Bradley J. Monk, MD

Bradley J. Monk, MD, FACS, FACOG, co‐director of GOG Partners, Arizona Oncology (US Oncology Network); professor of Gynecologic Oncology at University of Arizona, Creighton University; and medical director of the US Oncology Research Gynecology Program, discusses the remaining challenges in conducting clinical trials for patients with cervical cancer.

Clinical trials evaluating treatments for patients with cervical remains difficult at this time, says Monk. These patients with cervical cancer often are younger than what is traditionally observed in gynecologic cancers. The average age of women with cervical cancer is late 40s to early 50s, so these women often still have children at home, compared with patients with ovarian cancer or endometrial cancer who are usually around 60 to 70 years old.

Cervical cancer also remains underdeveloped in many ways, Monk notes. The screening paradigm and the vaccination paradigm did not provide patients with cervical cancer an exceptional opportunity for treatment in clinical trials. Overall, Monk says that at its core, clinical research in cervical cancer remains complicated.

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Bradley J. Monk, MD, FACS, FACOG, discusses the remaining challenges in conducting clinical trials for patients with cervical cancer.

Challenges Remain in Conducting Clinical Trials for Patients With Cervical Cancer

The American Cancer Society has estimated that in 2019 in the United States, approximately 13,240 new patients will receive a diagnosis of cervical cancer and 4170 individuals will die from the disease. However, because of effective screening programs using cytology and/or high-risk human papillomavirus (HPV) DNA testing in industrialized nations, incidence and mortality rates have declined.1 In 2018, the FDA granted an expanded indication for the HPV vaccine Gardasil 9 for men and women aged 27 to 45 years.

In 2018, the International Federation of Gynecology and Obstetrics (FIGO) revised its staging system for cervical cancer with the following updates:

FIGO 2018 stage IB now includes 3 subgroups increasing with tumor size:

o Stage IB1 involves invasive carcinoma >5 mm depth of stromal invasion and <2 cm in greatest dimension.

o  Stage IB2 (formerly 2014 FIGO stage IB1) involves

invasive carcinoma >2 and <4 cm in greatest dimension.

o  Stage IB3 (formerly 2014 FIGO stage IB2) involves

invasive carcinoma >4 cm in greatest dimension.

FIGO 2018 stage IIIC is designated for disease with lymph node involvement:

o Stage IIIC involves pelvic and/or para-aortic nodes, regardless of tumor size and extent.

o Stage IIIC1 involves pelvic lymph node metastasis only. o Stage IIIC2 involves para-aortic lymph node metastasis.

o Surgery is acceptable. Cervical conization or extrafascial hysterectomy can be considered with FIGO stage IA. Trachelectomy with laparoscopic pelvic lymphadenectomy can be attempted as a fertility- preserving option for cervical lesions <2 cm in diameter. Radical hysterectomy can be considered in FIGO stage IB2.

o Multimodality therapy consists of concurrent chemoradiation (weekly cisplatin 40 mg/m2) comprising external-beam radiation therapy with systemic chemotherapy (CCRT) then intracavitary brachytherapy.

Management of FIGO 2018 stages IVB and recurrent disease:

o From the GOG-0204 trial, paclitaxel 135 mg/m2 over 24 hours plus cisplatin 50 mg/m2 every 21 days emerged as the palliative standard, with an associated median survival of 7 to 12 months. Transition to a 3-hour outpatient paclitaxel regimen is common. The Japanese Clinical Oncology Group demonstrated significant noninferiority with substitution of carboplatin (area under the curve 5) for cisplatin in the phase III clinical trial JCOG0505 (HR, 0.994) but noted that carboplatin was associated with shorter overall survival among cisplatin-naïve patients.

The rationale to study antiangiogenesis therapy in GOG-0240, a phase III open-label randomized study of chemotherapy doublets with and without bevacizumab (Avastin) at 15 mg/kg every 21 days until progression, was based on clinical, pathologic, molecular, and therapeutic factors.

Genitourinary and/or rectovaginal fistulas were new adverse events occurring in 8.6% of patients being treated with bevacizumab. All fistulas occurred in preirradiated patients. The triplet regimen was approved by the FDA on August 14, 2014,3 and designated category 1 by the National Comprehensive Cancer Network.

Evidence for activity of checkpoint inhibitors is accumulating. The cervical cancer cohort of 77 women with refractory disease in the KEYNOTE-158 phase II study of pembrolizumab (Keytruda) demonstrated an objective response rate of 14.3%, with all 13 responses in PD-L1 positive tumors.

On June 12, 2018, the FDA granted pembrolizumab at 200 mg every 3 weeks accelerated approval as a second-line agent along with a companion diagnostic, the PD-L1 IHC 22C3 pharmDx Kit.

