The immune system is a key mediator of tumor destruction, and the introduction of immunotherapy in the treatment of solid tumor malignancies has dramatically expanded the treatment armamentarium. However, malignant cells can evade normal immunological responses through complex mechanisms, including activation of immunosuppression, which allow for unregulated growth. Immune checkpoint blockade (ICB) releases T-cell-negative co-stimulation, which allows for the release of antitumor T-cell responses that can recognize and destroy tumor antigens . Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and programmed cell death protein 1 (PD-1) act as negative regulators, attenuating normal T-cell activation to prevent pathologic over-activation. PD-1 is expressed on the surface of activated T cells, regulatory T cells (Tregs), activated B cells, and natural killer (NK) cells, and inhibits the immunosuppressive PD-1 ligands (PD-L1/PD-L2) expressed by tumor cells .
Unlike in melanoma, lung cancer, and colorectal cancer [3–5], with few exceptions, ICB monotherapy has not been associated with robust antitumor activity in advanced gynecologic cancers [6▪▪,7▪▪,8]. In this review, we highlight the most recent ICB therapy developments and discuss ongoing immunotherapeutic and combination investigative approaches in advanced gynecologic cancers.
In 2019, more than 22 000 new cases of epithelial ovarian cancer will be diagnosed in the United States, of which greater than 70% will be advanced stage. Approximately 14 000 women die from advanced ovarian cancer per year in the United States; because of the late stage at the time of diagnosis, high recurrence rates, and limited options for patients with platinum-resistant disease, the overall 5-year survival rate is only 47% . In ovarian cancer, the tumor immune environment, including the presence of CD3+ tumor-infiltrating T cells and intraepithelial CD8+ tumor-infiltrating lymphocytes (TILs) has been shown to correlate with survival and progression . Numerous immunomodulatory strategies are being explored in advanced ovarian cancer, including ICB approaches; cancer vaccines; and adoptive immunotherapies alone or in combination with other approaches.
Immune checkpoint blockade monotherapy
ICB monotherapy trials with anti-PD-1 and anti-PD-L1 monoclonal antibodies have shown response rates of 15% or less, with some indication that patients with high PD-L1 expression may have improved responses [9,10]. Results from the phase 1b JAVELIN trial demonstrated an objective response rate (ORR) of 9.6% with avelumab (anti-PD-L1) in advanced ovarian cancer (N = 125), and responses occurred regardless of tumor PD-L1 status [11▪]. The phase 2 KEYNOTE-100 trial of pembrolizumab (anti-PD-1) in advanced ovarian cancer was composed of two cohorts [cohort A: one to three three prior lines with a platinum-free interval (PFI) or treatment-free interval (TFI) of 3–12 months; and cohort B: four to six prior lines with a PFI/TFI of ≥3 months]. The ORRs were 7.4 and 9.9%, respectively. Higher PD-L1 expression was correlated with higher response [12▪].
Poly (ADP-ribose) polymerase inhibitors and immune checkpoint blockade
Poly (ADP-ribose) polymerase inhibitors (PARPis) have dramatically changed the treatment paradigm for ovarian cancer in the advanced/recurrent setting but also in the frontline setting, especially for BRCA1/2-mutated high-grade serious ovarian cancers (HGSOCs) . PARP enzymes detect single-stand breaks and mediate DNA repair, and PARPis cause cell death in homologous repair-deficient cells because of increased double-stand DNA breaks. As PARPis drive DNA damage, the rationale is that their use may result in further immune priming for ICB responses . Homologous repair-deficient HGSOCs have higher neoantigen load and TILs, which may result in improved responses to ICB therapy .
