Phase 3 studies presented at the ESMO Congress 2023 may change the way gynecologic cancers are treated, immediately or in the near future, according to researchers.
An immediate change may be prompted by results from the INTERLACE trial, which suggest that induction chemotherapy before chemoradiotherapy (CRT) should be the new standard of care for patients with locally advanced cervical cancer.1
Results from the KEYNOTE-A18 study suggest an alternative first-line standard for cervical cancer — pembrolizumab plus CRT.2 And results from the innovaTV 301 trial suggest that tisotumab vedotin may be a new standard for patients with recurrent or metastatic cervical cancer.3
Data from the FLAMES trial showed an “unprecedented” improvement in progression-free survival (PFS) with senaparib maintenance in patients with advanced ovarian cancer who responded to first-line chemotherapy.4
In the AtTEnd trial, adding atezolizumab to chemotherapy improved PFS in patients with advanced, newly diagnosed or recurrent endometrial cancer.5
In the DUO-E trial, adding durvalumab to chemotherapy, followed by maintenance with durvalumab alone or in combination with olaparib, improved PFS in patients with advanced or recurrent endometrial cancer.6
INTERLACE: Induction Chemo Plus CRT in Locally Advanced Cervical Cancer
The phase 3 INTERLACE trial enrolled 500 patients with newly diagnosed, locally advanced cervical cancer.1 The patients were randomly assigned to receive induction chemotherapy (6 weeks of carboplatin and paclitaxel) plus standard CRT (n=250) or standard CRT alone (n=250). The median follow-up was 64 months.
Patients who received induction chemotherapy had a significant improvement in PFS (hazard ratio [HR], 0.65; 95% CI, 0.46-0.91; P =.013). The 5-year PFS rate was 73% in the induction arm and 64% in the CRT-alone arm.
Patients in the induction arm also had a significant improvement in overall survival (OS; HR, 0.61; 95% CI, 0.40-0.91; P =.04). The 5-year OS rate was 80% in the induction arm and 72% in the CRT-alone arm.
“This is the first phase 3 randomized trial in locally advanced cervical cancer to show a survival benefit in over 2 decades,” said study discussant Krishnansu Tewari, MD, of the University of California, Irvine.
Grade 3-4 adverse events (AEs) occurred in 59% of patients in the induction chemotherapy arm and 48% of those in the CRT-alone arm. There were 2 grade 5 AEs in the CRT-alone arm, and there was 1 in the induction chemotherapy arm.
These results suggest that induction chemotherapy before CRT should be considered the new standard in locally advanced cervical cancer, according to study presenter Mary McCormack, MBBS, PhD, of University College Hospital in London, UK.
This treatment can be implemented in the clinic immediately, and INTERLACE data support discussing this option with patients, said Antonio González-Martín, MD, PhD, of Clinica Universidad de Navarra in Madrid, who reviewed data from this study during a “highlights” session at the ESMO Congress.
KEYNOTE-A18: Pembrolizumab Plus CRT in Locally Advanced Cervical Cancer
The phase 3 KEYNOTE-A18 trial (ClinicalTrials.gov Identifier: NCT04221945) included 1060 patients with treatment-naive, high-risk, locally advanced cervical cancer.2 The patients were randomly assigned to receive pembrolizumab and CRT (n=529) or placebo and CRT (n=531). The median follow-up was 17.9 months.
The median PFS was not reached with either treatment, but PFS was improved with pembrolizumab (HR, 0.70; 95% CI, 0.55-0.89; P =.0020). There was a trend toward improved OS with pembrolizumab as well (HR, 0.73; 95% CI, 0.49-1.07).
Grade 3 or higher treatment-related AEs occurred in 67.0% of patients in the pembrolizumab arm and 60.6% of those in the placebo arm. Two patients in each arm died from treatment-related AEs.
“These data support pembrolizumab plus chemoradiotherapy as a new potential standard of care for patients with newly diagnosed, previously untreated, high risk, locally advanced cervical cancer,” said study presenter Domenica Lorusso, MD, PhD, of Università Cattolica del Sacro Cuore in Rome, Italy.
Pembrolizumab will probably be approved for this indication in the near future, Dr González-Martín predicted.
innovaTV 301: Tisotumab Vedotin in Recurrent, Metastatic Cervical Cancer
The phase 3 innovaTV 301 trial (ClinicalTrials.gov Identifier: NCT04697628) included 502 patients with recurrent or metastatic cervical cancer who had received a maximum of 2 lines of prior therapy.3
The patients were randomly assigned to receive tisotumab vedotin (n=253) or investigator’s choice of chemotherapy (n=249), which was gemcitabine, irinotecan, pemetrexed, topotecan, or vinorelbine. The median follow-up was 10.8 months.
The median PFS was 4.2 months in the tisotumab vedotin arm and 2.9 months in the chemotherapy arm (HR, 0.67; 95% CI, 0.54-0.82; P <.0001).
The median OS was 11.5 months in the tisotumab vedotin arm and 9.5 months in the chemotherapy arm (HR, 0.70; 95% CI, 0.54-0.89; P =.0038).
