‘Window of opportunity’ exists for durvalumab as pancreatic cancer maintenance therapy

Gentry T. King

A randomized clinical trial is underway to assess the efficacy of the novel immunotherapy durvalumab as maintenance therapy for patients with pancreatic cancer.

Gentry T. King, MD, chief fellow in hematology and oncology at University of Colorado, and colleagues are randomly assigning patients durvalumab (Imfinzi, AstraZeneca) — an anti-PD-L1 therapy approved for urothelial cancer and non-small cell lung cancer — or standard-of-care surveillance monitoring for 1 year after successful curative surgical intervention.

HemOnc Today spoke with King about the need for more effective therapies to prevent pancreatic cancer recurrence, as well as the potential efficacy of durvalumab in this setting.

 

Question: Can you describe the need for more effective therapies to prevent pancreatic cancer recurrence?

A: Pancreatic cancer is an aggressive cancer that is projected to be the second leading cause of cancer-related death by 2030. Surgical resection remains the only potentially curative treatment for pancreatic cancer. In a subgroup of patients with locally advanced pancreatic cancer who are initially unresectable or borderline resectable, conversion to a resectable state is possible with preoperative chemotherapy and radiation. These patients then would proceed to additional adjuvant chemotherapy after successful surgical resection to decrease the chances for recurrence. Thereafter, the standard of care would be to observe these patients with periodic lab tests and imaging to catch early recurrence. Unfortunately, despite going through all of this therapy and having their localized tumor resected, many patients still recur. There is a vital need for additional and effective treatment strategies to decrease recurrence rates for this aggressive cancer.

 

Q: Why might durvalumab be an effective option?

A: Pancreatic cancer is classically known as an immunologically cold tumor with sparse antitumor T-cell infiltrate. We know from phase 1 trials of patients with metastatic pancreas cancer that anti-PD-1/PD-L1 monotherapy is ineffective in this setting. The low response rates have been postulated to be secondary to the very immunosuppressive tumor microenvironment that builds up in these heavily pretreated patients. Preclinical data from the lab of our collaborator — Lei Zheng, MD, at Johns Hopkins University — have suggested that chemotherapy and radiation have the potential to sensitize pancreas adenocarcinoma to anti-PD-L1 therapy. We believe that resected postneoadjuvant pancreas cancer represents a window of opportunity for anti-PD-L1 therapy with durvalumab. This approach has the potential to be effective against minimal residual disease, if any, that has been sensitized by preoperative chemotherapy and radiation. We believe this is a setting in which immunosuppressive mechanisms are not as advanced and complex as they would be in the metastatic setting.

 

Q: What type of safety profile do you expect durvalumab to exhibit in this setting?

A: In general, single-agent immunotherapy with anti-PD-1 and anti-PD-L1 inhibitors are well tolerated, with a more favorable side effect profile than standard chemotherapy. Of course, the adverse event profile is completely different compared with chemotherapy, comprised mostly of immune-related adverse events. Some of these immune-related adverse events like pneumonitis and colitis can be serious, but increasing awareness and experience among oncologists have made these quite manageable. A paper in JAMA Oncology by Powles and colleagues reported the incidence of grade 3 or grade 4 immune-related adverse events in a cohort of 970 patients with different tumor types receiving durvalumab was 1.6% or less. As such, we predict this to be a well-tolerated maintenance strategy.

 

Q: Why might PD-L1 inhibition be effective in this setting?

A: PD-L1 is an imperfect biomarker. Although many studies have suggested prognostic value of PD-L1 expression in pancreas adenocarcinoma, the predictive value is unknown. However, pre-clinical data from the Zheng lab has demonstrated that PD-L1 expression in pancreas cancer more than doubles after treatment with chemotherapy and radiation. This increase in PD-L1 is a major reason for our hypothesis that PD-L1 antibody therapy has the potential to be effective in this setting. Moreover, as previously mentioned, we expect it to be well tolerated and provide a feasible maintenance strategy.

