Kaufman, Dawid MaciorowskiAbstract:Talimogene Laherparepvec (T-VEC) is an oncolytic virus approved for the treatment of patients with recurrent melanoma. Now, a recent study in patients with primary cutaneous B cell lymphoma confirms prior results in melanoma and reveals new mechanisms of action. Herein, we discuss these findings and their implications for expanding the role of oncolytic viruses.
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An Update on the Role of Talimogene Laherparepvec (T-VEC) in the Treatment of Melanoma: Best Practices and Future Directions
American Journal of Clinical Dermatology, 2020Co-Authors: Cecilia A. Larocca, Nicole R Leboeuf, Ann W Silk, Howard L. KaufmanAbstract:Talimogene Laherparepvec (T-VEC) is the first agent approved for cancer in the emerging class of oncolytic viral therapies. While T-VEC was approved for the treatment of advanced melanoma in 2015, clinical utilization has been hampered by rapid changes in the therapeutic landscape of melanoma related to advances in both immune checkpoint blockade and targeted therapy, cumbersome logistics involved in T-VEC administration, biosafety concerns, and a perception that T-VEC has limited impact on uninjected, visceral disease. However, with further survival follow-up from the phase III OPTiM (Oncovex^GM-CSF Pivotal Trial in Melanoma), along with new real-world data and consensus guidelines on safe administration of oncolytic viruses, a roadmap for when and how to use T-VEC has been emerging. In addition, preliminary data have demonstrated improved therapeutic responses to T-VEC in combination with immune checkpoint blockade in patients with melanoma without additive toxicity. This review provides an update on recent data with T-VEC alone and in combination with other agents. The emerging data provide guidance for how to better utilize T-VEC for patients with melanoma and identifies critical areas for clinical investigation to expand the role of T-VEC in combination strategies for the treatment of melanoma and perhaps other cancers.
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final analyses of optim a randomized phase iii trial of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in unresectable stage iii iv melanoma
Journal for ImmunoTherapy of Cancer, 2019Co-Authors: Robert H I Andtbacka, Frances A Collichio, Kevin J Harrington, Gerald Downey, Mark R Middleton, Katarina ӧhrling, Howard L. KaufmanAbstract:Talimogene Laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma. Patients were randomized 2:1 to receive intratumoral Talimogene Laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators. Of 436 patients in the intent-to-treat population, 295 were allocated to Talimogene Laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5–29.6) and 18.9 months (95% CI, 16.0–23.7) in the Talimogene Laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62–1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0–69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the Talimogene Laherparepvec and GM-CSF arms, respectively, achieved CR. In Talimogene Laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene Laherparepvec efficacy was more pronounced in stage IIIB–IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis. In this final planned OPTiM analysis, Talimogene Laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that Talimogene Laherparepvec was associated with durable CRs that were associated with prolonged survival. ClinicalTrials.gov identifier: NCT00769704 .
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a phase ii study of Talimogene Laherparepvec followed by Talimogene Laherparepvec nivolumab in refractory t cell and nk cell lymphomas cutaneous squamous cell carcinoma merkel cell carcinoma and other rare skin tumors nci 10057
Journal of Clinical Oncology, 2018Co-Authors: Ann W Silk, Igor Puzanov, Nicole R Leboeuf, Guilherme Rabinowits, Melissa Amber Burgess, Sumana Devata, Dirk F Moore, James S Goydos, Helen X Chen, Howard L. KaufmanAbstract:TPS219Background: Talimogene Laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of Talimogene Laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene Laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral Talimogene Laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed ...
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chronic granulomatous dermatitis induced by Talimogene Laherparepvec therapy of melanoma metastases
Journal of Cutaneous Pathology, 2018Co-Authors: Ashlyn S Everett, Howard L. Kaufman, Svetlana B Mckee, Peter G Pavlidakey, Carlo M Contreras, Jennifer F De Los Santos, Ju Y Kim, Robert M ConryAbstract:Talimogene Laherparepvec (TVEC) is the first oncolytic viral immunotherapy approved by the FDA, for advanced melanoma consisting of genetically modified herpes simplex type 1 virus which selectively replicates causing tumor lysis, expressing granulocyte macrophage-colony stimulating factor (GM-CSF) and activating dendritic cells. Intratumoral injection of TVEC produces objective response in 41% of stage IIB-IV M1a melanoma. However, clinical response assessment can be problematic due to immune-related inflammation at established tumor sites. Herein, we report 5 cases of granulomatous dermatitis developing at sites of TVEC injection associated with pathologic complete response in 4 of 5 patients. Over 5 months, TVEC injections were administrated in a median of 20 tumors per patient for 9 median doses prior to biopsy of persistent, indurated nodules. Granulomatous dermatitis with melanophages and melanin pigment incontinence was observed in all samples without evidence of melanoma cells in 4 patients. The fifth patient was rendered melanoma-free by resection of the 1 nodule out of 4 with persistent tumor. Repetitive administration of TVEC or other oncolytic viral immunotherapies mimicking unresolved infection can produce granulomatous inflammation confounding assessment of the degree of tumor response and need for additional TVEC therapy. Tumor biopsies are encouraged after 4 to 6 months of TVEC administration to differentiate melanoma from granulomatous inflammation. Patients with confirmed granulomatous dermatitis replace continued with remained in remission after treatment discontinuation. Inflammatory nodules typically regress spontaneously.
