Meeting NewsPerspective

Immunotherapy, chemotherapy combination shows promising antitumor activity in metastatic pancreatic cancer

ATLANTA — The combination of the experimental CD40 antibody APX005M with nivolumab and standard chemotherapy demonstrated a manageable safety profile and promising antitumor activity among previously untreated patients with metastatic ductal pancreatic adenocarcinoma, according to results of an open-label, multicenter study presented at American Association for Cancer Research Annual Meeting.

Patients with ductal pancreatic adenocarcinoma have not derived benefit from single-agent anti-PD-1 agents. Because preclinical data suggest chemotherapy with agonistic CD40 antibodies may trigger effective T-cell immunity when combined with anti-PD-1 therapy, researchers evaluated the safety and efficacy of the combination of APX005M (Apexigen) with nivolumab (Opdivo, Bristol-Myers Squibb) and standard gemcitabine and nab-paclitaxel chemotherapy.

“The idea is to attack the cancer from different angles,” Robert H. Vonderheide, MD, DPhil, member of the Cancer Research Institute Clinical Accelerator leadership and director of Abramson Cancer Center of University of Pennsylvania, said in a press release. “Although the results are early, we see encouraging signs that anti-CD40 immunotherapy, checkpoint inhibition and chemotherapy in combination could be an effective new approach to treat patients with metastatic pancreatic cancer.”

Researchers enrolled 30 patients (median age, 66 years; range, 39-79; men, 53.3%) into four therapy cohorts, which included gemcitabine and nab-paclitaxel with 0.1 mg/kg APX005M (n = 7), 0.3 mg/kg APX005M (n = 7), nivolumab and 0.1 mg/kg APX005M (n = 8), or nivolumab and 0.3 mg/kg APX005M (n = 8).

Safety and determining the recommended phase 2 dose of APX005M served as the study’s primary objectives.

Secondary objectives included tumor response and immune pharmacodynamics.

Median time on treatment was 30.3 weeks (range, 0.4-59.1+).

“One concern about combining standard-of-care chemotherapy with two different immunotherapy agents is that patients may received fewer doses of chemotherapy agents than if they had just received chemotherapy alone,” Mark H. O'Hara, MD, assistant professor of medicine at the Hospital of the University of Pennsylvania, said during his presentation. “This in fact was not the case for this trial. Overall, we noted that exposure to all drugs on trial was 85%.”

Twenty-four patients — six from each cohort — were evaluable for dose-limiting toxicity, including patients who received at least one dose of APX005M and two or more doses of chemotherapy during cycle 1 and remained on the study through day 1 of cycle 2.

Thirteen patients (54%) evaluable for dose-limiting toxicity experienced an adverse event that led to treatment discontinuation, and 10 patients (42%) experienced a serious treatment-related adverse event.

Two dose-limiting toxicities occurred — grade 3 and grade 4 febrile neutropenia — in the second and third dosing cohorts.

“These were thought to be related to chemotherapy and not treatment with APX005M or nivolumab,” O’Hara said.

The most common grade 3 to grade 4 adverse events thought to be related to APX005M included lymphocytopenia, anemia, fatigue and increased aspartate aminotransferase. Researchers did not observe any cases of grade 3 or grade 4 cytokine release syndrome.

Four patients (17%) died due to disease progression (n = 2) or sepsis and septic shock in the setting of neutropenia (n = 2).

Researchers recommended a phase 2 dose of 0.3 mg/kg APX005M given with gemcitabine and nab-paclitaxel with or without nivolumab

Among patients evaluable for dose-limiting toxicity, 13 (54%) achieved a partial response, nine (38%) achieved stable disease, one (4%) demonstrated progressive disease and one patient was not evaluable.

Two of the six dose-limiting toxicity-inevaluable patients showed stable disease (n = 1) or confirmed partial response (n = 1) on post-baseline tumor assessments.

When researchers evaluated circulating tumor DNA for mutated KRAS DNA, they observed a rapid decrease in some patients, which correlated with tumor shrinkage, O’Hara said. Also, baseline and on-treatment immune profiling of peripheral blood mononuclear cells showed remodeling of the myeloid compartment in response to treatment, with most patients showing rapid activation of dendritic cells.