 

Q: Do you expect to use durvalumab in combination with other drugs in this patient population? If so, what drugs or classes might have efficacy?

A: Yes, we think combination therapies are needed to increase responses to immunotherapy. This trial is, in essence, a combination therapy with chemotherapy, radiation and surgery being used in combination with immunotherapy as a treatment strategy. Combining checkpoint inhibitor therapy, such as durvalumab, with other immunotherapeutic drugs has the potential to increase responses. There are multiple phase 1 trials of combination immunotherapies targeting different immune checkpoints other than PD-1/PD-L1, and also a variety of trials combining immune active agents with other chemotherapies or targeted therapies. The interest and activity in clinical trials for pancreas cancer is exciting and encouraging, but we also temper this with knowing the notorious track record of multiple failed trials in pancreas cancer. This is why we are so appreciative of the tireless efforts of our scientists and courage of our patients to participate in these trials to look for novel therapies that can help us treat this very aggressive disease.

 

Q: What might future research entail?

A: In addition to determining whether this trial can show the efficacy of durvalumab in the adjuvant maintenance setting for pancreas cancer, this trial is also important for helping us know more about the immune contexture of pancreas cancer. Part of the correlative studies we have planned for this study entails analyzing all the resected specimens with novel techniques to more comprehensively characterize the immune microenvironment of pancreas cancer. In particular, this would be one of the largest analyses in the setting of a prospective trial. We hope that this gives us powerful information that can help guide us in coming up with rational and more effective immunotherapy combinations. Durvalumab has great potential for future combination immunotherapy trials, especially noting it’s favorable adverse effect profile and increasing clinical experience. – by Rob Volansky

 

For more information:

Gentry T. King, MD, can be reached at University of Colorado, Denver, Medical Oncology, MS 8117, 12801 E. 17th Ave. 8101, 8th Floor, Aurora, CO 80045; email: gentry.king@ucdenver.edu.

 

Disclosure: King reports no relevant financial disclosures.

Gentry T. King

A randomized clinical trial is underway to assess the efficacy of the novel immunotherapy durvalumab as maintenance therapy for patients with pancreatic cancer.

Gentry T. King, MD, chief fellow in hematology and oncology at University of Colorado, and colleagues are randomly assigning patients durvalumab (Imfinzi, AstraZeneca) — an anti-PD-L1 therapy approved for urothelial cancer and non-small cell lung cancer — or standard-of-care surveillance monitoring for 1 year after successful curative surgical intervention.

HemOnc Today spoke with King about the need for more effective therapies to prevent pancreatic cancer recurrence, as well as the potential efficacy of durvalumab in this setting.

 

Question: Can you describe the need for more effective therapies to prevent pancreatic cancer recurrence?

A: Pancreatic cancer is an aggressive cancer that is projected to be the second leading cause of cancer-related death by 2030. Surgical resection remains the only potentially curative treatment for pancreatic cancer. In a subgroup of patients with locally advanced pancreatic cancer who are initially unresectable or borderline resectable, conversion to a resectable state is possible with preoperative chemotherapy and radiation. These patients then would proceed to additional adjuvant chemotherapy after successful surgical resection to decrease the chances for recurrence. Thereafter, the standard of care would be to observe these patients with periodic lab tests and imaging to catch early recurrence. Unfortunately, despite going through all of this therapy and having their localized tumor resected, many patients still recur. There is a vital need for additional and effective treatment strategies to decrease recurrence rates for this aggressive cancer.

 

Q: Why might durvalumab be an effective option?

