PD-1 pathway–targeted agents in development

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    JerryfromFauq
    Participant

      http://onlinelibrary.wiley.com/doi/10.1002/cam4.106/full

      Table 1. PD-1 pathway–targeted agents in development

      http://onlinelibrary.wiley.com/doi/10.1002/cam4.106/full

      Table 1. PD-1 pathway–targeted agents in development

      Target Name Description Sponsor Phase
      PD-1 Nivolumab Fully human IgG4 monoclonal antibody Bristol-Myers Squibb 3
      Lambrolizumab Humanized IgG4 monoclonal antibody Merck 3
      Pidilizumab Humanized IgG1 monoclonal antibody CureTech 2
      AMP-224 B7-DC/IgG1 fusion protein GlaxoSmithKline/Amplimmune 1
      PD-L1 BMS-936559 Fully human IgG4 monoclonal antibody Bristol-Myers Squibb 1
      RG7446/MPDL3280A Monoclonal antibody Roche/Genentech 1
      MEDI4736 Monoclonal antibody MedImmune 1

       

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      Role of the PD-1 Pathway in the Immune Response

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        JerryfromFauq
        Participant

          Patterns of response to PD-1 blockade

          While a subset of melanoma and lung cancer patients treated with PD-1-pathway–targeted agents have experienced encouraging ORs, fewer have experienced SD. It is possible that the response to PD-1 pathway blockade is “all or nothing.” In comparison, while only a small percentage of patients treated with ipilimumab achieve ORs, this agent improved median OS in phase 3 trials, suggesting a clinical benefit in patients who did not meet response criteria [9, 50]. It is possible that PD-1-pathway–directed agents may impart a survival benefit only to those patients on the “tail” of the survival curve. Whether these agents will improve median OS in unselected patients will be determined by ongoing, randomized phase 3 trials.

           

          It should be noted that select responding patients who discontinued PD-1 antibody therapy subsequently demonstrated disease progression, suggesting that the optimal duration of anti–PD-1 agent dosing may vary from patient to patient. However, some patients who progressed after discontinuation of anti–PD-1 therapy have demonstrated durable responses after retreatment [47]. The optimal duration of PD-1-pathway–targeted agent treatment is still being determined; if shorter treatment durations are proven efficacious, this approach would be more cost-effective. The ultimate benefit of immunotherapeutics (e.g., IL-2, ipilimumab) is their ability to produce remissions that are durable when therapy is discontinued. Although this has been observed in select patients treated with anti–PD-1 agents, the percentage of patients who achieve durable remissions remains to be determined. Nonetheless, the potential benefits for patients who experience “treatment-free survival” include decreased treatment-associated toxicity, improved quality of life, and decreased cost to the healthcare system. While this endpoint is not currently standard for approving therapies, its value to the patient merits consideration in future studies.

          T-cell stimulating agent combinations

          IL-2 is a cytokine that supports T-cell survival and proliferation. The combination of HD IL-2 and ipilimumab has demonstrated manageable toxicity and impressive efficacy (CR rate of 17%) in patients with advanced MEL [57]. Thus, it is conceivable that the combination of HD IL-2, to induce T-cell expansion, and PD-1 blockade, to eliminate tumor-induced immune suppression, might prove equally or more efficacious in select patients.

           

           

          JerryfromFauq
          Participant

            Patterns of response to PD-1 blockade

            While a subset of melanoma and lung cancer patients treated with PD-1-pathway–targeted agents have experienced encouraging ORs, fewer have experienced SD. It is possible that the response to PD-1 pathway blockade is “all or nothing.” In comparison, while only a small percentage of patients treated with ipilimumab achieve ORs, this agent improved median OS in phase 3 trials, suggesting a clinical benefit in patients who did not meet response criteria [9, 50]. It is possible that PD-1-pathway–directed agents may impart a survival benefit only to those patients on the “tail” of the survival curve. Whether these agents will improve median OS in unselected patients will be determined by ongoing, randomized phase 3 trials.

             

            It should be noted that select responding patients who discontinued PD-1 antibody therapy subsequently demonstrated disease progression, suggesting that the optimal duration of anti–PD-1 agent dosing may vary from patient to patient. However, some patients who progressed after discontinuation of anti–PD-1 therapy have demonstrated durable responses after retreatment [47]. The optimal duration of PD-1-pathway–targeted agent treatment is still being determined; if shorter treatment durations are proven efficacious, this approach would be more cost-effective. The ultimate benefit of immunotherapeutics (e.g., IL-2, ipilimumab) is their ability to produce remissions that are durable when therapy is discontinued. Although this has been observed in select patients treated with anti–PD-1 agents, the percentage of patients who achieve durable remissions remains to be determined. Nonetheless, the potential benefits for patients who experience “treatment-free survival” include decreased treatment-associated toxicity, improved quality of life, and decreased cost to the healthcare system. While this endpoint is not currently standard for approving therapies, its value to the patient merits consideration in future studies.

            T-cell stimulating agent combinations

            IL-2 is a cytokine that supports T-cell survival and proliferation. The combination of HD IL-2 and ipilimumab has demonstrated manageable toxicity and impressive efficacy (CR rate of 17%) in patients with advanced MEL [57]. Thus, it is conceivable that the combination of HD IL-2, to induce T-cell expansion, and PD-1 blockade, to eliminate tumor-induced immune suppression, might prove equally or more efficacious in select patients.

             

             

            JerryfromFauq
            Participant

              Patterns of response to PD-1 blockade

              While a subset of melanoma and lung cancer patients treated with PD-1-pathway–targeted agents have experienced encouraging ORs, fewer have experienced SD. It is possible that the response to PD-1 pathway blockade is “all or nothing.” In comparison, while only a small percentage of patients treated with ipilimumab achieve ORs, this agent improved median OS in phase 3 trials, suggesting a clinical benefit in patients who did not meet response criteria [9, 50]. It is possible that PD-1-pathway–directed agents may impart a survival benefit only to those patients on the “tail” of the survival curve. Whether these agents will improve median OS in unselected patients will be determined by ongoing, randomized phase 3 trials.

               

              It should be noted that select responding patients who discontinued PD-1 antibody therapy subsequently demonstrated disease progression, suggesting that the optimal duration of anti–PD-1 agent dosing may vary from patient to patient. However, some patients who progressed after discontinuation of anti–PD-1 therapy have demonstrated durable responses after retreatment [47]. The optimal duration of PD-1-pathway–targeted agent treatment is still being determined; if shorter treatment durations are proven efficacious, this approach would be more cost-effective. The ultimate benefit of immunotherapeutics (e.g., IL-2, ipilimumab) is their ability to produce remissions that are durable when therapy is discontinued. Although this has been observed in select patients treated with anti–PD-1 agents, the percentage of patients who achieve durable remissions remains to be determined. Nonetheless, the potential benefits for patients who experience “treatment-free survival” include decreased treatment-associated toxicity, improved quality of life, and decreased cost to the healthcare system. While this endpoint is not currently standard for approving therapies, its value to the patient merits consideration in future studies.

              T-cell stimulating agent combinations

              IL-2 is a cytokine that supports T-cell survival and proliferation. The combination of HD IL-2 and ipilimumab has demonstrated manageable toxicity and impressive efficacy (CR rate of 17%) in patients with advanced MEL [57]. Thus, it is conceivable that the combination of HD IL-2, to induce T-cell expansion, and PD-1 blockade, to eliminate tumor-induced immune suppression, might prove equally or more efficacious in select patients.

               

               

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