Frances A Collichio - One of the best experts on this subject based on the ideXlab platform.
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ultrasound guided intralesional injection of Talimogene Laherparepvec imlygic for advanced melanoma technical note on a preliminary experience
CardioVascular and Interventional Radiology, 2021Co-Authors: Lauren M B Burke, David W Ollila, Raphael J Louie, Kaleigh Burke, Morgan E Gwynn, Frances A CollichioAbstract:To evaluate the safety and feasibility of ultrasound-guided intralesional injection of Talimogene Laherparepvec (Imlygic, T-VEC) in patients with advanced non-palpable melanoma. Fourteen consecutive patients (mean age, 67.9 years ± 13.0; range, 40–88; 12 males) with unresectable, locally advanced melanoma underwent ultrasound-guided intralesional injections of T-VEC (July 2016–March 2020) into subcutaneous lesions. Tumor response to the injection was evaluated at the last follow-up. Technical success and complication rates were recorded. The T-VEC injection was technically successful in all patients with all lesions successfully punctured (100%). The mean number of lesions, injection cycles, and injection volumes were 4.1 ± 2.6 (1–9), 6.5 ± 3.0 (3–12), and 2.6 mL ± 1.4 (1–4 mL), respectively. During the follow-up period (mean, 21.0 months ± 13.4; range 1–43.6 months), complete remission, partial remission, persistent disease, and disease progression were observed in 6 (42.9%), 3 (21.4%), 1 (7.1%), and 4 (28.6%) patients, respectively. Post-treatment symptoms observed in 9 patients (64.3%), including fever (n = 2), fatigue (n = 1), headache (n = 1), pain (n = 1), mouth sores (n = 1), and flu-like symptoms (n = 3). No injection-related complications occurred in all procedures. Intralesional injection of T-VEC for non-palpable metastases under ultrasound guidance is safe and feasible in patients with advanced melanoma.
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433 Talimogene Laherparepvec t vec in combination with ipilimumab ipi versus ipi alone for advanced melanoma 4 year interim analysis of a randomized open label phase 2 trial
Journal for ImmunoTherapy of Cancer, 2020Co-Authors: Igor Puzanov, Omid Hamid, Jason Chesney, Frances A Collichio, Parminder Singh, Mohammed M Milhem, John A Glaspy, Merrick I Ross, Philip Friedlander, Claus GarbeAbstract:Background This is the first randomized trial evaluating an oncolytic virus with an immune checkpoint inhibitor in advanced melanoma. Improved objective response rate (ORR) was observed for T-VEC plus IPI compared to IPI alone (39% vs. 18%; OR 2.9; 95% Cl, 1.5–5.5; P=0.002).1 At 3-year follow-up, median OS was not reached in either arm (HR, 0.85; 95% CI, 0.55–1.32; P=0.480).2 Here we present 4-year interim analysis results including BRAF V600 mutation subgroup analysis. Methods Patients with unresectable or metastatic (IIIB-IV) melanoma were randomized 1:1 to receive T-VEC plus IPI or IPI alone. T-VEC was injected day 1, week 1, at 106 PFU/mL, followed by 108 PFU/mL on day 1, week 4, and Q2W thereafter. IPI (3 mg/kg) was given Q3W starting day 1, week 6, up to 4 doses, for T-VEC arm; day 1, week 1 for IPI alone. Response was assessed per immune-related response criteria (irRC) Q12W until disease progression. The primary endpoint was ORR; key secondary endpoints were overall survival (OS), progression-free survival (PFS), durable response rate (DRR), and safety (NCT01740297). Results A total of 198 patients (98 combination, 100 IPI alone) were randomized. As of February 25, 2020, median follow-up was 48.3 months for combination and 35.7 months for IPI alone. DRR improved for combination vs. IPI (33.7% vs. 13.0%; OR 3.4; 95% CI, 1.7–7.0; P=0.001). Median PFS was 13.5 months with combination and 6.4 months with IPI (HR 0.81; 95% Cl, 0.57–1.15; P=0.23). Median OS was not reached for combination and was 50.1 months for IPI (HR 0.82; 95% CI, 0.54–1.25; P=0.36). For combination, 47 (48.0%) patients received subsequent anti-cancer therapy vs. 64 (64.0%) for IPI; median time from randomization to first subsequent therapy was 27.7 months and 8.3 months, respectively. In subgroup analysis, patients without BRAF V600 mutation (63% combination, 60% IPI) improved DRR and PFS for combination vs. IPI alone (DRR: 33.9% vs. 5.0%; median PFS: 18.0 months vs. 4.5 months); BRAF V600 mutation positive patients (36% combination, 34% IPI) were similar between arms (DRR: 34.3% vs. 26.5%; median PFS: 4.2 months vs. 6.4 months). No additional safety signals observed in follow-up. Conclusions The improved PFS and DRR for the combination arm at 4-year follow-up indicates continued benefit of combination therapy. Patients receiving IPI alone were more likely to receive subsequent anti-cancer therapy in a shorter time. Subsequent anticancer therapies may confound OS analysis. The BRAF mutant post-hoc analysis requires further mechanistic investigation. Acknowledgements • The authors thank the investigators, patients, and study staff who contributed to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT01740297 Ethics Approval The study was approved by all institutional ethics boards. References Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of Talimogene Laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol 2018;36:1658–1667. Chesney JA, Puzanov I, Collichio F, et al. Talimogene Laherparepvec (T-VEC) in combination (combo) with ipilimumab (ipi) versus ipi alone for advanced melanoma: 3-year landmark analysis of a randomized, open-label, phase 2 trial. Ann Oncol 2019;30:mdz394-067.