“We are very excited about the encouraging data so far, especially because metastatic pancreatic cancer has a 5-year survival rate of less than 9%, making it an area of high unmet medical need,” Parker Institute for Cancer Immunotherapy’s chief medical officer, Ramy Ibrahim, MD, said in the release. “What we learn in this trial can inform the work being done on other solid tumor types, so that we can make immunotherapy beneficial for more patients. We could not have gotten this far without our partners and Parker Institute for Cancer Immunotherapy’s unique collaborative infrastructure, which allows us to be nimble and follow the science.”

Based on these data, this trial is moving on to a phase 2 analysis. – by Alexandra Todak

Reference:

O’Hara MH. Abstract CT004. Presented at: AACR Annual Meeting: March 29-April 3, 2019; Atlanta.

Disclosures: Vonderheide reports financial relationships with Apexigen, AstraZeneca, Celgene, Eli Lilly, Genentech, Inovio, Janssen, MedImmune, Merck and Verastem. HemOnc Today could not confirm Ibrahim’s relevant financial disclosures at the time of reporting. Please see the abstract for all other authors’ relevant financial disclosures.

ATLANTA — The combination of the experimental CD40 antibody APX005M with nivolumab and standard chemotherapy demonstrated a manageable safety profile and promising antitumor activity among previously untreated patients with metastatic ductal pancreatic adenocarcinoma, according to results of an open-label, multicenter study presented at American Association for Cancer Research Annual Meeting.

Patients with ductal pancreatic adenocarcinoma have not derived benefit from single-agent anti-PD-1 agents. Because preclinical data suggest chemotherapy with agonistic CD40 antibodies may trigger effective T-cell immunity when combined with anti-PD-1 therapy, researchers evaluated the safety and efficacy of the combination of APX005M (Apexigen) with nivolumab (Opdivo, Bristol-Myers Squibb) and standard gemcitabine and nab-paclitaxel chemotherapy.

“The idea is to attack the cancer from different angles,” Robert H. Vonderheide, MD, DPhil, member of the Cancer Research Institute Clinical Accelerator leadership and director of Abramson Cancer Center of University of Pennsylvania, said in a press release. “Although the results are early, we see encouraging signs that anti-CD40 immunotherapy, checkpoint inhibition and chemotherapy in combination could be an effective new approach to treat patients with metastatic pancreatic cancer.”

Researchers enrolled 30 patients (median age, 66 years; range, 39-79; men, 53.3%) into four therapy cohorts, which included gemcitabine and nab-paclitaxel with 0.1 mg/kg APX005M (n = 7), 0.3 mg/kg APX005M (n = 7), nivolumab and 0.1 mg/kg APX005M (n = 8), or nivolumab and 0.3 mg/kg APX005M (n = 8).

Safety and determining the recommended phase 2 dose of APX005M served as the study’s primary objectives.

Secondary objectives included tumor response and immune pharmacodynamics.

Median time on treatment was 30.3 weeks (range, 0.4-59.1+).

“One concern about combining standard-of-care chemotherapy with two different immunotherapy agents is that patients may received fewer doses of chemotherapy agents than if they had just received chemotherapy alone,” Mark H. O'Hara, MD, assistant professor of medicine at the Hospital of the University of Pennsylvania, said during his presentation. “This in fact was not the case for this trial. Overall, we noted that exposure to all drugs on trial was 85%.”

Twenty-four patients — six from each cohort — were evaluable for dose-limiting toxicity, including patients who received at least one dose of APX005M and two or more doses of chemotherapy during cycle 1 and remained on the study through day 1 of cycle 2.

Thirteen patients (54%) evaluable for dose-limiting toxicity experienced an adverse event that led to treatment discontinuation, and 10 patients (42%) experienced a serious treatment-related adverse event.

Two dose-limiting toxicities occurred — grade 3 and grade 4 febrile neutropenia — in the second and third dosing cohorts.

“These were thought to be related to chemotherapy and not treatment with APX005M or nivolumab,” O’Hara said.

The most common grade 3 to grade 4 adverse events thought to be related to APX005M included lymphocytopenia, anemia, fatigue and increased aspartate aminotransferase. Researchers did not observe any cases of grade 3 or grade 4 cytokine release syndrome.

Four patients (17%) died due to disease progression (n = 2) or sepsis and septic shock in the setting of neutropenia (n = 2).