Investigators have launched the confirmatory, front- line, placebo-controlled phase III randomized KEYNOTE- 826 trial studying platinum-based chemotherapy plus optional bevacizumab with and without pembrolizumab (NCT03635567), as well as the frontline phase III randomized BEATcc trial evaluating triplet therapy with cisplatin, paclitaxel, and bevacizumab with or without atezolizumab (Tecentriq; NCT03556839).

A second-line, phase III randomized trial, EMPOWER CERVICAL-1/GOG 3016, activated in 2017, is comparing the antiPD-1 agent cemiplimab (Libtayo) to physician&rsquo;s choice of chemotherapy (NCT03257267).

Finally, CALLA is a 714-patient prospective international randomized clinical trial among women with newly diagnosed locally advanced high-risk cervical cancer (NCT03830866). Progression-free survival associated with standard CCRT will be compared with CCRT plus durvalumab (Imfinzi) followed by durvalumab mono- therapy for up to 24 months or until progression from the date of randomization.

Tewari KS, Monk BJ. Evidence-based treatment paradigms for management of invasive cervical carcinoma.

. 2019;37(27):2472-2489. doi: 10.1200/JCO.18.02303.

FDA approves expanded use of Gardasil 9 to include individuals 27 through 45 years old. FDA website. fda.gov/news-events/press-announcements/fda-approves-expanded-use-gardasil-9-include-individuals-27-through-45-years-old. Published October 5, 2018. Accessed October 17, 2019.

FDA approves Genentech&rsquo;s Avastin plus chemotherapy for treatment of advanced cervical cancer [news release]. South San Francisco, CA: Genentech; August 14, 2014. gene.com/media/press-releases/14571/2014-08-14/fda-approves-genentechs-avastin-plus-che. Accessed October 17, 2019.

NCCN Clinical Practice Guidelines in Oncology. Cervical Cancer, version 5.2019. National Comprehensive Cancer Network website.  nccn.org/professionals/physician_gls/pdf/cervical.pdf. Published September 16, 2019. Accessed October 17, 2019.

Cheol Chung H, Ros W, Delord J-P, et al. Efficacy and safety of pembrolizumab in previously treated advanced cervical cancer: results from the phase II KEYNOTE-158 study.

. 2019;37(17):1470-1478. doi: 10.1200/JCO.18.01265.

FDA approves pembrolizumab for advanced cervical cancer with disease progression during or after chemotherapy. FDA website. fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-advanced-cervical-cancer-disease-progression-during-or-after-chemotherapy. Published June 12, 2018. Accessed October 17, 2019.

Articles

The American Cancer Society has estimated that in 2019 in the United States, approximately 13,240 new patients will receive a diagnosis of cervical cancer and 4170 individuals will die from the disease. However, because of effective screening programs using cytology and/or high-risk human papillomavirus DNA testing in industrialized nations, incidence and mortality rates have declined.

Clinically Important Updates in Cervical Cancer Management

Ovarian cancer is the most lethal of the gynecologic malignancies. Over 22,000 new cases of ovarian cancer are diagnosed each year in the United States, resulting in more than 14,000 deaths per year. The 5-year survival rate is less than 25% for women with a diagnosis of advanced stage disease (stage III or IV) despite aggressive treatment with surgery and adjuvant chemotherapy. Although more than 80% of patients will respond to initial therapy, epithelial ovarian cancer ultimately recurs in most of them. Recurrence is associated with a poor prognosis because of the eventual development of chemotherapy-resistant disease. Thus, there is a great needand opportunity&mdash;to improve ovarian cancer outcomes by understanding the immune milieu of ovarian cancers and harnessing the power of immunotherapy.

While there have been various approaches, from cancer vaccines to adoptive immune-cell therapies, immune checkpoint inhibitors have caused a paradigm shift in cancer treatment (Table 1

). The enthusiasm for this approach stems from evidence of complete and long-lasting tumor regression in malignancies that are often refractory to chemotherapy.

Three principal measures have emerged to predict effective treatment with immune checkpoint inhibitors: (1) accessibility of the tumor by effector immune cells, (2) dominance of the immune checkpoint pathways in suppressing antitumor immunity, and (3) the number of neoantigens, sometimes expressed as mutational burden. The first is frequently defined by the presence of tumor-infiltrating lymphocytes (TIL) or the ratio of effector immune cells (Table 2

). The second principle is less well defined, as no accurate biomarker has been identified, although multiple approaches are being evaluated. Expression of PD-L1 on tumor cells has been suggested as a predictive biomarker to identify cancers that may be more responsive to PD-1/PD-L1 inhibitors.