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patterns of response with Talimogene Laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma
British Journal of Cancer, 2019Co-Authors: Jason Chesney, Claus Garbe, Igor Puzanov, Frances A Collichio, Parminder Singh, Mohammed M Milhem, Lisa Chen, Axel Hauschild, Anjali Sharma, Janice M MehnertAbstract:Talimogene Laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB–IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors. Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT01740297","term_id":"NCT01740297"}}NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).
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final analyses of optim a randomized phase iii trial of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in unresectable stage iii iv melanoma
Journal for ImmunoTherapy of Cancer, 2019Co-Authors: Robert H I Andtbacka, Frances A Collichio, Kevin J Harrington, Gerald Downey, Mark R Middleton, Katarina ӧhrling, Howard L. KaufmanAbstract:Talimogene Laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma. Patients were randomized 2:1 to receive intratumoral Talimogene Laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators. Of 436 patients in the intent-to-treat population, 295 were allocated to Talimogene Laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5–29.6) and 18.9 months (95% CI, 16.0–23.7) in the Talimogene Laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62–1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0–69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the Talimogene Laherparepvec and GM-CSF arms, respectively, achieved CR. In Talimogene Laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene Laherparepvec efficacy was more pronounced in stage IIIB–IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis. In this final planned OPTiM analysis, Talimogene Laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that Talimogene Laherparepvec was associated with durable CRs that were associated with prolonged survival. ClinicalTrials.gov identifier: NCT00769704 .
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real world outcomes of Talimogene Laherparepvec therapy a multi institutional experience
Journal of The American College of Surgeons, 2019Co-Authors: Raphael J Louie, Frances A Collichio, Jonathan S Zager, Matthew C Perez, Mohammad Raheel Jajja, James Sun, Keith A Delman, Michael C Lowe, Amod A Sarnaik, David W OllilaAbstract:Background Talimogene Laherparepvec (TVEC) is an FDA-approved oncolytic herpes virus used to treat unresectable stage IIIB to IV metastatic melanoma via intralesional injection. This study aims to characterize the efficacy TVEC in patients with unresectable stage IIIB to IV melanoma. Methods We performed a multi-institutional, IRB-approved review of all patients who received TVEC at 3 centers from October 2015 to October 2018. Clinicopathologic characteristics, TVEC treatment data, and outcomes were assessed. Results One hundred and twenty-one patients received TVEC, of which 80 patients had available treatment response data with at least 3-month follow-up. Anatomic sites treated were 19 (24%) head and neck, 9 (11%) upper extremity, 12 (15%) torso, and 40 (50%) lower extremity. Thirty-four (42.5%) patients did not receive therapy before TVEC. Side effects were mild and self-limited, most commonly flu-like symptoms seen in 22 (28%) patients. Median follow-up was 9 months (range 3 to 28 months), with complete local response in 31 (39%) and partial response in 14 (18%) patients. Of complete responders, 29 (37%) had no evidence of disease at last follow-up and received a median of 6 (range 2 to 12) cycles of therapy. Conclusions Talimogene Laherparepvec is a well-tolerated, durable treatment option for patients with unresectable locoregional melanoma, particularly in stage IIIB/C disease. Additionally, we found that TVEC can be administered safely across anatomic sites that are otherwise not amenable to other local therapies.
Igor Puzanov - One of the best experts on this subject based on the ideXlab platform.