A: Pancreatic cancer is classically known as an immunologically cold tumor with sparse antitumor T-cell infiltrate. We know from phase 1 trials of patients with metastatic pancreas cancer that anti-PD-1/PD-L1 monotherapy is ineffective in this setting. The low response rates have been postulated to be secondary to the very immunosuppressive tumor microenvironment that builds up in these heavily pretreated patients. Preclinical data from the lab of our collaborator — Lei Zheng, MD, at Johns Hopkins University — have suggested that chemotherapy and radiation have the potential to sensitize pancreas adenocarcinoma to anti-PD-L1 therapy. We believe that resected postneoadjuvant pancreas cancer represents a window of opportunity for anti-PD-L1 therapy with durvalumab. This approach has the potential to be effective against minimal residual disease, if any, that has been sensitized by preoperative chemotherapy and radiation. We believe this is a setting in which immunosuppressive mechanisms are not as advanced and complex as they would be in the metastatic setting.

 

Q: What type of safety profile do you expect durvalumab to exhibit in this setting?

A: In general, single-agent immunotherapy with anti-PD-1 and anti-PD-L1 inhibitors are well tolerated, with a more favorable side effect profile than standard chemotherapy. Of course, the adverse event profile is completely different compared with chemotherapy, comprised mostly of immune-related adverse events. Some of these immune-related adverse events like pneumonitis and colitis can be serious, but increasing awareness and experience among oncologists have made these quite manageable. A paper in JAMA Oncology by Powles and colleagues reported the incidence of grade 3 or grade 4 immune-related adverse events in a cohort of 970 patients with different tumor types receiving durvalumab was 1.6% or less. As such, we predict this to be a well-tolerated maintenance strategy.

 

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Q: Why might PD-L1 inhibition be effective in this setting?

A: PD-L1 is an imperfect biomarker. Although many studies have suggested prognostic value of PD-L1 expression in pancreas adenocarcinoma, the predictive value is unknown. However, pre-clinical data from the Zheng lab has demonstrated that PD-L1 expression in pancreas cancer more than doubles after treatment with chemotherapy and radiation. This increase in PD-L1 is a major reason for our hypothesis that PD-L1 antibody therapy has the potential to be effective in this setting. Moreover, as previously mentioned, we expect it to be well tolerated and provide a feasible maintenance strategy.

 

Q: Do you expect to use durvalumab in combination with other drugs in this patient population? If so, what drugs or classes might have efficacy?

A: Yes, we think combination therapies are needed to increase responses to immunotherapy. This trial is, in essence, a combination therapy with chemotherapy, radiation and surgery being used in combination with immunotherapy as a treatment strategy. Combining checkpoint inhibitor therapy, such as durvalumab, with other immunotherapeutic drugs has the potential to increase responses. There are multiple phase 1 trials of combination immunotherapies targeting different immune checkpoints other than PD-1/PD-L1, and also a variety of trials combining immune active agents with other chemotherapies or targeted therapies. The interest and activity in clinical trials for pancreas cancer is exciting and encouraging, but we also temper this with knowing the notorious track record of multiple failed trials in pancreas cancer. This is why we are so appreciative of the tireless efforts of our scientists and courage of our patients to participate in these trials to look for novel therapies that can help us treat this very aggressive disease.

 

Q: What might future research entail?

A: In addition to determining whether this trial can show the efficacy of durvalumab in the adjuvant maintenance setting for pancreas cancer, this trial is also important for helping us know more about the immune contexture of pancreas cancer. Part of the correlative studies we have planned for this study entails analyzing all the resected specimens with novel techniques to more comprehensively characterize the immune microenvironment of pancreas cancer. In particular, this would be one of the largest analyses in the setting of a prospective trial. We hope that this gives us powerful information that can help guide us in coming up with rational and more effective immunotherapy combinations. Durvalumab has great potential for future combination immunotherapy trials, especially noting it’s favorable adverse effect profile and increasing clinical experience. – by Rob Volansky

 

For more information:

Gentry T. King, MD, can be reached at University of Colorado, Denver, Medical Oncology, MS 8117, 12801 E. 17th Ave. 8101, 8th Floor, Aurora, CO 80045; email: gentry.king@ucdenver.edu.

 

Disclosure: King reports no relevant financial disclosures.

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