Ongoing trials in the frontline setting include phase 3 trials of rucaparib (PARPi) plus the anti–PD-1 nivolumab (ATHENA-NCT03522246) and olaparib (PARPi) plus pembrolizumab (OV43-NCT03740165) as maintenance following platinum-based chemotherapy. In platinum-sensitive recurrent disease, interim results from the phase 2 MEDIOLA study, which looked at the combination of olaparib with durvalumab (PD-L1) for the treatment and maintenance therapy of platinum-sensitive germline BRCA-mutated ovarian cancer (N = 32), showed an impressive ORR of 71.9% [16▪]. However, in platinum-resistant ovarian cancer, results from the phase 1/2 TOPACIO trial demonstrated an ORR of only 18% with the use of niraparib (PARPi) with pembrolizumab (N = 62), regardless of homologous repair status . Confirming preclinical data, these two trials showed that PARPis can augment ICB response in ovarian cancer even in patients with BRCA wild-type status and homologous repair proficiency .
Chemotherapy and immune checkpoint blockade therapy
Two recent phase 3 trials investigated avelumab (anti-PD-L1) with chemotherapy. The JAVELIN Ovarian 100 trial was a three-arm study of avelumab in combination with and/or as a maintenance treatment following carboplatin/paclitaxel chemotherapy in previously untreated advanced/metastatic ovarian cancer; the study was terminated as it failed to meet its primary progression-free survival (PFS) endpoint at the time of planned interval analysis . In the JAVELIN Ovarian 200 trial, platinum-resistant ovarian cancer patients were randomized to avelumab, pegylated liposomal doxorubicin (PLD), or combination therapy. Response rates were 13.3% for the combination, 4.7% for PLD, and 3.7% for avelumab; the study missed the primary endpoints of overall survival (OS) and PFS for superiority . In a small phase 2 study (N = 26), pembrolizumab in combination with PLD (NCT02865811) for recurrent platinum-resistant ovarian cancer showed a response rate of 11.5%, with final maturation of data pending .
Findings from a recent phase 1 study showed the promising activity of the combination of durvalumab (anti-PD-L1), olaparib, and cediranib (antivascular endothelial growth factor [VEGF]) (N = 9), with an ORR of 44% . Studies to further evaluate triplet combinations either with PARPi or anti-VEGF therapy are underway. Combination talazoparib (PARPi), avelumab, and chemotherapy was investigated in the JAVELIN Ovarian PARP 100 study (NCT03642132), but the study was discontinued. The FIRST [(first-line treatment (NCT03602859)], DUO-O [first-line maintenance (NCT03737643)], and NSGO-AVATAR [platinum-sensitive, recurrent (NCT03307785)] trials are investigating chemotherapy-free triplet therapy with the addition of bevacizumab to ICB and PARPi. The IMAGYN50 [first-line (NCT03038100)], ATALANTE [recurrent, platinum-sensitive (NCT02891824)], and OVAR 2.29 [recurrent, platinum-resistant (NCT03353831)] trials are exploring combinations of bevacizumab plus ICB and chemotherapy.
The combination of ipilimumab (anti-CTLA-4) and nivolumab is also under investigation in the NRG-GY003 trial. Recently presented results showed an ORR of 31.4% with the combination versus 12.2% with nivolumab alone . With many drug combinations in clinical trials in the upfront, platinum-sensitive and platinum-resistant settings, the best way to harness the immunological response in ovarian cancer remains undetermined.
Although still early in development, studies with adoptive T-cell therapies, including a phase 1 trial of MUC16-directed chimeric antigen receptor (CAR) T cells in women with recurrent ovarian cancer (NCT02587689) and two phase 1/2b studies of NY-ESO-1-targeted T-cell receptor (TCR) therapy (NCT01567891 and NCT02650986, respectively), are ongoing.
There will be approximately 62 000 new cases of endometrial cancer diagnosed in 2019, and alarmingly, both the incidence and disease-associated mortality are expected to increase at a rate of 1–2% per year . Endometrial cancers are genetically heterogeneous malignancies composed of four distinct phenotypes: POLE ultramutated, microsatellite instability (MSI) hypermutated, copy number-low, and copy number-high . The molecular characterization of endometrial cancer has provided the initial rationale for using ICB in this malignancy. Through defective proofreading and DNA replication, POLE-inactivating mutations and mismatch repair (MMR) protein deficiency (MLH1, MSH2, MSH6, PMS2), and resulting MSI, lead to significantly higher mutations rates , which correlate with higher neoantigens and TILs. This creates a tumor microenvironment that is favorable to improved immunological responses . However, the majority of relapsed endometrial cancers are copy number-low or copy number-high microsatellite stable (MSS) tumors that are often treatment-recalcitrant, and optimizing ICB therapy and combination approaches in these subtypes remains challenging.