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433 Talimogene Laherparepvec t vec in combination with ipilimumab ipi versus ipi alone for advanced melanoma 4 year interim analysis of a randomized open label phase 2 trial
Journal for ImmunoTherapy of Cancer, 2020Co-Authors: Igor Puzanov, Omid Hamid, Jason Chesney, Frances A Collichio, Parminder Singh, Mohammed M Milhem, John A Glaspy, Merrick I Ross, Philip Friedlander, Claus GarbeAbstract:Background This is the first randomized trial evaluating an oncolytic virus with an immune checkpoint inhibitor in advanced melanoma. Improved objective response rate (ORR) was observed for T-VEC plus IPI compared to IPI alone (39% vs. 18%; OR 2.9; 95% Cl, 1.5–5.5; P=0.002).1 At 3-year follow-up, median OS was not reached in either arm (HR, 0.85; 95% CI, 0.55–1.32; P=0.480).2 Here we present 4-year interim analysis results including BRAF V600 mutation subgroup analysis. Methods Patients with unresectable or metastatic (IIIB-IV) melanoma were randomized 1:1 to receive T-VEC plus IPI or IPI alone. T-VEC was injected day 1, week 1, at 106 PFU/mL, followed by 108 PFU/mL on day 1, week 4, and Q2W thereafter. IPI (3 mg/kg) was given Q3W starting day 1, week 6, up to 4 doses, for T-VEC arm; day 1, week 1 for IPI alone. Response was assessed per immune-related response criteria (irRC) Q12W until disease progression. The primary endpoint was ORR; key secondary endpoints were overall survival (OS), progression-free survival (PFS), durable response rate (DRR), and safety (NCT01740297). Results A total of 198 patients (98 combination, 100 IPI alone) were randomized. As of February 25, 2020, median follow-up was 48.3 months for combination and 35.7 months for IPI alone. DRR improved for combination vs. IPI (33.7% vs. 13.0%; OR 3.4; 95% CI, 1.7–7.0; P=0.001). Median PFS was 13.5 months with combination and 6.4 months with IPI (HR 0.81; 95% Cl, 0.57–1.15; P=0.23). Median OS was not reached for combination and was 50.1 months for IPI (HR 0.82; 95% CI, 0.54–1.25; P=0.36). For combination, 47 (48.0%) patients received subsequent anti-cancer therapy vs. 64 (64.0%) for IPI; median time from randomization to first subsequent therapy was 27.7 months and 8.3 months, respectively. In subgroup analysis, patients without BRAF V600 mutation (63% combination, 60% IPI) improved DRR and PFS for combination vs. IPI alone (DRR: 33.9% vs. 5.0%; median PFS: 18.0 months vs. 4.5 months); BRAF V600 mutation positive patients (36% combination, 34% IPI) were similar between arms (DRR: 34.3% vs. 26.5%; median PFS: 4.2 months vs. 6.4 months). No additional safety signals observed in follow-up. Conclusions The improved PFS and DRR for the combination arm at 4-year follow-up indicates continued benefit of combination therapy. Patients receiving IPI alone were more likely to receive subsequent anti-cancer therapy in a shorter time. Subsequent anticancer therapies may confound OS analysis. The BRAF mutant post-hoc analysis requires further mechanistic investigation. Acknowledgements • The authors thank the investigators, patients, and study staff who contributed to this study.• The study was sponsored and funded by Amgen Inc. • Medical writing support was provided by Christopher Nosala (Amgen Inc.). Trial Registration NCT01740297 Ethics Approval The study was approved by all institutional ethics boards. References Chesney J, Puzanov I, Collichio F, et al. Randomized, open-label phase II study evaluating the efficacy and safety of Talimogene Laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced, unresectable melanoma. J Clin Oncol 2018;36:1658–1667. Chesney JA, Puzanov I, Collichio F, et al. Talimogene Laherparepvec (T-VEC) in combination (combo) with ipilimumab (ipi) versus ipi alone for advanced melanoma: 3-year landmark analysis of a randomized, open-label, phase 2 trial. Ann Oncol 2019;30:mdz394-067.
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observational study of Talimogene Laherparepvec use in the anti pd 1 era for melanoma in the us cosmus 2
Melanoma management, 2020Co-Authors: James Sun, Igor Puzanov, Brian R Gastman, Lucy Mccahon, Elizabeth I Buchbinder, Michele Nanni, James M Lewis, Richard D Carvajal, Shahnaz Singhkandah, Anupam M DesaiAbstract:Aim Talimogene Laherparepvec (T-VEC) is an intralesional therapy for unresectable, metastatic melanoma. T-VEC real-world use in the context of anti-PD1-based therapy requires further characterization. Materials & methods A retrospective review of T-VEC use from 1 January 2017 and 31 March 2018 for melanoma patients was conducted at seven US institutions. Results Among 83 patients, three categories of T-VEC and anti-PD-1 therapy were identified: T-VEC used without anti-PD-1 (n = 29, 35%), T-VEC after anti-PD-1-based therapy (n = 22, 27%) and concurrent T-VEC and anti-PD-1-based therapy (n = 32, 39%). 25% of patients discontinued T-VEC therapy due to no remaining injectable lesions, 37% discontinued T-VEC due to progressive disease. Discontinuation of T-VEC did not differ by anti-PD-1-based therapy use or timing. Conclusion In real-world settings, T-VEC may be used concurrently with or after anti-PD-1-based therapy.
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patterns of response with Talimogene Laherparepvec in combination with ipilimumab or ipilimumab alone in metastatic unresectable melanoma
British Journal of Cancer, 2019Co-Authors: Jason Chesney, Claus Garbe, Igor Puzanov, Frances A Collichio, Parminder Singh, Mohammed M Milhem, Lisa Chen, Axel Hauschild, Anjali Sharma, Janice M MehnertAbstract:Talimogene Laherparepvec (T-VEC) has demonstrated efficacy for unresectable melanoma. We explored response patterns from a phase 2 study evaluating patients with unresectable stage IIIB–IVM1c malignant melanoma who received T-VEC plus ipilimumab or ipilimumab alone. Patients with objective response per modified irRC were evaluated for pseudo-progression (single ≥25% increase in tumour burden before response). Patients without pseudo-progression were classified by whether they responded within or after 6 months of treatment start; those with pseudo-progression were classified by whether pseudo-progression was due to increase in existing lesions or development of new lesions. Overall, 39% (n = 38/98) in the combination arm and 18% (n = 18/100) in the ipilimumab arm had an objective response. Eight responders (combination, n = 7 [18.4%]; ipilimumab, n = 1 [5.6%]) had pseudo-progression; most occurred by week 12 and were caused by an increase in existing lesions. These data reinforce use of T-VEC through initial progression when combined with checkpoint inhibitors. Trial Registration {"type":"clinical-trial","attrs":{"text":"NCT01740297","term_id":"NCT01740297"}}NCT01740297 (ClinicalTrials.gov; date of registration, December 4, 2012); 2012-000307-32 (ClinicalTrialsRegister.eu; date of registration, May 13, 2014).
