Checkpoint Blockade Therapy Clears Safety Hurdle for Patients With HIV and Cancer

Thomas S. Uldrick, MD

Although there has been reluctance among oncology researchers to administer immunotherapy to patients with HIV who develop cancer, early signals from a small clinical trial suggest that such a strategy may be safe in certain settings.

Pembrolizumab (Keytruda) demonstrated an acceptable safety profile when given concurrently with antiretroviral therapy (ART) for patients with HIV and relapsed, refractory, or disseminated malignancies, according to interim results of the CTIN-12 clinical trial.

The early results were from the first 17 patients with HIV and various advanced cancers enrolled in the small multicenter phase I study. Only 1 unacceptable adverse event (AE) had been observed to date, justifying further evaluation of checkpoint inhibitors in patients with HIV-associated cancers, according to lead investigator Thomas S. Uldrick, MD.

“Anti—PD-1 therapy should be considered in patients with HIV and malignancies with FDA-approved indications,” Uldrick, clinical director of HIV and AIDS malignancies at the National Cancer Institute, said during a presentation at the 2017 Society for Immunotherapy of Cancer Annual Meeting. “The study also demonstrates a feasibility of including patients with HIV on immunotherapy studies, and we believe that patients with HIV who meet appropriate eligibility criteria for a given cancer should be included in immunotherapy studies.”

Cancer is the leading cause of morbidity in patients living with HIV, who account for over 35 million individuals worldwide, said Uldrick. Yet, patients with HIV have been excluded from clinical trials for immune checkpoint inhibitors, he continued.

Concerns regarding safety are due, in part, to the unknown clinical significance of HIV-associated immune dysregulation. PD-1 is upregulated in both CD4 and CD8 cells in relation to HIV viremia and is inversely related to the degree of immunosuppression, Uldrick noted. Concerns also exist over concurrent infections in this population, as well as the unexpected toxicities from giving a PD-1 inhibitor in addition to ART.

Patients were studied in 3 parallel cohorts based on their CD4-positive T-cell counts. Patients with 100 to 199 CD4-positive T cells/ mcL were included in cohort 1, 200 to 350 T cells/mcL in cohort 2, and more than 350 CD4- positive T cells/mcL in cohort 3. Patients with hepatitis B or C infection were not eligible for inclusion in the study, nor were patients with prior allogeneic stem cell transplant or uncontrolled central nervous system disease.

Pembrolizumab was administered at 200 mg intravenously every 3 weeks for up to 2 years, and ART was started at least 4 weeks prior to enrollment to maintain HIV control. Patients had a median of 56 years and had an ECOG performance status of 0 (47%) or 1 (53%). Patients had received a median of 1 prior cancer therapy (range, 0-4), and 71% had received prior radiation. Thirteen patients had non-AIDS defining cancers, including 5 with anal cancer and 1 each with head and neck cancer, metastatic squamous cell carcinoma of the skin, non—small cell lung cancer, hepatocellular carcinoma, sarcomatoid lung cancer, transitional cell carcinoma, pancreatic cancer, and cholangiocarcinoma. Of the AIDS-defining cancers, 2 had primary effusion lymphoma and 1 each had Kaposi sarcoma and diffuse large B-cell lymphoma.

Median CD4-positive T-cell counts tended to increase over time; however, Uldrick noted that this was not deemed to be statistically significant. The 17 patients received pembrolizumab for a median of 4 cycles (range, 1-20). Interim findings showed that 82 treatment-emergent AEs (TEAEs) were observed that were considered possibly due to pembrolizumab; 93% of these were grade 1 or 2. Frequent TEAEs of any grade included anemia in 64.7% of patients, hypothyroidism in 35.3%, abdominal pain in 23.5%, nausea in 29.4%, fatigue in 41.2%, and alkaline phosphatase increase, lymphocyte decrease, and pruritus in 23.5% each.

Grade 3/4 TEAEs included 3 cases of anemia and 1 each of alanine aminotransferase (ALT) increase, aspartate aminotransferase (AST) increase, and neutrophil decrease. Uldrick noted that there were no differences in the rates of grade 3/4 AEs between the 3 cohorts.

Immune-related AEs (irAEs) included hypothyroidism in 35.3%, ALT increase in 17.6%, joint stiffness in 5.9%, and pneumonitis in 11.8%; all were grade 1 to 3 in severity. These irAEs required therapy, which was managed with levothyroxine for 6 patients and steroids for 4.

There were 10 serious AEs across the study, all 2 to 4 in severity. “Almost all of them were attributable to the underlying cancer, with only 1 case at least possibly due to pembrolizumab, and that was ALT/AST elevations.” In this patient with sarcomatoid lung cancer and liver metastases who experienced an unacceptable toxicity, Uldrick noted that they found T-cell infiltrates in the viable tumor and strong PD-L1 expression. Additionally, he had a high CD4-positive T-cell count of 382 cells/mcL.

One unanticipated problem that came up after the interim analysis of 17 patients was a patient with disseminated Kaposi sarcoma herpesvirus (KSHV) who died during the trial. “It’s unknown if this was due to pembrolizumab; it’s possibly due to pembrolizumab. The alternative explanation is that’s due to the fact that we stopped his previous paclitaxel, which was received with steroids every 2 to 3 weeks,” Uldrick said.

This was not observed in 4 other patients with Kaposi sarcoma (KS) or 2 with primary effusion lymphoma, and he believed that this did not take away from the safety data of the trial. However, special consideration should be given to patients with KSHV-associated Multicentric Castleman disease or unexplained KSHV viremia, Uldrick said.

Enrollment is ongoing for this study, with 36 patients expected to be included (NCT02595866). Additionally, Uldrick hopes to further investigate pembrolizumab in patients with KS.

Uldrick TS, Gonçalves PH, Fling SP, et al. Interim safety analysis of Cancer Immunotherapy Trials Network — 12 (CITN-12): a phase 1 study of pembrolizumab in patients with HIV and relapsed, refractory or disseminated malignancies. Presented at: 32nd SITC Annual Meeting; November 8-12, 2017; National Harbor, MD. Abstract O40.