Immune checkpoint blockade monotherapy
In 2017, as part of a pivotal phase 2 trial assessing activity of pembrolizumab across 12 different mismatch repair-deficient (dMMR) tumor types, including endometrial cancer (N = 15), an impressive ORR of 53% was observed . This study also showed that MMR deficiency is a biomarker for response, indicating a new therapeutic option for dMMR cancers. Since the 2017 site-agnostic approval of pembrolizumab for the treatment of advanced, previously treated dMMR/MSI-H tumors, including endometrial cancer , pembrolizumab (N = 24) and the anti–PD-L1 atezolizumab have both been evaluated in PD-L1-positive endometrial cancer, regardless of MSI status, and have evinced modest activity, with ORRs of ∼13% [27,28]. In a phase 2 trial in advanced endometrial cancer (N = 23), nivolumab monotherapy was associated with an ORR of 23%, regardless of MSI status .
In a phase 1/2 trial of dostarlimab (anti-PD-1) in advanced endometrial cancer, clinically meaningful responses regardless of MSI status were observed, with an ORR of 29.6% (N = 125). The response rates in the MSI-H and MSS cohorts were 48.8 and 20.3%, respectively. With a median follow-up of 10 months, 84% of responders were still on treatment and the median duration of response (DOR) had not been reached [30▪▪]. A phase 3 frontline trial of dostarlimab versus placebo in combination with carboplatin and paclitaxel chemotherapy (RUBY-NCT03981796) is ongoing. Similarly, phase 3, trials of atezolizumab versus placebo in combination with carboplatin and paclitaxel chemotherapy (AtTEnd-NCT0363184) and carboplatin with paclitaxel with or without pembrolizumab followed by maintenance pembrolizumab or placebo in advanced/recurrent endometrial cancer (GY018- NCT02549209) are also enrolling.
In phase 2 trials, the PD-L1 inhibitors avelumab (N = 31) and durvalumab (N = 70) have shown ORRs of 26.7 and 43% in dMMR and 6.25 and 3% in pMMR-advanced endometrial cancer cohorts, respectively [31,32]. There are currently ongoing studies of ICB monotherapy in the relapsed endometrial cancer setting including: nivolumab in MSI or dMMR endometrial cancer (NCT03241745), and pembrolizumab in ultramutated and hypermutated endometrial cancer (NCT02899793). In both studies, patients were selected according to MSI, POLE, or dMMR status.
The modest responses with ICB monotherapy underscore the general principle that immunogenicity and antitumor responses may be largely driven by neoantigens as opposed to PD-L1 positivity, and strategies to alter the immunological response with combination therapies are desperately needed.
Immune checkpoint blockade combination therapies
The Food and Drug Administration, the Australian Therapeutic Goods Administration, and Health Canada recently granted accelerated approval for the combination of the oral multikinase inhibitor lenvatinib (VEGFR1-3, FGFR 1-4, KIT, RET, PDGFRα) and pembrolizumab for the treatment of advanced endometrial cancer that is not MSI-H/dMMR and has progressed following prior therapy. This approval was based on the impressive results of KEYNOTE-146, a phase 1b/2 trial that enrolled 108 patients (94 pMMR; 11 dMMR) with previously treated endometrial cancer. The ORRs at week 24 by investigator review per irRECIST were 36.2 and 63.6% for the pMMR and dMMR cohorts, respectively. The ORR and DOR by independent radiologic review per RECIST 1.1 were 38.3% and not reached, respectively for the pMMR and 63.6% and not reached, respectively, for the dMMR cohorts. Median follow-up was 18.7 months, and activity was seen in patients regardless of MSI status, PD-L1 status, or histology [7▪▪]. A phase 3 trial of lenvatinib with pembrolizumab versus doxorubicin or weekly paclitaxel in advanced endometrial cancer (NCT03517449) as well as frontline lenvatinib with pembrolizumab versus carboplatin and paclitaxel chemotherapy are currently ongoing (NCT03884101).
