Plasmid IL-12 Added to Pembrolizumab Elicits Deep and Durable Responses in Advanced Melanoma

The strategy of adding the plasmid IL-12 (pIL-12-EP) agent tavokinogene telseplasmid to pembrolizumab (Keytruda) led to deep systemic responses in patients with actively progressing anti–PD-1–refractory advanced melanoma, according to interim results from the KEYNOTE-695 clinical trial (NCT03132675).

Interim data presented during the Society for Immunotherapy of Cancer (SITC) Virtual Annual Meeting 2020 by Adil Daud, MD, was from 56 out of 100 patients with unresectable or metastatic melanoma who received anti–PD-1 therapy alone or in combination with another agent for 12 weeks prior to study entry. Patients were required to have confirmed RECIST v1.1 progression with no intervening therapy before joining the study and measurable disease per RECIST v1.1.

Pembrolizumab was administered at 200 mg via intravenous infusion every 3 weeks. The pIL-12-EP agent was administered to at least one accessible lesion on days 1, 5, and 8, every 6 weeks. The goal of the study was to determine the objective response rate (ORR) by blinded independent review. The secondary end points of the study include duration of response (DOR), progression-free survival (PFS), immune PFS (iPFS), immune ORR, and overall survival (OS).

Key baseline characteristics showed that the study population was predominantly male (55.4%) with a median age of 66 years (range, 30-86). Most patients (62.5%) had an ECOG performance status of 0 at baseline. BRAF mutations were found in 21.4% of patients and BRAF wild type in 78.6% of patients. Most patient were also stage IVa and b (53.6%) or stage IVc and d (30.4%). The mean number of target lesions was 8.9 (range, 1-169), and the median number of prior therapies was 2.9 (range, 1-17).

“The data demonstrate that the addition of pIL-12-EP to PD-1 antibody therapy induces a high complete response rate of 6% (3/54 evluated patients) and a best in class overall response rate of 30% (16/54 evaluated patients) in a clinically proven PD-1 antibody refractory patient population as determined by rigorous enrollment criteria. The data are extremely relevant since checkpoint resistant metastatic melanoma patients currently rely on systemic administration of immune-stimulating drugs associated with severe toxicity,” Daud, HS clinical professor, Department of Medicine (Hematology/Oncology), UCSF; director, Melanoma Clinical Research, UCSF Helen Diller Family Comprehensive Cancer Center, told Targeted Oncology in an interview.

Complete responses (CRs) in 6% of patients and partial response in 24% contributed to the 30% (95% CI, 18.0%-43.6%) ORR. Stable disease (SD) was also observed in this study, in 19% of patients. It was also shown that 52% of patients had progressive disease (PD). Notably, 2 patients from the study were not evaluable for response.

ORR was also assessed in the subset of 17 patients with M1c/M1d disease and a higher ORR of 35.3% was reported. The 15 patients who received prior ipilimumab (Yervoy) achieved an even higher ORR of 40%.

Based on the response observed with tavokinogene telseplasmid plus pembrolizumab, investigators noted that the lesions treated were predominantly skin/subcutaneous lesions (82%) or local and regional lymph node lesions (18%). Untreated lesions were mainly those found in the kidney, liver, lung, and other visceral metastases (45%). However, the combination left 25% of lymph node lesions and 15% of lymph node distant lesions untreated as well.

In explanation of these data, Daud said, “additionally, this research shows deep responses in 9% of patients (5/54 patients), who had 100% reduction of target lesions. Also remarkable is the high response rate of 35.3% (n=6/17) in patients with metastatic M1c/M1d disease. Patients at this stage usually have a poor prognosis and often do not respond to current treatments.”

Investigators looked closely at patients with actively progressing disease and how prior anti–PD-1 treatment impacted response to therapy in this study. It was shown that patients who had anti–PD-1 therapy within 1.2 months of entering the study were more likely to have a CR or PR. Moreover, SD was achieved more often in patients who received prior immune checkpoint inhibition within roughly 1.2 months of joining KEYNOTE-695.

According to Daud, the data further demonstrates that tavokinogene telseplasmid intratumoral approach leads to a systemic/whole body effect, since tumor responses were observed in distant and visceral lesions. Responses were durable with a current median duration of response (mDOR) of 12.2 months censored before 12 months. All responses are confirmed by investigator assessed RECIST v1.1

The safety of this combination was shown through the emergence of treatment-related adverse events (TRAEs). The most common (>5%) any-grade TRAEs were fatigue (26.8%), procedural pain (23.2%), and diarrhea (19.6%). Most event were grades 1 and 2, but grade 3 events were observed in 5.4% of patients. The grade 3 TRAEs included cellulitis, enteritis, and lichen planus (1 patient each).

In the interview, Daud describe the safety profile of tavokinogene telseplasmid plus pembrolizumab as “an unparalleled safety profile vs current standard of care.” He also stated, “due to the unique approach of intratumoral delivery of plasmid DNA via electric gene transfer system, we observe increase in the levels of immune-stimulating IL-12 in the tumor without increasing IL-12 levels in the blood or elsewhere, avoiding systemic toxic effects. Our study only showed grade 3 treatment-related adverse events in 5.4% of patients and no grade 4/5 treatment-related AEs.”

On-treatment biomarker signatures were tested and showed the ability of the combination to make immunologically quiescent tumors achieve local and systemic immune responses. Specifically, patients who responded to treatment had significantly more CD8+ tumor-infiltrating lymphocytes compared with those who did not respond after only 1 cycle of treatment. Responders to tavokinogene telseplasmid plus pembrolizumab also had significantly more cancer-targeting t-cell receptor clones compared with non-responders after treatment. Additionally, responders showed an increase in short-lived effector cells and fewer myeloid-derived suppressor cells compared with non-responders. The responders also had a greater frequency of Cloistridiales microbiota versus non-responders.

The interim results from KEYNOTE-695 suggest a potential to use similar combinations in the future as treatment of patients with advanced melanoma, Daud explained.

“We believe intratumoral therapy will be pulled forward in treatment of patients because of its safety profile, patient experience and ease of use. Intratumoral therapy is both practice and patient friendly. It presents off-the-shelf availability and offers ease of administration to accessible lesions within 10 minutes on average in an outpatient setting. Patients do not require post-treatment observation, such as waiting in an infusion clinic post treatment. In addition, it does not require high blood sugar level special handling like talimogene laherparepvec.”

_Reference:

_{Fernandez-Penas P, Carlino MS, Tsai KK, et al. Durable responses and immune activation with intratumoral electroporation of pIL-12 plus pembrolizumab in actively progressing anti-PD-1 refractory advanced melanoma: KEYNOTE 695 interim data. Presented at the 2020 SITC Virtual Annual Meeting; November 9-14, 2020. Abstract 799.}