GX-188E Plus Pembrolizumab Proves Safe, Effective in HPV16/18+ Recurrent or Metastatic Cervical Cancer

The therapeutic DNA vaccine, GX-188E, in combination with pembrolizumab (Keytruda) produced encouraging responses in patients with human papillomavirus (HPV) 16- or 18-positive, recurrent or metastatic cervical cancer who did not respond to standard-of-care treatment, according to data from an ongoing phase 1b/2 trial (NCT03444376).

In the 60 patients who comprised the efficacy set, the combination regimen elicited an objective response rate (ORR) of 31.7% (95% CI, 20.3%-45.0%), which was comprised of a complete response rate of 10.0%, a partial response rate of 21.7%, and a stable disease rate of 16.7%. Moreover, 51.7% of patients experienced disease progression. The disease control rate (DCR) in this population was 48.3% (95% CI, 35.2%-61.6%).

Among the 19 patients who responded to treatment, the median duration of response (DOR) was 12.3 months (95% CI, 7.8-16.9). The median progression-free survival (PFS) with the regimen was 3.0 months (95% CI, 0.3-5.8), and the median overall survival (OS) was 17.2 months (95% CI, 6.6-27.8).

“[The regimen] was safe and tolerable—comparable to pembrolizumab monotherapy,” lead study author Sung-Jong Lee, PhD, MS, of the Catholic University of Korea, Seoul St. Mary’s Hospital, Seocho-gu, Seoul, Korea, said in a presentation on the data delivered at the 2022 ESMO Congress. “A phase 3 clinical trial is warranted based on [the] promising efficacy and safety [observed] in this trial.”

The open-label, early-phase trial enrolled previously treated patients with recurrent, persistent, and metastatic cervical cancer who had measurable disease by RECIST v1.1 criteria, HPV 16 or 18 positivity, an ECOG performance status of 0 or 1, and a life expectancy of at least 6 months.

A total of 65 patients were enrolled to the trial, and they were vaccinated with GX-188E at 2 mg intramuscularly at weeks 1, 2, 4, 7, 13, and 19. Patients were also intravenously administered pembrolizumab at 200 mg every 3 weeks.

Participants underwent a tumor assessment at 10 weeks; they were evaluated every 9 weeks thereafter. Four weeks after disease progression, a confirmatory assessment was conducted.

ORR by RECIST v1.1 criteria served as the primary objective for the research. Key secondary objectives included DCR, DOR, PFS, OS, and safety. Exploratory objectives comprised T-cell response analysis, as well as evaluation of biomarkers such as PD-L1, CEA, TA4, and others.

The median age of the 65 patients who received treatment was 53 years (range, 27-79). Most patients (60.0%) had a PD-L1 combined positive score (CPS) of 1 or more, the remainder had negative status. Moreover, 49.2% of patients had an ECOG performance status of 0, and 50.8% had a status of 1. Regarding HPV type, 75.4% had HPV 16, 23.1% had HPV 18, and 1.5% had both. Most patients (76.9%) had squamous cell carcinoma (SCC), but the remaining 23.1% of patients had adenocarcinoma (AC). The number of prior lines of adjuvant and/or neoadjuvant treatment received was 3, with 44.6% of patients having received 1 line, 35.4% having received 2 lines, and 15.4% having received 3 or more lines.

Additional data showed that the combination produced relatively higher ORRs in those with PD-L1 positivity and those with SCC.

The regimen induced an ORR of 36.1% (95% CI, 20.8%-53.8%) in those with PD-L1–positive status (n = 36) vs 25.0% (95% CI, 9.8%-46.7%) in those with negative status (n = 24); the CBRs in these groups were 55.6% (95% CI, 38.1%-72.1%) and 37.5% (95% CI, 18.8%-59.4%), respectively.

Among those who responded, those with PD-L1 positivity (n = 13) experienced a median DOR of 12.3 months vs 14.4 months in those with negative status (n = 6). In the PD-L1–positive group, the median PFS was 4.4 months and the median OS was 23.8 months. In the PD-L1–negative group, the median PFS and OS were 2.1 months and 14.0 months, respectively.

In those with HPV16 (n = 45), the ORR achieved with the regimen was 31.1% (95% CI, 18.2%-46.6%) vs 33.3% (95% CI, 11.8%-61.6%) in those with HPV18 or both (n = 15); the CBRs in these groups were 48.9% (95% CI, 33.7%-64.2%) and 46.7% (95% CI, 21.3%-73.4%), respectively. In those with SCC (n = 46) and AC (n = 14), the ORRs were 32.6% (95% CI, 19.5%-48.0%) and 28.6% (95% CI, 8.4%-58.1%), respectively; the DCRs were 50.0% (95% CI, 34.9%-65.1%) and 42.9% (95% CI, 17.7%-71.1%), respectively.

Regarding safety, any-grade treatment-related adverse effects (TRAEs) were reported in 33.8% of patients; these effects were grade 3 in 4.6% of patients and grade 4 in 1.5% of patients.

The most common TRAEs experienced with the combination regimen were hypothyroidism (13.8%), diarrhea (3.1%), nausea (3.1%), vomiting (3.1%), urticaria (3.1%), increased alanine and aspartate (AST) aminotransferase (3.1% each), increased TSH (3.1%), thyroiditis (1.5%), gastrointestinal pain (1.5%), oral mucositis (1.5%), pruritus (1.5%), rash (1.5%), xerotic eczema (1.5%), increased T3 (1.5%), decreased neutrophil count (1.5%), back pain (1.5%), myalgia (1.5%), extremity pain (1.5%), syncope (1.5%), dizziness (1.5%), and peripheral sensory neuropathy (1.5%).

Grade 3 TRAEs included increased AST (1.5%), decreased neutrophil count (1.5%), and syncope (1.5%). Only 1 grade 4 TRAE of increased ALT was reported.

No treatment-related deaths occurred.

“Overall, GX-188E combined with pembrolizumab was safe and tolerable,” Lee said.

Reference

1. Lee S, Lim M-C, Kim YM, et al. Efficacy and safety of GX-188E, a therapeutic DNA vaccine, combined with pembrolizumab in HPV 16- and/or 18-positive advanced cervical cancer (phase II): safe and effective in both PD-L1 positive and negative. Ann Oncol. 2022;33(suppl 7):S1398. doi:10.1016/j.annonc.2022.08.028