Coleman Centers the Discussion on Practice-Affirming ASCO Trials in Gynecologic Oncology

Robert L. Coleman, MD, FACOG, FACS

Practice-validating trials in cervical cancer, endometrial cancer, and ovarian cancer were the focus of the 2021 ASCO Annual Meeting in gynecologic oncology, explained Robert L. Coleman, MD, FACOG, FACS, each carrying relevant implications on extended therapy, surveillance, and biomarker testing.

Cervical Cancer

Cervical cancer is the fourth most common cancer responsible for 90% of deaths in low- and middle-income countries where access to standard-of-care treatment is limited or inaccessible. Launched to fill this unmet global need, the phase 3 OUTBACK study (NCT01414608) randomized women with cervical cancer eligible for chemoradiation with curative intent to concurrent chemoradiation with weekly cisplatin or concurrent chemoradiation with weekly cisplatin followed by adjuvant carboplatin plus paclitaxel.

Most patients in both arms received 5 cycles of cisplatin in the induction phase and radiation without interruption, the latter of which was completed in 8 weeks. However, in the adjuvant phase, 22% of patients didn’t receive any chemotherapy; only 62% of patients received the 4 full doses of carboplatin and paclitaxel.

The 5-year overall survival (OS) rate was 71% in the chemoradiation arm vs 72% in the chemoradiation plus adjuvant chemotherapy arm (HR, 0.90; 95% CI, 0.70-1.17; P = .8). The 5-year progression-free survival (PFS) rates were 61% vs 63%, respectively (HR, 0.86; 95% CI, 0.69-1.07; P = .6).

Moreover, hematologic, general, and neurologic toxicities were increased in the adjuvant chemotherapy arm and the global quality-of-life scores were worse during adjuvant treatment and 3 to 6 months thereafter.

“Pelvic chemoradiation with concurrent weekly cisplatin continues to be the standard of care for the treatment of locally advanced cervical cancer,” said Coleman, chief scientific officer of The US Oncology Network, in a virtual presentation during the 2021 ASCO Direct HighlightsTM webcast in Dallas, a program developed by Physicians’ Education Resource®(PER®), LLC.

“Further research should focus on adjuvant therapies that may be more tolerable and effective when given after standard therapy,” added Coleman, who is also a 2020 Giant of Cancer Care® winner in Gynecologic Oncology.

Endometrial Cancer

The TOTEM trial (NCT00916708)² was launched to understand the necessity of an intensive surveillance strategy for patients with early-stage endometrial cancer. Although most patients with early-stage disease can be cured with surgery alone, approximately 20% will recur within 3 years of diagnosis.

In the study, patients with a low risk of recurrence––stage IA, grade 1 to 2 tumors––were randomized to intensified surveillance or minimalist surveillance, and patients with a high risk of recurrence––stage IA, grade 3 tumors, or stage IB or greater tumors––were randomized to intensified surveillance or minimalist surveillance.

Intensive surveillance for low-risk patients consisted of physical exams every 4 months and annual pap smears for 5 years, and annual imaging studies for the first 2 years vs minimalist surveillance, which consisted only of physical exams every 6 months.

“This seems like it’s a lot for a stage IB, grade 3–type tumor, but this is what’s happening in the community and in academic centers. We outlawed pap swears when I was at [The University of Texas MD Anderson Cancer Center] a couple years ago, but it took an act of congress to make it happen,” said Coleman.

Intensive surveillance for high-risk patients consisted of physical exams every 4 months, CA125 evaluation every 4 months, abdomen and transvaginal ultrasound, annual pap smears, and annual chest, abdomen, and pelvic CT scans for 5 years vs minimalist surveillance, which consisted only of physical exams and annual chest, abdomen, and pelvic CT scans for the first 2 years.

Compliance with the intended follow-up schedule was similar between the intensive and minimalist arms, at 74.7% vs 75.9%, respectively.

At a median follow-up of 66 months, OS was no different between arms (HR, 1.12; 95% CI, 0.85-1.48; P = .424). Similar results were found when the population was stratified by risk (low: HR, 1.48; 95% CI, 0.92-2.37; P = .104; high, HR, 0.96; 95% CI, 0.68-1.36; P = .814).

Relapse-free survival (RFS), also broken down by risk (low, HR, 1.45; 95% CI, 0.95-2.22; P = .085; high, HR, 1.00; 95% CI, 0.72-1.39; P = .997) showed no difference in outcomes with intensified vs minimalist surveillance.

“The take-home message here is that if you’re wedded to doing intensified monitoring, you don’t need to be,” said Coleman.

Ovarian Cancer

The BOOST trial (NCT01462890)³ evaluated the extended use of bevacizumab (Avastin) in patients with newly diagnosed ovarian cancer. In the study, patients with stage IIB to IV cancer who had undergone primary debulking within 8 weeks prior to the start of treatment and more than 4 weeks before the first dose of bevacizumab were randomized to 15 mg/kg of bevacizumab every 3 weeks for 22 cycles plus 175 mg/m² of paclitaxel and carboplatin at an area under the curve of 5 every 3 weeks or 15 mg/kg of bevacizumab every 3 weeks for 44 cycles plus 175 mg/m² of paclitaxel and carboplatin at an area under the curve of 5 every 3 weeks.

Most patients in both arms received each study drug at the intended relative dose intensity, said Coleman.