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a phase ii study of Talimogene Laherparepvec followed by Talimogene Laherparepvec nivolumab in refractory t cell and nk cell lymphomas cutaneous squamous cell carcinoma merkel cell carcinoma and other rare skin tumors nci 10057
Journal of Clinical Oncology, 2018Co-Authors: Ann W Silk, Igor Puzanov, Nicole R Leboeuf, Guilherme Rabinowits, Melissa Amber Burgess, Sumana Devata, Dirk F Moore, James S Goydos, Helen X Chen, Howard L. KaufmanAbstract:TPS219Background: Talimogene Laherparepvec, a modified herpes virus agent, induces a response in 65% of injected melanoma tumors. The combination of Talimogene Laherparepvec with ipilimumab or pembrolizumab appears promising in clinical trials of advanced melanoma. Talimogene Laherparepvec-based therapy may be effective in other cancers of the skin and lymph nodes that are anatomically accessible for intratumoral injection. Methods: This phase II study will evaluate intratumoral Talimogene Laherparepvec monotherapy in 4 parallel disease cohorts: 1) Refractory T cell and NK cell lymphomas including cutaneous T cell lymphoma, 2) Merkel cell carcinoma 3) Cutaneous squamous cell carcinoma and 4) Other advanced/refractory non-melanoma skin cancers. Lymphoma patients must be refractory to or intolerant of all standard life-prolonging therapies. Skin cancer patients must be advanced/unresectable or refractory to one or more treatments including surgery, radiation therapy, or medical therapy. Prior PD-1-directed ...
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randomized open label phase ii study evaluating the efficacy and safety of Talimogene Laherparepvec in combination with ipilimumab versus ipilimumab alone in patients with advanced unresectable melanoma
Journal of Clinical Oncology, 2017Co-Authors: Jason Chesney, Omid Hamid, Igor Puzanov, Frances A Collichio, Parminder Singh, Mohammed M Milhem, John A Glaspy, Merrick I Ross, Philip Friedlander, Claus GarbeAbstract:Purpose We evaluated the combination of Talimogene Laherparepvec plus ipilimumab versus ipilimumab alone in patients with advanced melanoma in a phase II study. To our knowledge, this was the first randomized trial to evaluate addition of an oncolytic virus to a checkpoint inhibitor. Methods Patients with unresectable stages IIIB to IV melanoma, with no more than one prior therapy if BRAF wild-type, no more than two prior therapies if BRAF mutant, measurable/injectable disease, and without symptomatic autoimmunity or clinically significant immunosuppression were randomly assigned 1:1 to receive Talimogene Laherparepvec plus ipilimumab or ipilimumab alone. Talimogene Laherparepvec treatment began in week 1 (first dose, ≤ 4 mL × 106 plaque-forming units/mL; after 3 weeks, ≤ 4 mL × 108 plaque-forming units/mL every 2 weeks). Ipilimumab (3 mg/kg every 3 weeks; up to four doses) began week 1 in the ipilimumab alone arm and week 6 in the combination arm. The primary end point was objective response rate evaluated by investigators per immune-related response criteria. Results One hundred ninety-eight patients were randomly assigned to Talimogene Laherparepvec plus ipilimumab (n = 98), or ipilimumab alone (n = 100). Thirty-eight patients (39%) in the combination arm and 18 patients (18%) in the ipilimumab arm had an objective response (odds ratio, 2.9; 95% CI, 1.5 to 5.5; P = .002). Responses were not limited to injected lesions; visceral lesion decreases were observed in 52% of patients in the combination arm and 23% of patients in the ipilimumab arm. Frequently occurring adverse events (AEs) included fatigue (combination, 59%; ipilimumab alone, 42%), chills (combination, 53%; ipilimumab alone, 3%), and diarrhea (combination, 42%; ipilimumab alone, 35%). Incidence of grade ≥ 3 AEs was 45% and 35%, respectively. Three patients in the combination arm had fatal AEs; none were treatment related. Conclusion The study met its primary end point; the objective response rate was significantly higher with Talimogene Laherparepvec plus ipilimumab versus ipilimumab alone. These data indicate that the combination has greater antitumor activity without additional safety concerns versus ipilimumab.
Robert H I Andtbacka - One of the best experts on this subject based on the ideXlab platform.
