Dramatic Increase in Cervical Cancer Research Is Driving Treatment Progress

Despite significant advancements in prevention and screening, cervical cancer remains a fierce opponent, and the disease continues to affect many women worldwide. In 2022, an estimated 14,100 new cases of cervical cancer will be diagnosed, and 4,280 projected deaths will occur because of the disease in the United States alone.¹

Approximately 40-50% of cervical cancer cases are diagnosed in the locally advanced stage, and women diagnosed with metastatic cervical cancer have a particularly poor prognosis, with a 5-year survival rate estimated at only 16%.² These grim statistics are driving an urgent need for new treatment options.

Thankfully, there is renewed hope and tremendous excitement about the future, as over the last several years, clinical trials for patients with recurrent and metastatic cervical cancer have increased at a pace never experienced in the field of gynecologic oncology.

The cervical cancer landscape is dramatically changing for the better as new drug therapies, including antibody drug conjugates and immunotherapies, come into play vs traditional chemotherapy. Taking a closer look at what is driving all this excitement is worthwhile, as these developments will likely impact the standard of care for patients with cervical cancer for years to come.

Recent Trials

There are a few interesting trials recently published or presented at various conferences that will hopefully contribute to our understanding of cervical cancer and help guide the path forward:

KEYNOTE-826 (NCT03635567)

This international phase 3 randomized controlled trial is particularly exciting because it brings pembrolizumab (Keytruda) to the first-line treatment of patients with metastatic cervical cancer.³ Before this study, the standard of care was carboplatin or cisplatin with paclitaxel (Taxol), plus or minus bevacizumab (Avastin), which yielded a median overall survival (OS) ranging from approximately 13 to 17 months. Adding pembrolizumab to that regimen increased median OS to 24 months, which is very promising because this improvement in OS has not been seen before in this population of patients.

While progression free survival (PFS) improvements are often seen in clinical trials, they unfortunately do not always translate to OS. In the KEYNOTE-826 trial, adding pembrolizumab reduced the hazard of disease progression by 38% in patients with a PD-L1 combined positive score of 1 or more, and by 35% in the intention to treat population, additionally, the hazard of death was reduced by 36% and 33%, respectively.

OUTBACK Trial (NCT01414608)

OUTBACK was an international randomized phase 3 trial designed to determine the effects on survival of giving adjuvant chemotherapy after current standard of care chemoradiation.⁴ Participants were patients with locally advanced cervical cancer who traditionally would have received the standard of care chemoradiation with curative intent. Patients were randomly assigned to either standard chemoradiation or standard chemoradiation followed by adjuvant chemotherapy consisting of 4 cycles of carboplatin and paclitaxel. The primary endpoint was OS at 5 years, while secondary endpoints included PFS, adverse events, and patterns of disease recurrence.

Unfortunately, this turned out to be a negative trial, as the findings did not show that receiving adjuvant chemotherapy after standard chemoradiation improved OS or PFS. Additionally, the therapy was also associated with more grade 3-5 adverse effects at less than one year from randomization. Beyond that point, adverse effects were similar between the two groups.

CALLA Trial (NCT03830866)

Results of the CALLA trial were presented at the International Gynecologic Cancer Society (IGCS) conference in September of 2022, and unfortunately, like the OUTBACK trial, the CALLA trial yielded negative results.⁵ A randomized phase 3 trial, CALLA examined an immunotherapy drug called durvalumab (Imfinzi) in combination with and following chemoradiation.

The study found durvalumab did not significantly improve PFS in patients with high-risk, locally advanced cervical cancer vs chemoradiation alone. The important point about this trial was that it used an immunotherapy drug in addition to chemotherapy in the upfront setting. Interestingly, the subgroup of patients at highest risk of progression and death, specifically the lymph node–positive stage III group, had a hazard ratio of 0.71.

Safety was comparable in both arms of the study, and no new or unexpected toxicities were noted. Although data is still immature, and results are not published yet, so far there has been no detriment to survival.

Studies in Cervical Cancer Actively Recruiting

Some interesting trials are still recruiting to look at treatments in this patient population:

40 InnovaTV 301/ENGOT-cx12/GOG-3057 (NCT04697628)

A randomized open label phase 3 trial, GOG-3057 is studying the drug tisotumab vedotin (Tivdak) vs choice chemotherapy in second-and third-line treatment of recurrent or metastatic cervical cancer.⁶ The encouraging point about this drug is that in phase 1 and 2 trials, it demonstrated a response in second-and third-line treatment for patients with recurrent cervical cancer where traditionally good options did not exist for these women. Based on these early results, the drug received an accelerated FDA approval for patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. It will be highly interesting to see the phase 3 results, which are still a few years away.

