Efficacy and Safety of pIL-12
A single-arm, open-label phase 2 study (ClinicalTrials.gov Identifier: NCT01502293) treated 29 patients with in-transit or M1a melanoma with up to 4 cycles of pIL-12. The overall response rate (ORR) was 33%, including a complete response (CR) among 11% of patients. Interestingly, noninjected lesions regressed among 62% of evaluable patients.3
“We also see evidence of systemic immune responses in patients’ blood when we compare circulating immune cells before and after pIL-12 treatment,” said Dr Algazi, noting that intratumoral therapy “can stimulate a whole-body immune response.”
An exploratory analysis of this study demonstrated that the number of natural killer (NK) cells increased by about 2-fold at days 11 and 39 after treatment with pIL-12 compared with pretreatment.
There were no grade 3 to 4 adverse events (AEs), and the most common grade 1 to 2 drug-related AEs were transient pain and inflammation at the treatment site.
Combining pIL-12 With Systemic Immunotherapy
Another phase 2 study treated 34 patients with stage III to IV melanoma with pIL-12, of whom, 14 subsequently received a systemic anti-PD-1 or -PD-L1 antibody. Among these patients, the best overall response rate (BOR) was 64%, with 36% of patients achieving CR, 29% partial response (PR), and 14% stable disease. The BOR was 75%, with 50% CR and 25% PR rates, among patients who received a PD-1/PD-L1 inhibitor without other intervening therapy after pIL-12.4
The rationale, according to Dr Algazi, is promoting an immune response through 2 different mechanisms. “Anti-PD-1 antibodies tend not to work if no immune cells are present or if there aren’t enough proinflammatory signals. pIL-12 increases immune cell infiltration and inflammatory signals — pIL-12 helps ‘tune in’ immune cells and pembrolizumab helps ‘turn on’ dormant immune cells.”
A combination phase 2 study treated patients with CD8+ tumor infiltrating lymphocytes with less than 25% PD-1hiCTLA-4+ melanoma with pIL-12 and pembrolizumab. The ORR was 40%, and patients who responded demonstrated increased number and ratio of CD8+:PD-L1+ expression, upregulation of NK cells, and increased clonality of T cells compared with non-responders.5
“A confirmatory trial is starting now and a larger, randomized phase 3 study is planned,” said Dr Algazi.
The open-label, phase 2 PISCES trial (ClinicalTrials.gov Identifier: NCT03132675) was initiated in early 2017 and will enroll patients with stage III or IV melanoma who have progressed during treatment with pembrolizumab or nivolumab. Patients will receive pIL-12 plus pembrolizumab for 24 weeks and after completion of treatment can enter a long-term extension study.6
PISCES is expected to begin enrollment of about 48 patients in June 2017, with final data collected expected early September 2018.
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Dr Algazi noted that provisional approval prior to completion of the phase 3 trial is possible, if the PISCES trial confirms the results from the previous phase 2 studies.
- Agarwala SS. The role of intralesional therapies in melanoma. Oncology (Williston Park). 2016;30:436-41.
- OncoSec granted Orphan Drug Designation from the U.S. FDA for the treatment of unresectable metastatic melanoma [news release]. San Diego, CA: PR Newswire; June 8, 2017. http://www.prnewswire.com/news-releases/oncosec-granted-orphan-drug-designation-from-the-us-fda-for-the-treatment-of-unresectable-metastatic-melanoma-300471377.html. Accessed June 27, 2017.
- Daud A, Algazi AP, Ashworth MT, et al. Systemic antitumor effect and clinical response in a phase 2 trial of intratumoral electroporation of plasmid interleukin-12 in patients with advanced melanoma. J Clin Oncol. 2014;32(suppl; abstr 9025).
- Algazi A, Tsai KK, Takamura KT, et al. Intratumoral electroporation of plasmid IL-12 can prime response to anti-PD1/PD-L1 blockade in patients with stage III/IV-M1a melanoma. Paper presented at: AACR 107th Annual Meeting 2016; New Orleans, LA; April 16-20, 2016.
- Algazi AP, Tsai KK, Rosenblum M, et al. Immune monitoring outcomes of patients with stage III/IV melanoma treated with a combination of pembrolizumab and intratumoral plasmid interleukin 12 (pIL-12). Paper presented at: 2017 ASCO-SITC Clinical Immuno-Oncology Symposium; Orlando, FL; February 23-25, 2017.
- Clinicaltrials.gov. pIL-12 and pembrolizumab in patients with stage III/IV melanoma progressing on pembrolizumab or nivolumab treatment (PISCES). NCT03132675. https://clinicaltrials.gov/ct2/show/NCT03132675. Accessed June 2017.