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biodistribution shedding and transmissibility of the oncolytic virus Talimogene Laherparepvec in patients with melanoma
EBioMedicine, 2019Co-Authors: Robert H I Andtbacka, Jason Chesney, Jonathan S Zager, Thomas Amatruda, John Nemunaitis, John Walker, Kate Liu, Chengpang Hsu, Cheryl A Pickett, Janice M MehnertAbstract:Abstract Background Talimogene Laherparepvec (T-VEC) is an intralesionally delivered, modified herpes simplex virus type-1 oncolytic immunotherapy. The biodistribution, shedding, and potential transmission of T-VEC was systematically evaluated during and after completion of therapy in adults with advanced melanoma. Methods In this phase 2, single-arm, open-label study, T-VEC was administered into injectable lesions initially at 106 plaque-forming units (PFU)/mL, 108 PFU/mL 21 days later, and 108 PFU/mL every 14 (±3) days thereafter. Injected lesions were covered with occlusive dressings for ≥1 week. Blood, urine, and swabs from exterior of occlusive dressings, surface of injected lesions, oral mucosa, anogenital area, and suspected herpetic lesions were collected throughout the study. Detectable T-VEC DNA was determined for each sample type; infectivity was determined for all swabs with detectable T-VEC DNA. Findings Sixty patients received ≥1 dose of T-VEC. During cycles 1–4, T-VEC DNA was detected in blood (98·3% of patients, 36·7% of samples), urine (31·7% of patients, 3·0% of samples) and swabs from injected lesions (100% of patients, 57·6% of samples), exterior of dressings (80% of patients,19·5% of samples), oral mucosa (8·3% of patients, 2·5% of samples), and anogenital area (8·0% of patients, 1·1% of samples). During the safety follow-up period, T-VEC DNA was only detected on swabs from injected lesions (14% of patients, 5.8% of samples). T-VEC DNA was detected in 4/37 swabs (3/19 patients) of suspected herpetic lesions. Among all samples, only those from the surface of injected lesions tested positive for infectivity (8/740 [1·1%]). Three close contacts reported signs and symptoms of suspected herpetic origin; however, no lesions had detectable T-VEC DNA. Interpretation Using current guidelines, T-VEC can be administered safely to patients with advanced melanoma and is unlikely to be transmitted to close contacts with appropriate use of occlusive dressings. Fund This study was funded by Amgen Inc.: ClinicalTrials.gov , NCT02014441 .
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final analyses of optim a randomized phase iii trial of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in unresectable stage iii iv melanoma
Journal for ImmunoTherapy of Cancer, 2019Co-Authors: Robert H I Andtbacka, Frances A Collichio, Kevin J Harrington, Gerald Downey, Mark R Middleton, Katarina ӧhrling, Howard L. KaufmanAbstract:Talimogene Laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma. Patients were randomized 2:1 to receive intratumoral Talimogene Laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators. Of 436 patients in the intent-to-treat population, 295 were allocated to Talimogene Laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5–29.6) and 18.9 months (95% CI, 16.0–23.7) in the Talimogene Laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62–1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0–69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the Talimogene Laherparepvec and GM-CSF arms, respectively, achieved CR. In Talimogene Laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene Laherparepvec efficacy was more pronounced in stage IIIB–IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis. In this final planned OPTiM analysis, Talimogene Laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that Talimogene Laherparepvec was associated with durable CRs that were associated with prolonged survival. ClinicalTrials.gov identifier: NCT00769704 .
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oncolytic virotherapy promotes intratumoral t cell infiltration and improves anti pd 1 immunotherapy
Cell, 2017Co-Authors: Antoni Ribas, Reinhard Dummer, Igor Puzanov, Ari M Vanderwalde, Robert H I Andtbacka, Olivier Michielin, Anthony J Olszanski, Josep Malvehy, Jonathan Cebon, Eugenio FernandezAbstract:Here we report a phase 1b clinical trial testing the impact of oncolytic virotherapy with Talimogene Laherparepvec on cytotoxic T cell infiltration and therapeutic efficacy of the anti-PD-1 antibody pembrolizumab. Twenty-one patients with advanced melanoma were treated with Talimogene Laherparepvec followed by combination therapy with pembrolizumab. Therapy was generally well tolerated, with fatigue, fevers, and chills as the most common adverse events. No dose-limiting toxicities occurred. Confirmed objective response rate was 62%, with a complete response rate of 33% per immune-related response criteria. Patients who responded to combination therapy had increased CD8+ T cells, elevated PD-L1 protein expression, as well as IFN-γ gene expression on several cell subsets in tumors after Talimogene Laherparepvec treatment. Response to combination therapy did not appear to be associated with baseline CD8+ T cell infiltration or baseline IFN-γ signature. These findings suggest that oncolytic virotherapy may improve the efficacy of anti-PD-1 therapy by changing the tumor microenvironment. VIDEO ABSTRACT.
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efficacy and safety of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in patients with stage iiib c and ivm1a melanoma subanalysis of the phase iii optim trial
OncoTargets and Therapy, 2016Co-Authors: Kevin J Harrington, Robert H I Andtbacka, Frances A Collichio, Gerald Downey, Lisa Chen, Zsolt Szabo, Howard L. KaufmanAbstract:Objectives: Talimogene Laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), Talimogene Laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB-IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB-IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB-IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio) to intralesional Talimogene Laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit-risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB-IVM1a melanoma, DRR was higher with Talimogene Laherparepvec compared with GM-CSF (25.2% versus 1.2%; P < 0.0001). ORR was also higher in the Talimogene Laherparepvec arm (40.5% versus 2.3%; P < 0.0001), and 27 patients in the Talimogene Laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments. Conclusion: The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from Talimogene Laherparepvec compared with GM-CSF. Talimogene Laherparepvec was well tolerated.