RaPiDS (NCT03894215)

This is a randomized, blinded, non-comparative 2-arm phase 2 study that will assess the efficacy and safety of anti-PD1 balstilimab with placebo or in combination with anti-CTLA-4 zalifrelimab for treatment of patients with advanced cervical cancer after relapse or progression following first-line platinum-based chemotherapy.⁷ Each arm will be evaluated against historical controls. The primary end point is objective response rate (ORR), but duration of response (DOR), PFS, OS, and quality of life outcomes will also be evaluated.

GOG 3047 (NCT04221945)

This is a randomized phase 3 study that will evaluate chemoradiation with or without the immunotherapy drug, pembrolizumab, for treatment of high-risk patients with locally advanced cervical cancer.⁸ Like pembrolizumab’s benefit in the KEYNOTE-826 study for patients with metastatic or recurrent disease, investigators are hoping that pembrolizumab plus chemoradiation is superior to standard of care chemoradiation with respect to progression free survival and overall survival.

GOG 3043 (NCT04831580)

This study is a randomized controlled surgical trial of robotic vs open radical hysterectomy for patients with cervical cancer.⁹ Surgeons had been routinely performing minimally invasive surgery for cervical cancer until the results of the Laparoscopic Approach to Cervical Cancer (LACC) trial showed inferior disease-free and overall survival for women undergoing minimally invasive surgery for cervical cancer.

Unfortunately, these results have led to gynecologic oncologists performing radical hysterectomies via laparotomy for all patients with cervical cancer. There is a great need for more data, and hopefully this study will provide some answers. It is focusing on robot-assisted radical hysterectomy with a surgical technique for tumor containment prior to opening the vagina during the hysterectomy procedure. Investigators hope to determine if this approach is noninferior to performing an open radical hysterectomy with respect to disease free survival.

Trials Closed for Patient Accrual

Several studies have completed accrual, so results should be coming soon that oncologists should look out for including the NRG-GY006 study (NCT02466971).¹⁰ This randomized phase 3 trial examines the efficacy of triapine in combination with traditional chemoradiationin women with stage IB2 (> 5 cm), II, IIIB or IVA squamous, adenocarcinoma, or adenosquamous carcinoma of the cervix.

Another randomized phase 3 trial to look out for is the GOG 263 study (NCT01101451).¹¹ This study looks at postoperative adjuvant chemoradiation therapy compared to adjuvant radiation therapy alone in patients with stage I-IIA cervical cancer who have intermediate risk factors after treatment with radical hysterectomy.

Still too Soon to Predict Drug Approvals

While there are many trials in the works, it is difficult to foresee if any of the drugs under study will gain FDA approval anytime soon. There have been some negative trials associated with the immunotherapy drugs, so for now, everyone is in a wait-and-see mode to see which patients will benefit most from these therapies.

New Targets in Treating Cervical Cancer

Antibody drug conjugates are showing great promise for the future, and not just for patients with cervical cancer. Unlike chemotherapy, these biopharmaceutical drugs are designed to selectively kill tumor cells while sparing healthy cells, hopefully limiting toxicity. There has already been progress in antibody drug conjugates for treatment with patients with cervical cancer using the drug tisotumab vedotin (Tivdak).

The treatment is designed to target tissue factor (TF) using proprietary antibody drug conjugate technology. TF is highly expressed on many solid tumors, including ovarian, prostate, bladder, esophageal, endometrial, and lung tumors. As mentioned earlier, tisotumab vedotin is currently in phase 3 trials and received accelerated FDA approval in September 2021 after previous trials demonstrated a response in second-and third-line treatment for patients with recurrent cervical cancer.

Advice For the Community Oncologist

Community oncologists can play a vital role in prevention and early diagnosis of cervical cancer in their patients. Like other gynecologic malignancies, cervical cancer can often go unnoticed because there are no obvious signs of the disease. The most common symptoms are vaginal bleeding, unusual vaginal discharge, and pelvic pain. However, these symptoms might not be considered abnormal to a woman of reproductive age, so it is important for physicians to ask their patients if they are experiencing any of these possible warning signs. It is also critical to take women’s concerns seriously, especially those concerns related to their reproductive health.

Screening is also essential for these patients. Patients with cancer are often immunosuppressed, putting them at higher risk for cervical dysplasia and cervical cancer. Consequently, it is important to ask if patients are up to date on their cervical cancer pap screening, and if not, to make sure they have established OB-GYN care to manage their increased risk. Moreover, community oncologists who are treating adolescent and young adult cancer patients should be recommending the human papillomavirus (HPV) vaccine.

Pediatric adolescent and young adult patients undergoing cancer treatment, or receiving stem cell transplants, are at nearly three times the risk of developing a secondary HPV-associated malignancy, so it is very important for community oncologists to recommend the vaccine to this vulnerable population.

