Investigators Seek to Improve SOC in Cervical Cancer

Jyoti S. Mayadev, MD

Motivated to move the needle in cervical cancer, investigators are adding durvalumab (Imfinzi) to standard-of-care concurrent chemoradiation therapy (SOC CCRT) and brachytherapy to determine whether PD-L1 blockade is a key to improving survival outcomes.

“The National Cancer Institute issued a consensus statement more than 20 years ago changing the standard of care [SOC] for locally advanced cervical cancer from radiation alone to concurrent chemoradiation, and we still remain in the same treatment paradigm,” said Jyoti S. Mayadev, MD, a radiation oncologist at the University of California (UC) San Diego Health.

The phase III CALLA study (NCT03830866) is currently active and expects to enroll approximately 714 immunotherapy-, chemotherapy-, and radiotherapy-naïve patients with histologically confirmed cervical adenocarcinoma or squamous carcinoma. Patients will be randomized to receive CCRT with or without durvalumab followed by brachytherapy.¹

As one of the largest clinical trials in this patient population with more than 130 sites outside the United States, CALLA “has the potential to have a grand impact on the burden of cervical cancer” because it affords investigators the ability to deliver novel therapeutic treatments to patients throughout the world, said Mayadev, the principal investigator of CALLA’s site at UC San Diego Health.²

Better screening techniques and increased immunization against the human papillomavirus (HPV), which is thought to be the primary driver of the disease, has caused cervical cancer rates to decrease among women in the United States. However, incidence continues to be high in developing countries where 85% of cases are diagnosed because screening is not as widely available as it is in the United States.³

In 2019, it was estimated that there would be about 13,170 new cases of cervical cancer in the United States and 4250 deaths from the disease. Nationwide, the 5-year relative survival rate for patients with distant disease is 16.9% versus 91.8% for localized disease.⁴

The Current Paradigm

Treatment that includes surgery and CCRT, can lead to cures in 80% of women with stage I to stage II disease (early stage) and in 60% of women with stage III disease.² Patients with early-stage disease, defined as cancer that is less than 4 cm in size, typically undergo surgery. “Depending on the risk factors at the time of surgery, we may give radiation or a combination of radiation and chemotherapy after surgery,” Mayadev said.

Patients with stage Ib2 or higher disease generally receive CCRT. “Because the disease has usually gone outside of the cervix, patients are no longer candidates for surgery and are instead treated with a combination of cisplatin-containing chemotherapy once weekly at 40 mg/ m² and daily radiation,” Mayadev explained.

CCRT is followed by brachytherapy, a type of internal radiation therapy that directs radiation in and around the tumor and delivers a high dose of radiation after the external beam radiation therapy (EBRT) that patients receive during CCRT. Brachytherapy is used to intensify the anticancer effect of prior EBRT in this nonoperable patient population.⁵

“The increase in dose that you get from brachytherapy cannot be mimicked with external radiation and patients with cervical cancer who receive brachytherapy have shown an improvement in survival versus those who did not get brachytherapy,” Mayadev said.

Figure. Durvalumab and Chemoradiotherapy in Locally Advanced Cervical Cancer Phase III CALLA Trial (NCT03830866) (Click to Enlarge)

Despite the documented efficacy of EBRT and later brachytherapy, brachytherapy’s uptake is still low in cervical cancer, Mayadev said. “We’ve done a lot of research on the number of patients who get brachytherapy and found it to be around 50% in California, so we have to make a lot of strides within cervical cancer,” she added. “We need to make sure that all patients are offered brachytherapy.”

CALLA investigators will give EBRTincluding CCRT in both arms of the CALLA study. Patients randomized to the experimental arm will receive intravenous durvalumab at 1500 mg every 4 weeks for 96 weeks followed by durvalumab monotherapy for up to 24 months or until progression from the date of randomization.¹

All patients will receive either pelvis- or pelvis and para-aortic—directed CCRT at 45 Gy. Afterward, brachytherapy will be initiated in tandem with 40 mg/m² of cisplatin or carboplatin-based chemotherapy once weekly for 5 weeks. Patients will have the option to receive a sixth dose of therapy.¹

Randomization will be stratified by disease stage and geographic region.¹ The primary end point is progressionfree survival. OS and the objective and complete response rates are among the CALLA study’s several secondary end points (Figure).

To be eligible to enroll in the CALLA trial, patients must have locally advanced disease that meets the 2018 International Federation of Gynecology and Obstetrics criteria for stage Ib2 to IIN node-positive disease or stage IIIa to stage IVa disease with any node.

Although CCRT is “very curative” for node-negative early-stage disease, said Mayadev, the SOC for patients with laterstage node-positive cervical cancer is not sufficient.

“The need for a new treatment option is great. Patients with stage IIIa to stage IVa node-positive cervical cancer, particularly those with periaortic lymph node metastasis represent a particularly poor prognostic group,” Mayadev said. This subset has high rates of systemic relapse and poor survival: the 3-year OS rate ranges from 30% to 50%, according to Mayadev.

For patients with periaortic lymph node metastasis, the survival rate is approximately 50% after CCRT and brachytherapy, Mayadev added. “We really want to push the needle for these patients who present with nodal-positive disease,” she said.

Boosting Immunogenicity

The hope of meeting the existing global need in cervical cancer and the antitumor activity that the addition of durvalumab to the SOC could promote propelled the development of the CALLA trial, Mayadev said.