Researchers recommended a phase 2 dose of 0.3 mg/kg APX005M given with gemcitabine and nab-paclitaxel with or without nivolumab

Among patients evaluable for dose-limiting toxicity, 13 (54%) achieved a partial response, nine (38%) achieved stable disease, one (4%) demonstrated progressive disease and one patient was not evaluable.

Two of the six dose-limiting toxicity-inevaluable patients showed stable disease (n = 1) or confirmed partial response (n = 1) on post-baseline tumor assessments.

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When researchers evaluated circulating tumor DNA for mutated KRAS DNA, they observed a rapid decrease in some patients, which correlated with tumor shrinkage, O’Hara said. Also, baseline and on-treatment immune profiling of peripheral blood mononuclear cells showed remodeling of the myeloid compartment in response to treatment, with most patients showing rapid activation of dendritic cells.

“We are very excited about the encouraging data so far, especially because metastatic pancreatic cancer has a 5-year survival rate of less than 9%, making it an area of high unmet medical need,” Parker Institute for Cancer Immunotherapy’s chief medical officer, Ramy Ibrahim, MD, said in the release. “What we learn in this trial can inform the work being done on other solid tumor types, so that we can make immunotherapy beneficial for more patients. We could not have gotten this far without our partners and Parker Institute for Cancer Immunotherapy’s unique collaborative infrastructure, which allows us to be nimble and follow the science.”

Based on these data, this trial is moving on to a phase 2 analysis. – by Alexandra Todak

Reference:

O’Hara MH. Abstract CT004. Presented at: AACR Annual Meeting: March 29-April 3, 2019; Atlanta.

Disclosures: Vonderheide reports financial relationships with Apexigen, AstraZeneca, Celgene, Eli Lilly, Genentech, Inovio, Janssen, MedImmune, Merck and Verastem. HemOnc Today could not confirm Ibrahim’s relevant financial disclosures at the time of reporting. Please see the abstract for all other authors’ relevant financial disclosures.

    Perspective
    Ryan D. Nipp

    Ryan D. Nipp

    Survival for patients with metastatic pancreatic ductal adenocarcinoma can be measured in months, and estimates suggest that pancreatic ductal adenocarcinoma could become the second-leading cause of cancer-related deaths in the next 10 to 15 years. Thus, efforts are urgently needed to develop and test novel therapies for these patients. Notably, studies to date involving immunotherapy for pancreatic ductal adenocarcinoma have not shown promising results, particularly when tested as single agents.

    The primary objectives of this analysis were to evaluate safety and determine the recommended phase 2 dose of APX005M. Secondary objectives included tumor response and, thus, we should cautiously interpret the results regarding response rates in this relatively small, single-arm study. The abstract states that, within the evaluable population, best overall responses included 14 (58%) with partial responses (11 confirmed, 3 unconfirmed) and eight (33%) with stable disease. It also is important to remember that patients received chemotherapy in the form of gemcitabine and nab-paclitaxel, which has demonstrated response rates in prior trials (without immunotherapy).

    Regarding the observed toxicity profile, we would expect some level of adverse events in a population receiving chemotherapy and immunotherapy, as prior studies have shown, and the authors mentioned that the regimen demonstrated a manageable safety profile. This level of adverse events certainly merits detailed discussions with patients about the risks and benefits when considering a regimen such as this.

    We are always encouraged to see new studies of novel treatment options for patients with pancreatic ductal adenocarcinoma, and I look forward to ongoing efforts to determine how best to incorporate immunotherapy into the treatment profile for this population. In the future, we should also consider additional strategies for how to incorporate FOLFIRINOX [leucovorin, fluorouracil, irinotecan and oxaliplatin] into this treatment paradigm as well, considering that many patients receive FOLFIRINOX as a first-line regimen.

    In addition, ongoing work should seek to determine predictive factors that may help clinicians understand which patients may respond best to certain treatment options in pancreatic cancer, and specifically immunotherapy options.

    Importantly, future work needs to include patient-reported outcomes, such as symptom burden and quality of life, to have the patient voice included as part of the narrative when testing novel agents in pancreatic cancer. Lastly, additional work is needed to understand how best to care for the geriatric oncology population with pancreatic cancer, as this group of patients represents those most commonly seen in routine clinical practice.

    • Ryan D. Nipp, MD
    • Massachusetts General Hospital Cancer Center

    Disclosures: Nipp reports no relevant financial disclosures.

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