The median PFS was 24.2 months in the standard bevacizumab arm vs 26.0 months in the extended bevacizumab arm (HR, 0.99; 95% CI, 0.85-1.15; P = .90). Additionally, there was no difference in PFS between arms in patients with stage IIB to IIIC disease and no residual tumor (HR, 0.93; 95% CI, 0.74-1.18; P= .55) or patients with stage IIB to IIIC disease with residual tumor or stage IV disease (HR, 1.06; 95% CI, 0.87-1.29; P = .58).

OS was also no different between arms. The median OS was 54.3 months in the standard bevacizumab arm vs 60.0 months in the extended bevacizumab arm (HR, 1.04; 95% CI, 0.87-1.23; P = .68).

“Longer treatment with bevacizumab for up to 30 months was feasible, [but] the duration of treatment for bevacizumab with 15 months as part of the first-line treatment in advanced ovarian cancer remains standard of care,” said Coleman.

Shifting to maintenance therapy, Coleman highlighted the phase 2b VITAL trial (NCT02346747),⁴ whichevaluated the autologous vaccine, gemogenovatucel-T (Vigil) vs placebo in patients with advanced stage IIIB to IV ovarian cancer who responded to frontline surgery and chemotherapy.

Gemogenovatucel-T was given at 1x10^e7 cells/dose via intradermal injection every 4 weeks for up to 12 doses; placebo was also given intradermally every 4 weeks for up to 12 doses.

The vaccine was well tolerated, mirroring the grade 1 to 3 adverse effects that were reported with placebo.

In terms of efficacy, there was no statistical difference between arms in terms of RFS (HR, 0.688; P = .078) or OS (HR, 0.630; P = .110). However, in homologous recombination proficient patients, a significant difference in RFS (HR, 0.386; P = .007) and OS (HR, 0.342; P = .019) was reported between arms, favoring the use of gemogenovatucel-T.

The OS data, which had been updated in April 2021, continued to demonstrate a favorable signal with gemogenovatucel-T (HR, 0.417; P = .02).

“We’re really interested in moving this into the homologous recombination–proficient space, which is an identifiable subset of patients who have ovarian cancer that we can treat,” said Coleman.

Another phase 2 trial (NCT02606305)⁵ evaluated the folate receptor-α (FRα) antibody-drug conjugate, mirvetuximab soravtansine, which has shown activity in platinum-resistant ovarian cancer. In the study, patients with platinum-resistant and platinum-sensitive disease and medium or high FRα expression received 6 mg/kg, adjusted to ideal body weight, of mirvetuximab soravtansine plus 15 mg/kg of intravenous bevacizumab on day 1 of every 3-week cycle.

The overall response rate (ORR) in the total population (n = 60) was 50%, 33% in medium FRα expressors (n = 27), and 64% in high FRα expressors (n = 33). Patients with platinum-resistant (n = 17) and platinum-sensitive (n = 16) disease had an ORR of 59% and 69%, respectively.

Moreover, the median duration of response exceeded 9 months in the overall population (9.7 months), neared 1 year (11.8 months) in high FRα expressors, and surpassed 1 year (12.7 months) in platinum-sensitive patients. Additionally, longer PFS was reported in high FRα tumors regardless of platinum status; in platinum-resistant status, the median PFS was 9.4 months.

In terms of safety, the adverse effects were consistent with those from prior experiences, said Coleman.

“The strength of these mature data in a broader population of recurrent ovarian cancer warrants further development of this novel, targeted combination and supports mirvetuximab soravtansine as the combination partner choice for bevacizumab,” concluded Coleman.

References

1. Mileshkin LR, Moore KN, Barnes E, et al. Adjuvant 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. 2021;39(suppl 15):LBA3. doi:10.1200/JCO.2021.39.15_suppl.LBA3
2. Zola P, Ciccone G, Piovano E, et al. Intensive versus minimalist follow-up in patients treated for endometrial cancer: a multicentric randomized controlled trial (the TOTEM study––NCT00916708). J Clin Oncol. 2021;39(suppl 15):5506. doi:10.1200/JCO.2021.39.15_suppl.5506
3. Pfisterer J, Joly F, Kristensen G, et al. Optimal treatment duration of bevacizumab combined with carboplatin and paclitaxel in patients with primary epithelial ovarian, fallopian tube or peritoneal cancer: a multicenter open-label randomized 2-arm phase 3 ENGOT/GCIG trial of the AGO Study Group, GINECO, and NSGO (AGO-OVAR17/BOOST, GINECO OV118, ENGOT Ov-15, NCT01462890). J Clin Oncol. 2021;39(suppl 15):5501. doi:10.1200/JCO.2021.39.15_suppl.5501
4. Rocconi RP, Ghamande SA, Barve MA, et al. Maintenance vigil immunotherapy in newly diagnosed advanced ovarian cancer: efficacy assessment of homologous recombination proficient patients in the phase IIb VITAL trial. J Clin Oncol. 2021;39(suppl 15):5502. doi:10.1200/JCO.2021.39.15_suppl.5502
5. O’Malley DM, Oaknin A, Matulonis UA, et al. Mirvetuximab soravtansine, a folate receptor alpha-targeting antibody-drug conjugate, in combination with bevacizumab in patients with platinum-agnostic ovarian cancer: final analysis. J Clin Oncol. 2021;39(suppl 15):5504. doi:10.1200/JCO.2021.39.15_suppl.5504