Evidence of the importance of the local tumor immune microenvironment in ovarian cancer emerged in 2003 when it was shown that infiltration of treatment-na&iuml;ve tumors with T cells was associated with significantly improved median progression-free survival (22.4 vs 5.8 months, P <.001) and overall survival (50.3 vs 18 months, P <.001) compared with tumors with no T cells present.2 However, we have since learned not only that the presence of T cells is important but also that the type of T cells also influences outcomes. The proportion of regulatory T cells (Tregs) in the tumor negatively affects clinical outcomes and was a predictor of increased risk of death in a multivariate analysis. Multiple studies have since confirmed that the ratio of immune suppressive to immune effector cells within ovarian tumors is associated with clinical outcome. Immune responses to ovarian cancer appear to vary by histologic subtype, with high-grade serous cancers most likely to be associated with a prognostically favorable tumor-infiltrating lymphocyte response. Classification of different histologic subtypes of ovarian cancers based on TIL and PD-L1 revealed that type I patterns were more common in high-grade serous cancers, while type IV patterns predominated in other histologic subtypes.

Hamanishi and colleagues first reported that high expression of PD-L1 on ovarian cancer cells was associated with poorer outcomes.3 The 5-year survival rate for patients with high- versus low-expressing PD-L1 tumors was 52.6 &plusmn; 7.7% versus 80.2 &plusmn; 8.9% (P = .016), respectively. PD-L2 expression was also associated with poorer outcomes, but that was not statistically significant. High expression of PD-L1 on ovarian cancer cells was associated with reduced infiltration of cytotoxic T lymphocytes into tumors, suggesting that PD-L1 expression promotes an immunosuppressive microenvironment by inhibiting T-cell infiltration. Both PD-L1 expression and TIL were independent prognostic factors, although PD-L1 expression was inversely correlated with survival. In preclinical models, PD-L1 expression can be induced by interferon gamma (often produced by TILs) and administration of chemotherapy, suggesting a balance that maintains an immune suppressive environment. PD-1/ PD-L1 blockade causes regression of ovarian tumors in a syngeneic ovarian cancer mouse model, further validating the importance of this regulatory pathway.

PD-L1 expression is not limited to tumor cells and has been reported on immune cells including antigen-presenting cells, T cells, and B cells. A recent study showed that PD-L1 expression is predominantly expressed by macrophages in ovarian cancer rather than on the ovarian cancer cells themselves; in this context, macrophage-associated PD-L1 expression was a marker of favorable prognosis. The differences between this study and the one above may be due to the differences in the antibodies used, but they reflect the developing understanding of PD-L1 expression and its prognostic role in ovarian cancer. PD-L1 expression may be a marker of a tumor poised to respond to immune stimulatory effects of chemotherapy; or, perhaps because PD-L1 may suppress the activity of immune-suppressive immune cells (ie, Tregs), PD-L1 expression on immune cells could tip the balance toward a more favorable immune microenvironment. Thus, evaluating PD-L1 expression on tumor cells in isolation is not sufficient to predict immune response and efficacy of immune checkpoint blockade in ovarian cancer.

Teng MW, Khanna R, Smyth MJ. Checkpoint immunotherapy: picking a winner. Cancer Discov. 2016;6(8):818-820. doi: 10.1158/2159-8290.CD-16-0694.

Zhang L, Conejo-Garcia JR, Katsaros D, et al. Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N Engl J Med. 2003:348(3):203-213. doi: 10.1056/NEJMoa020177.

Hamanishi J, Mandai M, Ikeda T, et al. Safety and antitumor activity of antiPD-1 antibody, nivolumab, in patients with platinum-resistant ovarian cancer. J Clin Oncol. 2015;33(34):4015-4022. doi: 10.1200/JCO.2015.62.3397.

Ovarian cancer is the most lethal of the gynecologic malignancies. Over 22,000 new cases of ovarian cancer are diagnosed each year in the United States, resulting in more than 14,000 deaths per year.

How Reliable is PD-L1 Expression as a Predictor of Immune Response?

Bradley J. Monk, MD, gynecologic oncologist, University of Arizona Cancer Center Phoenix Branch, discusses the TRINOVA-1 trial.

The TRINOVA-1 trial studied trebananib plus paclitaxel versus placebo plus paclitaxel in 919 patients who had recurrent ovarian cancer and up to three prior lines of therapy

Trebananib plus weekly paclitaxel improved the hazard ratio for progression by 0.66

The combination also improved response rate and the survival data, although not yet mature, showed a hazard ratio of 0.86

Bradley J. Monk, MD | Authors

Articles

Challenges Remain in Conducting Clinical Trials for Patients With Cervical Cancer

Clinically Important Updates in Cervical Cancer Management

How Reliable is PD-L1 Expression as a Predictor of Immune Response?

The Design and Results of TRINOVA-1