The interim results of an ongoing phase 2 study of durvalumab and tremelimumab (anti-CTLA-4) versus durvalumab alone in recurrent endometrial cancer regardless of MMR status (86% of patients in each cohort were pMMR) was recently reported. Response rates were a modest 14.8% in the durvalumab monotherapy and 11.1% in the durvalumab with tremelimumab arms . Ongoing trials are evaluating nivolumab with ipilimumab (anti-CTLA-4; NCT03508570 and NCT02982486) in advanced endometrial cancer. Other studies are exploring additional potentially synergistic approaches, including pembrolizumab in combination with doxorubicin (NCT03276013), PD-1/PDL-1 ICB therapies with indoleamine 2,3-dioxygenase (IDO) inhibitors (NCT04106414), PARP inhibitors (NCT03951415), and folate receptor antibodies (NCT03835819).
In 2019, approximately 13 000 new cases of invasive cervical cancer will be diagnosed in the United States, and an estimated 4000 women will die from this disease . Although the incidence of cervical cancer has significantly decreased because of increased screening and human papillomavirus (HPV) vaccination, limited therapeutic options contribute to poor prognosis in advanced disease. Most cervical cancers are caused by HPV subtypes 16 and 18, and as virally mediated cervical cancer can present viral antigens to T cells and initiate HPV-specific immune responses, ICB is of great interest as a treatment strategy . Furthermore, PD-1 and PD-L1 upregulation has been reported in cervical cancer and may be utilized as a biomarker of immune response .
Immune checkpoint blockade monotherapy
In a multicenter trial of patients with metastatic cervical cancer (N = 42), ipilimumab monotherapy failed to activity, with an ORR of 2.9% . In KEYNOTE-028, a phase 1b trial of pembrolizumab in PD-L1+ advanced cervical squamous cell cancers (N = 24), the ORR was 12.5%. After further study, pembrolizumab was recently granted accelerated approval for PD-L1-positive cervical cancer after progression on chemotherapy based on the results of the phase 2 KEYNOTE-158 Cohort E study (N = 77). Interim analysis showed an ORR of 12.2%, including one complete response and nine partial responses. The ORR in PD-L1-positive (>1% expression) tumors was 14.6%, with 91% of patients experiencing ongoing response after more than 6 months of follow-up, and a median DOR that had not yet been reached . In CheckMate 358, a phase 1/2 trial of nivolumab in HPV-associated tumors, including cervical cancer (N = 19), the ORR was 26.3% . The efficacy of avelumab for treating patients with cervical cancer is being assessed in two ongoing clinical trials (NCT03260023 and NCT03217747).
Immune checkpoint blockade combination therapies
In attempts to enhance monotherapy ICB responses, researchers are now evaluating combinations of ICB with radiation therapy, chemotherapy, bevacizumab, and Vigil (personalized cellular immunotherapy). Recently, interim results of a phase 1/2 study of nivolumab with or without ipilumumab in recurrent/metastatic cervical cancer, regardless of PD-L1 expression, were reported. Patients were randomized to receive either nivolumab 3 mg/kg every 2 weeks with ipilimumab 1 mg/kg every 6 weeks (nivo3 with ipi1) or nivolumab 1 mg/kg with ipilimumab 3 mg/kg every 3 weeks for four doses followed by nivolumab at 240 mg every 2 weeks (nivo1 with ipi3). At the time of analysis, the ORR with nivo3 with ipi1 was 31.6% in treatment-naïve patients and 23.1% in previously treated patients. The ORR with nivo1 with ipi3 was 45.8% in treatment-naïve patients and 36.4% in previously treated patients [38▪▪]. Final results are highly anticipated.