Investigators hypothesize that, when combined with CCRT, PD-1/PD-L1 pathway blockade may augment immunogenicity by increasing phagocytosis, antigen presentation, and ultimately, cell death.⁶ Cancer cells evade the immune system by disrupting phagocytosis, a process of foreign substance eradication and dead cell clearance enacted by a type of white blood cell known as a phagocyte. Phagocytosis is necessary for the detection and removal of malignant cells.^7,8

Antigen presentation is also critical to tumor-targeting approaches in cancer treatment. Downregulation or loss of antigen presentation enables tumor cells to avoid immune recognition, preventing antitumor T cells from seeking and destroying these cells.⁹

Most cervical cancers have a viral etiology, which compromises immune system function.8 Durvalumab could offset this immunogenic compromise and “reactivate immune-mediated tumor surveillance, translating to increased antitumor activity,” Mayadev explained.

Durvalumab is a PD-L1 inhibitor. PD-L1 interaction with PD-1 and CD80 prevents T-cell function and activation. Blockade of these PD-L1/PD-1 and PD-L1/CD80 interactions releases inhibited immune responses, supporting immune system activity. This mechanism of action makes durvalumab an attractive option to further investigate in the treatment of cervical cancer.^10,11

The drug currently is approved in locally advanced or metastatic urothelial carcinoma and in unresectable stage III non—small cell lung cancer settings.

The rationale for using immunotherapy in cervical cancer is also based on the nature of the disease. “Cervical cancer is highly immunogenic, and we know that virtually all cases of cervical cancer are induced by chronic HPV infection that develops with the activation of adaptive immune systems,” Mayadev said.

HPV is the most common sexually transmitted disease in the United States and manifests in both a low- and high-risk form. Of note, only high-risk HPV causes cancer. To date, 13 HPV types have been identified as cervical cancer drivers. Usually, the immune system naturally rids itself of the HPV infection within a 2-year period. However, when it cannot, the extended presence of the infection can convert healthy cells into abnormal cells, which eventually become cancerous.¹²

Although preventive immunizations such as the HPV 9-valent vaccine (Gardasil 9) can help protect individuals from cancer-associated strains of HPV, CALLA investigators hope that the addition of durvalumab to the SOC will offer promise to those with cervical cancer.

“We’re hoping that immunotherapy will be the next potential breakthrough in cervical cancer,” Mayadev said.

References

1. Mayadev J, Nunes AT, Li M, et al. CALLA: Efficacy and safety of concurrent and adjuvant durvalumab with chemoradiotherapy versus chemoradiotherapy alone in women with locally advanced cervical cancer: a phase III, randomized, double-blind, multicenter study [published online May 23, 2020]. International Journal of Gynecologic Cancer. 2020;0:1-6. doi:10.1136/ijgc-2019-001135
2. Monk BJ, Mayadev J, Nunes AT. Letter to the editor, reply to: Lee and Matulonis: immunotherapy and radiation combinatorial trials in gynecologic cancer: a potential synergy? Gynecol Oncol Rep. 2019;30:100506. doi: 10.1016/j.gore.2019.100506. 
3. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology. Cervical cancer (version 1.2020). nccn.org/professionals/physician_gls/pdf/cervical.pdf. Accessed February 17, 2020. 
4. Cancer stat facts: cervical cancer. National Cancer Institute website. seer.cancer.gov/statfacts/html/cervix.html. Accessed February 21, 2020. 
5. Radiation Therapy for Cervical Cancer. American Cancer Society website. Updated January 3, 2020. cancer.org/cancer/cervical-cancer/treating/radiation.html. Accessed February 21, 2020. 
6. Han K, Milosevic M, Fyles A, Pintilie M, Viswanathan AN. Trends in the utilization of brachytherapy in cervical cancer in the United States. Int J Radiat Oncol Biol Phys. 2013;87(1):111-119. doi: 10.1016/j.ijrobp.2013.05.033. 
7. Feng M, Jiang W, Kim BYS, Zhang CC, Fu Y-X, Weissman IL. Phagocytosis checkpoints as new targets for cancer immunotherapy. Nat Rev Cancer. 2019;19(10):568-586. doi: 10.1038/s41568-019-0183-z. 
8. Cohen AC, Roane BM, Leath CA. Novel therapeutics for recurrent cervical cancer: moving towards personalized therapy. Drugs. 2020;80(3):217-227. doi: 10.1007/s40265-019-01249-z. 
9. de Charette M, Marabelle A, Houot R. Turning tumour cells into antigen presenting cells: the next step to improve cancer immunotherapy? Eur J Cancer. 2016; 68: 134-147. doi: 10.1016/j.ejca.2016.09.010. 
10. Imfinzi [prescribing information]. Cambridge, UK: AstraZeneca; 2019. accessdata.fda.gov/drugsatfda_docs/label/2019/761069s013lbl.pdf. Accessed February 21, 2020. 
11. About Imfinzi. AstraZeneca website. Updated April 2019. www.imfinzihcp.com/about-imfinzi-durvalumab.html. Accessed February 21, 2020. 
12. Basic information about HPV and cancer. Centers for Disease Control and Prevention website. cdc.gov/cancer/hpv/basic_info/index.htm. Updated August 22, 2018. Accessed February 21, 2020. 

Findings from a retrospective study of 7359 patients with stage Ib2 to stage IVa cervical cancer confirmed the survival benefit conferred by EBRT and subsequent brachytherapy. Brachytherapy was associated with better overall survival (OS) than radiation treatment consisting only of EBRT (58.2% vs 46.2%; P < .001). Most patients (63%) received EBRT followed by brachytherapy. The remaining 37% concluded their radiation therapy with EBRT.⁶