Novel Combo Elicits Clinical Responses in Patients With "Cold" Melanomas

Combining the PD-1 inhibitor pembrolizumab (Keytruda) with intratumoral plasmid interkeukin-12 (IL-12; tavokinogene telseplasmid; Tavo) electroporation elicited clinical responses in patients with immunologically quiescent advanced melanoma, according to results of a single-arm, phase 2 study (NCT02493361) published in Clinical Cancer Research.¹

Notably, the combination demonstrated a 41% objective response rate (n = 22; RECIST 1.1), which included a 36% complete response (CR) rate.

At a median follow-up of 20.1 months, the median progression-free survival was 5.6 months, and the median overall survival was not reached.

“Combining pembrolizumab with Tavo electroporation improved responses for these patients who were predicted to have very poor responses to single-agent immune checkpoint inhibition,” said corresponding study author Adil Daud, MD, director of Melanoma Clinical Research at the University of California, San Francisco Helen Diller Family Comprehensive Cancer Center.² “By using electroporation to deliver Tavo locally, we were able to avoid many of the toxicities associated with systemic IL-12 administration, while still attaining clinical responses and inducing immune-cell infiltration in treated and untreated melanoma lesions.”

Forty-one patients were screened for trial enrollment, all of whom were 18 years of age or older and had metastatic or unresectable melanoma with accessible lesions. Eligible patients had a CD8+ checkpoint positive cytotoxic lymphocytes percentage of less than 25%, according to baseline tumor biopsy results (n = 23). All but 1 of these patients had RECIST measurable disease at baseline.

Ten patients had prior exposure to PD-L1 inhibitors and 7 had prior exposure to CTLA-4 inhibitors. Patients on current immunosuppressive therapies, or those with uveal melanoma, active central nervous systemic metastases, carcinomatous meningitis, or active autoimmune disease requiring immunosuppressive agents were not included in the trial.

Tavo was given via injection at a dose of one-quarter of the patient’s tumor volume and a concentration of 0.5 mg/mL. The injection was followed by in vivo electroporation of 6 pulses at 1500 V/cm field strength and a pulse width of 100 µs at 300-millisecond intervals; moreover, at least 0.1 mL of Tavo was injected for every lesion less than 0.1 cm³. Pembrolizumab was given intravenously at a flat dose of 200 mg.

Notably, Tavo was delivered via electroporation directly into the melanoma lesions to avoid the toxicities of conventional systemic IL-12 administration.

Additionally, Tavo and pembrolizumab were given concurrently on day 1. Pembrolizumab was continued on day 1 of each 3-week cycle, and Tavo was continued on days 1, 5, and 8 of every other cycle.

The regimen was continued for up to 2 years if patients had stable disease or better. Patients were allowed to continue on treatment until disease progression was confirmed.

The tumor specimens that were evaluated had a low likelihood of response to PD-L1 inhibition based on predictive PD-L1 immunohistochemistry (IHC) biomarker assays that tested the 22C3 monoclonal antibody and IFNγ gene expression signatures.

“Immune checkpoint inhibition has become a common first-line treatment for melanoma in recent years,” said Daud. “However, approximately 40% of melanomas are considered to be ‘cold,’ meaning that they lack sufficient infiltration of immune cells within the tumor and therefore have poor responses to this therapy. The big question in the field is how to turn these ‘cold’ melanomas into ‘hot’ ones that will respond to immune checkpoint inhibition.”

A proportion of the patients who achieved an objective response had elevated lactate dehydrogenase at baseline, prior anti–PD-L1 exposure, or stage IIIb to IVc disease. Additionally, clinical responses were observed regardless of tumor-infiltrating lymphocyte (TIL) levels or IHC-measured PD-L1 protein levels at baseline.

One patient who had greater than 50 in-transit lesions at baseline and progressed on 3 prior checkpoint inhibitors achieved a partial response prior to developing progressive disease on the combination. A posttreatment biopsy revealed that the patient’s lesions showed a siderotic scar, with no evidence of residual melanoma by histopathology.

Further results revealed that 29.2% of untreated metastatic lesions, including those in the liver and lungs, decreased by more than 30% in width.

Additionally, natural killer T cells, T-cell trafficking and costimulation, cDC1-associated antigen presentation genes, antigen cross-presentation, T-cell activation and adaptive resistance-associated genes were increased with the combination.

A correlative analysis revealed that the combination enhanced immune infiltration and sustained the IL-12/IFNγ feed-forward cycle, driving intratumoral cross-presenting dendritic cell subsets with increased TILs, emerging T-cell receptor clones, and systemic cellular immune responses.

Regarding safety, the combination was well tolerated. Grade 3 or higher treatment-related adverse events (AEs) were limited to pain (n = 1), cellulitis (n = 1), chills (n = 1), and sweats (n = 1).

“While our results are promising, a key limitation to this approach is that approximately 60% of patients still did not respond,” said Daud.

Despite this, studies are underway to further understand how to increase responses. A phase 2 study (NCT03132675) with pembrolizumab combined with Tavo is ongoing in patients who progressed on prior checkpoint inhibition.

References

1. Algazi AP, Twitty CG, Tsai KK, et al. Phase II trial of IL-12 plasmid transfection and PD-1 blockade in immunologically quiescent melanoma. [published online ahead of print May 6, 2020] Clin Can Research. doi:10.1158/1078-0432.CCR-19-2217
2. Interleukin-12 Electroporation May Sensitize Immunologically “Cold” Melanomas to Immune Checkpoint Inhibition [press release]. Philadelphia, PA: American Association for Cancer Research. May 6, 2020. Accessed May 11, 2020. bit.ly/2ztRepB.