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(MASTERKEY-265)
2016Co-Authors: Phase A I/iii, Antoni Ribas, Reinhard Dummer, Igor Puzanov, Robert H I Andtbacka, Olivier Michielin, Jonathan Cebon, Georgina V Long, Eugenio FernAbstract:Talimogene Laherparepvec (T-VEC) in combination with pembrolizumab for the treatment of unresected, stage IIIb-IV melanom
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final analyses of optim a randomized phase iii trial of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in unresectable stage iii iv melanoma
Journal for ImmunoTherapy of Cancer, 2019Co-Authors: Robert H I Andtbacka, Frances A Collichio, Kevin J Harrington, Gerald Downey, Mark R Middleton, Katarina ӧhrling, Howard L. KaufmanAbstract:Talimogene Laherparepvec is an oncolytic immunotherapy approved in the US, Europe, Australia and Switzerland. We report the final planned analysis of OPTiM, a randomized open-label phase III trial in patients with unresectable stage IIIB–IVM1c melanoma. Patients were randomized 2:1 to receive intratumoral Talimogene Laherparepvec or subcutaneous recombinant GM-CSF. In addition to overall survival (OS), durable response rate (DRR), objective response rate (ORR), complete responses (CR), and safety are also reported. All final analyses are considered to be descriptive and treatment responses were assessed by the investigators. Of 436 patients in the intent-to-treat population, 295 were allocated to Talimogene Laherparepvec and 141 to GM-CSF. Median follow-up in the final OS analysis was 49 months. Median OS was 23.3 months (95% confidence interval [CI], 19.5–29.6) and 18.9 months (95% CI, 16.0–23.7) in the Talimogene Laherparepvec and GM-CSF arms, respectively (unstratified hazard ratio, 0.79; 95% CI, 0.62–1.00; p = 0.0494 [descriptive]). DRR was 19.0 and 1.4% (unadjusted odds ratio, 16.6; 95% CI, 4.0–69.2; p < 0.0001); ORR was 31.5 and 6.4%. Fifty (16.9%) and 1 (0.7%) patient in the Talimogene Laherparepvec and GM-CSF arms, respectively, achieved CR. In Talimogene Laherparepvec-treated patients, median time to CR was 8.6 months; median CR duration was not reached. Among patients with a CR, 88.5% were estimated to survive at a 5-year landmark analysis. Talimogene Laherparepvec efficacy was more pronounced in stage IIIB–IVM1a melanoma as already described in the primary analysis. The safety reporting was consistent with the primary OPTiM analysis. In this final planned OPTiM analysis, Talimogene Laherparepvec continued to result in improved longer-term efficacy versus GM-CSF and remained well tolerated. The final analysis also confirms that Talimogene Laherparepvec was associated with durable CRs that were associated with prolonged survival. ClinicalTrials.gov identifier: NCT00769704 .
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Practical clinical guide on the use of Talimogene Laherparepvec monotherapy in patients with unresectable melanoma in Europe
European Journal of Dermatology, 2018Co-Authors: Ralf Gutzmer, Josep Malvehy, Christoph Hoeller, Kevin J Harrington, Gerald Downey, Katarina Ohrling, Celeste Lebbé, Reinhard DummerAbstract:Talimogene Laherparepvec, a herpes simplex virus type 1-based intrale-sional oncolytic immunotherapy, is approved in Europe for the treatment of adults with unresectable stage IIIB-IVM1a melanoma, with no bone, brain, lung or other visceral disease. It has direct oncolytic effects in injected lesions, leading to the release of tumour-derived antigens and systemic immune effects mediated by the induction of anti-tumour immunity, which is enhanced by the production of granulocyte macrophage colony-stimulating factor. Responses (which occur in >40% of stage IIIB-IVM1a patients) are often durable (>50% last >6 months) and occur in injected and uninjected lesions (in stage IIIB-IVM1c patients, 64%/34% of evaluable injected/uninjected non-visceral lesions, respectively, decreased in size by >50%). As with other immunotherapies, responses may be delayed or can arise after pseudoprogression. The pattern of treatment-emergent adverse events is distinct, being mostly grade 1/2, easy to manage, and rarely leading to treatment discontinuation. Systemic therapy represents the backbone of care for many metastatic melanoma patients. Nonetheless, the potential for durable locoregional control with a locally injected agent may make Talimogene Laherparepvec suitable for selected patients with stage IIIB/C disease, for whom surgery is not possible (e.g . with in-transit metastases, multiple melanoma lesions at different body sites, or those relapsing rapidly after repeated rounds of surgery) and slowly progressing disease. Here, we discuss which patients could be suitable for Talimogene Laherparepvec monotherapy based on the European indication, review the patterns/timing of response, and discuss the incidence/management of adverse events. Its potential use combined with immune checkpoint inhibitors is also discussed.
