Addition of GX-188E to pembrolizumab improves response rate in advanced cervical cancer
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The combination of pembrolizumab and GX-188E, a DNA vaccine targeting HPV types 16 and 18, conferred high response rates compared with pembrolizumab alone among a cohort of women with advanced, inoperable or metastatic cervical cancer, according to results of an interim analysis presented at the virtual American Association for Cancer Research Annual Meeting.
Additionally, the combination treatment and pembrolizumab monotherapy had similar safety profiles.
“HPV types 16 and 18 are the most persistent high-risk cervical cancer types and are responsible for nearly 70% of all cervical cancers,” Jung Won Woo, PhD, executive vice president of Genexine Inc. in South Korea, said during a presentation. “Previous research has shown that pembrolizumab [Keytruda, Merck] monotherapy in women with previously treated advanced cervical cancer was effective in certain patients.”
Results of the KEYNOTE-158 trial led to FDA approval of pembrolizumab for women with relapsed or metastatic cervical cancer whose disease progressed on or after chemotherapy and whose tumors express PD-L1.
In the current prospective, open-label, phase 2 study, Woo and colleagues hypothesized that pembrolizumab plus GX-188E (Genexine) would provide synergistic antitumor effects. The interim analysis included 22 women (median age, 52 years; range, 27-68) with advanced, inoperable or metastatic cervical cancer. All women had ECOG performance status of 0 to 1, were HPV 16- and/or 18-positive, and had failed all available standard-of-care options, including surgery, chemotherapy and radiotherapy, or refused two or more lines of treatment.
The women received 2 mg GX-188E intramuscularly seven times at weeks 1, 2, 4, 7, 13, 19 and 46 plus 200 mg IV pembrolizumab every 3 weeks for up to 2 years or until disease progression.
Assessment of preliminary antitumor efficacy, safety and tolerability served as objectives of the interim analysis.
Median follow-up was 5.3 months (range, 0.9-16.3) at the time of data cutoff.
Results showed an objective response rate of 42.3%. Four women experienced complete response, seven experienced partial response and one had stable disease at week 14. More than three-quarters of women (78.3%) demonstrated HPV-specific T-cell responses.
Median PFS was 4.1 months (range, 1.7 to not reached). Median OS and duration of response were not yet reached.
Researchers observed high response rates in PD-L1-positive (50%), HPV type 16 (47.4%) and squamous cell carcinoma (45%) tumors. A therapeutic effect of the combined therapy also was observed in PD-L1-negative and HPV type 18 tumors (28.6% for both).
The most common adverse events associated with pembrolizumab plus GX-188E were gastrointestinal disorders (20.8%) and respiratory, thoracic and mediastinal disorders (16.7%), which mirrored those of pembrolizumab alone.
Further evaluation of antitumor response and antigen-specific immune response is ongoing among a larger number of patients with and without PD-L1 expression, according to the researchers.
“GX-188E combined with pembrolizumab is a safe, effective treatment for patients with HPV types 16 and 18 recurrent or metastatic cervical cancer who failed on standard-of-care treatment,” Woo said. “We are now considering testing the combination in other HPV type 16- and 18-induced cancers, such as in patients with head and neck cancers. At this time, we do not have a clear plan for this research, but we are very interested in expanding the indication for this combination treatment.” – by Jennifer Southall
Reference:
Woo JW, et al. Abstract CT033. Presented at: AACR Annual Meeting; April 27-28, 2020 (virtual meeting).
Disclosures: The study was funded by National Onco Venture in Korea. Merck Sharp & Dohme Corp. provided pembrolizumab for the study. Woo reports financial relationships with Genexine. Please see the abstract for all other researchers’ relevant financial disclosures.
Perspective
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Mihaela Cristea, MD
On June 12, 2018, the PD-1 receptor inhibitor pembrolizumab received FDA approval for recurrent or metastatic cervical cancer with PD-L1 expression that progressed after at least one line of chemotherapy based on the cervical cancer cohort of the KEYNOTE-158 study.
GX-188E is a therapeutic DNA vaccine encoding the E6/E7 fusion protein of HPV subtypes 16 and 18, the most common HPV types involved in cervical carcinogenesis. This vaccine may elicit a cytotoxic T-lymphocyte (CTL) response against cervical cancer cells expressing E6 and E7 oncoproteins, resulting in tumor cell lysis.
At AACR, Hur and colleagues presented the preliminary efficacy and safety results of a phase 2 study of pembrolizumab and GX-188E for patients with HPV 16-positive and/or HPV 18-positive advanced cervical cancer who have failed all available standard-of-care therapies. The investigators reported an impressive overall response rate of 45.5% compared with a 14.3% historical response to single-agent pembrolizumab, without new safety signals. This suggests great synergy between GX-188E and pembrolizumab and, in contrast to pembrolizumab monotherapy, responses were independent of PD-L1 expression.
It is too early to know if these initial responses will translate into long-lasting immunity, and the modest PFS reported at this interim analysis may be related to the short follow-up. Provided these early results are validated in a larger number of patients, the combination of GX-188E and pembrolizumab may establish a new paradigm in the treatment of advanced cervical cancer.
Perspective
Back to TopNina Bhardwaj, MD, PhD
Woo and colleagues are to be congratulated for this study, and I am looking forward to the results of the expansion cohort. Whether or not this will ever become first-line therapy is still unknown, so we will have to wait and see. GX-188E introduces potent viral antigens on strong adjuvant platforms to induce polyfunctional T-cell immunity associated with HPV clearance. It has shown promising antitumor activity, also among PD-L1-positive patients. An immunotherapy-based combination of vaccine and anti-PD-1 may improve antitumor immunity by activating, expanding and recruiting T cells into the tumor microenvironment. A manageable safety profile was observed, and identification of correlates and response or resistance will inform further adaptation of combined immunotherapy.
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