Radiation therapy may result not only in local tumor control at an irritated site but also distant tumor response through immune priming via a rare phenomenon known as the abscopal effect . In an effort to overcome immune tolerance and improve systemic efficacy of ICB therapy, a number of radiation therapy and ICB therapy approaches are being investigated. Thus far, a phase 1 trial of sequential ipilimumab with chemoradiation in locally advanced cervical cancer has demonstrated a 1-year disease-free survival rate of 74% . In the adjuvant or definitive radiation space, two important phase 2 trials with pembrolizumab (NCT02635360) and atezolizumab (NCT03612791) are under investigation with either concurrent or sequential definitive chemoradiation.
In the metastatic/recurrent disease setting, the PRIMMO study (NCT03192059) will evaluate pembrolizumab with radiation in combination with an immunomodulatory cocktail in patients with cervical/uterine cancer. Other exploratory combination approaches in cervical cancer include durvalumab with radiotherapy, ADXS11-001, tremelimumab, and Vigil (NCT03452332, NCT02291055, NCT01975831, and NCT02725489); atezolizumab with chemotherapy, chemoradiation, radiation, bevacizumab, and Vigil (NCT03614949, NCT03340376, NCT02921269, NCT03073525, and NCT02914470); pembrolizumab with cisplatin/radiation therapy (PAPAYA-NCT03144466); chemotherapy with pembrolizumab versus placebo (KETNOTE-826-NCT03635567); and chemotherapy with bevacizumab with or without atezolizumab (NCT03556839).
Vaccine therapies under investigation include ADXS11-001, a vaccine based on genetically modified bacteria Listeria monocytogenes to induce the immunological response against E7 oncoprotein of HPV. In a phase 2 study (N = 109), ADXS11-001 was administered with or without cisplatin, and the ORRs were 17.1 versus 14.7%, respectively . VGX-3100 is a therapeutic synthetic DNA vaccine targeting HPV subtypes 16, 18 E6, and E7 proteins, and based on promising results from a phase 2b trial (REVEAL 1) in intraepithelial grade 2/3 lesions, phase 3 study of VGX-3100 (REVEAL 2) in high-grade squamous intraepithelial lesions associated with HPV-16/ HPV-18 is in progress (NCT03721978). Additionally, adoptive T-cell strategies are being explored in a phase 1/2 trial evaluating engineered TCR targeting HPV E7 in HPV-associated cervical cancers (NCT02858310).
A list of select reported ICB trials in gynecologic cancer are described in Table 1[5,11▪,12▪,16▪,17,19–22,27,28,30▪▪,31,33,34,37,38▪▪,39,42–47].
ICB monotherapy has resulted in only modest activity in advanced gynecologic cancers. However, numerous combination strategies with targeted therapies, other immunotherapeutic agents, chemotherapy and radiation therapy, which have the potential to alter the treatment landscape, are ongoing. Additionally, vaccine strategies and adoptive T-cell approaches are generating exciting preliminary data. The key to advances in this field will be optimal patient selection based on tumor molecular and immunophenotypic properties [tumor mutational burden, MS status, PD-L1 status (tumor proportion score, combined positive score), and TILs classification]. Concerted efforts to better understand host factors, such as microbiome composition are warranted, as a more robust understanding of the molecular and immunologic drivers of response and resistance are critical to optimal design of next-generation studies in advanced gynecologic malignancies.
Financial support and sponsorship
M.R. and V.M. are supported in part by the NIH/NCI Cancer Center Support Grant P30 CA008748.
Conflicts of interest
V.M. reports the following potential conflicts: advisory board/honoraria/travel from ArQule, Eisai, Karyopharm, Merck, IBM Watson, as well as study funding from AstraZeneca, Eisai, Karyopharm, Lilly, Merck, Takeda, and Genentech.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
- ▪ of special interest
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