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a practical guide to the handling and administration of Talimogene Laherparepvec in europe
OncoTargets and Therapy, 2017Co-Authors: Kevin J Harrington, Olivier Michielin, Josep Malvehy, Isabella Pezzani Gruter, Lorna Grove, Anna L Frauchiger, Reinhard DummerAbstract:Talimogene Laherparepvec is a herpes simplex virus-1-based intralesional oncolytic immunotherapy and is the first oncolytic virus to be approved in Europe. It is indicated for the treatment of adults with unresectable melanoma that is regionally or distantly metastatic (stage IIIB, IIIC, and IVM1a) with no bone, brain, lung, or other visceral disease. Talimogene Laherparepvec is a genetically modified viral therapy, and its handling needs special attention due to its deep freeze, cold-chain requirements, its potential for viral shedding, and its administration by direct intralesional injection. This review provides a practical overview of handling, storage, and administration procedures for this agent in Europe. Talimogene Laherparepvec vials should be transported/stored frozen at a temperature of -90°C to -70°C, and once thawed, vials must not be refrozen. Universal precautions for preparation, administration, and handling should be followed to avoid accidental exposure. Health care providers should wear personal protective equipment, and materials that come into contact with Talimogene Laherparepvec should be disposed of in accordance with local institutional procedures. Individuals who are immunocompromised or pregnant should not prepare or administer this agent. Talimogene Laherparepvec is administered by intralesional injection into cutaneous, subcutaneous, and/or nodal lesions that are visible, palpable, or detectable by ultrasound. Treatment should be continued for ≥6 months. As with other immunotherapies, patients may experience an increase in the size of existing lesion(s) or the appearance of new lesions (ie, progression) prior to achieving a response ("pseudo-progression"). As several health care professionals (eg, physicians [dermatologists, surgeons, oncologists, radiologists], pharmacists, nurses) are involved in different stages of the process, there is a need for good interdisciplinary collaboration when using Talimogene Laherparepvec. Although there are specific requirements for this agent's storage, handling, administration, and disposal, these can be effectively managed in a real-world clinical setting through the implementation of training programs and straightforward standard operating procedures.
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efficacy and safety of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor in patients with stage iiib c and ivm1a melanoma subanalysis of the phase iii optim trial
OncoTargets and Therapy, 2016Co-Authors: Kevin J Harrington, Robert H I Andtbacka, Frances A Collichio, Gerald Downey, Lisa Chen, Zsolt Szabo, Howard L. KaufmanAbstract:Objectives: Talimogene Laherparepvec is the first oncolytic immunotherapy to receive approval in Europe, the USA and Australia. In the randomized, open-label Phase III OPTiM trial (NCT00769704), Talimogene Laherparepvec significantly improved durable response rate (DRR) versus granulocyte-macrophage colony-stimulating factor (GM-CSF) in 436 patients with unresectable stage IIIB-IVM1c melanoma. The median overall survival (OS) was longer versus GM-CSF in patients with earlier-stage melanoma (IIIB-IVM1a). Here, we report a detailed subgroup analysis of the OPTiM study in patients with IIIB-IVM1a disease. Patients and methods: The patients were randomized (2:1 ratio) to intralesional Talimogene Laherparepvec or subcutaneous GM-CSF and were evaluated for DRR, overall response rate (ORR), OS, safety, benefit-risk and numbers needed to treat. Descriptive statistics were used for subgroup comparisons. Results: Among 249 evaluated patients with stage IIIB-IVM1a melanoma, DRR was higher with Talimogene Laherparepvec compared with GM-CSF (25.2% versus 1.2%; P < 0.0001). ORR was also higher in the Talimogene Laherparepvec arm (40.5% versus 2.3%; P < 0.0001), and 27 patients in the Talimogene Laherparepvec arm had a complete response, compared with none in GM-CSF-treated patients. The incidence rates of exposure-adjusted adverse events (AE) and serious AEs were similar with both treatments. Conclusion: The subgroup of patients with stage IIIB, IIIC and IVM1a melanoma (57.1% of the OPTiM intent-to-treat population) derived greater benefit in DRR and ORR from Talimogene Laherparepvec compared with GM-CSF. Talimogene Laherparepvec was well tolerated.
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cutaneous head and neck melanoma in optim a randomized phase 3 trial of Talimogene Laherparepvec versus granulocyte macrophage colony stimulating factor for the treatment of unresected stage iiib iiic iv melanoma
Head and Neck-journal for The Sciences and Specialties of The Head and Neck, 2016Co-Authors: C Robert M H I Andtbacka, Mohammed M Milhem, Kevin J Harrington, Thomas Amatruda, John Nemunaitis, Lisa Chen, Sanjiv S Agarwala, David W Ollila, Sigrun Hallmeyer, Mark ShilkrutAbstract:Background Cutaneous head and neck melanoma has poor outcomes and limited treatment options. In OPTiM, a phase 3 study in patients with unresectable stage IIIB/IIIC/IV melanoma, intralesional administration of the oncolytic virus Talimogene Laherparepvec improved durable response rate (DRR; continuous response ≥6 months) compared with subcutaneous granulocyte-macrophage colony-stimulating factor (GM-CSF). Methods Retrospective review of OPTiM identified patients with cutaneous head and neck melanoma given Talimogene Laherparepvec (n = 61) or GM-CSF (n = 26). Outcomes were compared between Talimogene Laherparepvec and GM-CSF treated patients with cutaneous head and neck melanoma. Results DRR was higher for Talimogene Laherparepvec–treated patients than for GM-CSF treated patients (36.1% vs 3.8%; p = .001). A total of 29.5% of patients had a complete response with Talimogene Laherparepvec versus 0% with GM-CSF. Among Talimogene Laherparepvec–treated patients with a response, the probability of still being in response after 12 months was 73%. Median overall survival (OS) was 25.2 months for GM-CSF and had not been reached with Talimogene Laherparepvec. Conclusion Treatment with Talimogene Laherparepvec was associated with improved response and survival compared with GM-CSF in patients with cutaneous head and neck melanoma. © 2016 The Authors Head & Neck Published by Wiley Periodicals, Inc. Head Neck, 2016