Most cervical cancer is caused by HPV 16 and 18, and those 2 types are protected against with the vaccine, which has proven to be extremely effective. For instance, a recently published population-based cohort study of more than 1.5 million adolescent and adult females from 10 to 30 years of age found the quadrivalent HPV vaccine was associated with a substantially reduced risk of invasive cervical cancer.¹²

We know that a recommendation by a trusted physician is the strongest predictor for HPV vaccination initiation and completion, so community oncologists can play an important role in making sure these young adults are educated and vaccinated.

Hope Is On the Horizon

Cervical cancer is the fourth most common cancer among women globally, with an estimated 604,000 new cases and 342,000 deaths in 2020.¹³ While cervical cancer is on the rise in some countries, in the United States progress is being made and we are seeing the incidence of cervical cancer declining, largely attributed to an increase in HPV vaccination. It is important to highlight that although HPV vaccination coverage continues to increase in the United States, it remains lower than coverage with most other routinely recommended vaccines and HPV vaccination coverage in other high-income countries.

For women who are facing a diagnosis of cervical cancer, there is much to be optimistic about today, as this is an unprecedented time for new trials that are leading to significant advancements and improvements in survival. This level of activity in cervical cancer clinical research has not been seen in the past decade. It is encouraging that this disease is finally getting the attention it deserves. Thanks to this dramatic increase in research, patients who previously had few treatment options now have promising therapies available to them, with many more on the horizon.

^References:

^{1. Cancer Stat Facts: Cervical Cancer. National Cancer Institute. December 30, 2020. Accessed: November 16, 2022. https://bit.ly/3jnteLM}

^{2. Survival Rates for Cervical Cancer. American Cancer Society. March 1, 2022. Accessed: November 17, 2022. https://bit.ly/2GHnhVl}

^{3. Shapira-Frommer R, Alexandre J, et al. KEYNOTE-826: A phase 3, randomized, double-blind, placebo-controlled study of pembrolizumab plus chemotherapy for first-line treatment of persistent, recurrent, or metastatic cervical cancer. J Clin Oncol. 2019;37(suppl 15). doi: 10.1200/JCO.2019.37.15_suppl.TPS5595}

^{4. Mileshkin L, Moore K, et al. Adjuvant chemotherapy following chemoradiation as primary treatment for locally advanced cervical cancer compared to chemoradiation alone: The randomized phase III OUTBACK Trial (ANZGOG 0902, RTOG 1174, NRG 0274). J Clin Oncol. 2022;39(suppl 18). doi: 10.1200/JCO.2021.39.15_suppl.LBA3}

^{5. 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. Int J Gynecol Cancer. 2020 Jul;30(7):1065-1070. doi: 10.1136/ijgc-2019-001135}

^{6. Vergote I, Randall L, et al. 40 InnovaTV 301/ENGOT-cx12/GOG-3057: tisotumab vedotin vs investigator’s choice chemo in second- or third-line recurrent or metastatic cervical cancer. Int J Gynecol Cancer. 2021;31(suppl 3). doi: 10.1136/ijgc-2021-ESGO.1}

^{7. O’Malley DM, Randall LM, Jackson CG, et al. RaPiDS (GOG-3028): randomized Phase II study of balstilimab alone or in combination with zalifrelimab in cervical cancer. Future Oncol. 2021 Sep;17(26):3433-3443. doi: 10.2217/fon-2021-0529}

^{8. Study of Chemoradiotherapy With or Without Pembrolizumab (MK-3475) For The Treatment of Locally Advanced Cervical Cancer (MK-3475-A18/KEYNOTE-A18/ENGOT-cx11/GOG-3047). National Cancer Institute. Accessed: December 12, 2022. https://bit.ly/3HTBVYb}

^{9. Bixel KL, Leitao MM, et al. ROCC/GOG-3043: A randomized non-inferiority trial of robotic versus open radical hysterectomy for early-stage cervical cancer. J Clin Oncol. 2022; 40(suppl 16) TPS5605-TPS5605. doi: 10.1200/JCO.2022.40.16_suppl.TPS5605}

^{10. Leath, C. A Randomized Phase III Trial of Radiation Therapy and Cisplatin Alone or in Combination with Intravenous Triapine in Women with Newly Diagnosed Bulky Stage IB2, Stage II, IIIB, or IVA Cancer of the Uterine Cervix or Stage II-IVA Vaginal Cancer. NRG Oncology. 2019. Accessed: December 12, 2022. https://bit.ly/3WHPOgt}

^{11. Radiation Therapy With or Without Chemotherapy in Patients With Stage I-IIA Cervical Cancer Who Previously Underwent Surgery. NIH U.S. National Library of Medicine. Accessed: December 12, 2022. https://bit.ly/3GcuXw7}

^{12. Lei J, Ploner A, Elfström K, et al. HPV Vaccination and the Risk of Invasive Cervical Cancer. N Engl J Med. 2020; 383:1340-1348. doi: 10.1056/NEJMoa1917338}

^{13. Cervical Cancer Key Facts. World Health Organization. February 22, 2022. Accessed: November 17, 2022.https://bit.ly/3BVIGou}