Grade 3 or higher treatment-related AEs occurred in 29.2% of patients in the tisotumab vedotin arm and 45.2% of those in the chemotherapy arm. There were 2 fatal treatment-related AEs in the tisotumab vedotin arm, and there was 1 in the chemotherapy arm.
“Based on these data, I believe that tisotumab vedotin should be considered as a potential new standard of care for patients who have progressed after first-line systemic therapy,” said study presenter Ignace B. Vergote, MD, PhD, of UZ Leuven in Belgium.
“I think this is a practice-changing study,” said Dr Tewari, who was the discussant for this study as well. “It’s going to convert the accelerated approval of TV [tisotumab vedotin] in the United States to full approval.”
FLAMES: Senaparib Maintenance in Advanced Ovarian Cancer
The phase 3 FLAMES trial (ClinicalTrials.gov Identifier: NCT04169997) enrolled patients with stage III/IV, high-grade serous or endometrioid ovarian, fallopian tube, or primary peritoneal cancer who had a response to frontline platinum-based chemotherapy.4
The patients were randomly assigned to receive senaparib (n=271) or placebo (n=133) maintenance. The median follow-up was 22.3 months.
The median PFS was not reached in the senaparib arm and was 13.6 months in the placebo arm (HR, 0.43; 95% CI 0.32-0.58, P <.0001). Patients had a PFS benefit with senaparib regardless of BRCA mutation status.
The rate of grade 3 or higher treatment-emergent AEs was 66.3% in the senaparib arm and 20.3% in the placebo arm. There were no grade 5 AEs.
These results support the use of senaparib maintenance in this patient population, according to study presenter Xiaohua Wu, MD, PhD, of Fudan University Shanghai Cancer Center in China.
He said the improvement in PFS observed with senaparib was “unprecedented.”
AtTEnd: Atezolizumab Plus Chemo in Advanced Endometrial Cancer
The phase 3 AtTEnd trial (ClinicalTrials.gov Identifier: NCT03603184) included 549 patients with stage III-IV endometrial cancer.5 Patients could have newly diagnosed or recurrent disease, but they could not have received prior therapy for recurrence.
The patients were randomly assigned to receive atezolizumab (n=360) or placebo (n=189), each in combination with paclitaxel and carboplatin every 21 days for 6 to 8 cycles. This was followed by atezolizumab or placebo maintenance until disease progression.
The median PFS was 10.1 months in the atezolizumab arm and 8.9 months in the placebo arm (HR, 0.74; 95% CI, 0.61-0.91; P =.0219). OS data were not mature, but the median OS was 38.7 months in the atezolizumab arm and 30.2 months in the placebo arm (HR, 0.82; 95% CI, 0.63-1.07; P =.0483).
The improvement in PFS was mainly due to the benefit observed with atezolizumab in patients with mismatch repair-deficient (dMMR) disease, said study presenter Nicoletta Colombo, MD, PhD, of the European Institute of Oncology in Milan, Italy.
In the dMMR cohort, the median PFS was not reached in the atezolizumab arm and was 6.9 months in the placebo arm (HR, 0.36; 95% CI, 0.23-0.57; P =.0005). The median OS in this cohort was not reached in the atezolizumab arm and was 25.7 months in the placebo arm (HR, 0.41; 95% CI, 0.22-0.76).
In the overall cohort, grade 3 or higher AEs related to atezolizumab or placebo occurred in 25.8% of patients in the atezolizumab arm and 14.1% of those in the placebo arm. There was 1 grade 5 AE related to atezolizumab or placebo in each arm.
“AtTEnd confirms the outstanding efficacy of immune checkpoint inhibitors, including PD-L1 inhibitors, in combination with chemotherapy in patients with advanced/recurrent endometrial carcinoma, particularly in those with dMMR status,” Dr Colombo said.
These results validate that immunotherapy plus chemotherapy “really works” for patients with dMMR endometrial cancer, echoed study discussant David Tan, MBBS, PhD, of the National University Cancer Institute in Singapore.
DUO-E: Adding Durvalumab and Olaparib to Chemo in Endometrial Cancer
The phase 3 DUO-E trial (ClinicalTrials.gov Identifier: NCT04269200) included 718 patients with recurrent or newly diagnosed, stage III/IV endometrial cancer who had not received PARP inhibitors, immune-mediated therapy, or any systemic therapy for advanced disease.6
The patients were randomly assigned to receive placebo plus chemotherapy with placebo maintenance (n=241), durvalumab plus chemotherapy with durvalumab maintenance (n=238), or durvalumab plus chemotherapy and maintenance with durvalumab and olaparib (n=239).
The median PFS was 9.6 months in the placebo-chemotherapy arm, 10.2 months in the durvalumab-chemotherapy arm (HR, 0.71; 95% CI, 0.57-0.89; P =.003), and 15.1 months in the durvalumab-olaparib-chemotherapy arm (HR, 0.55; 95% CI, 0.43-0.69; P <.0001).
The median OS was 25.9 months in the placebo-chemotherapy arm, not reached in the durvalumab-chemotherapy arm (HR, 0.77; 95% CI, 0.56-1.07; P =.120), and not reached in the durvalumab-olaparib-chemotherapy arm (HR, 0.59; 95% CI, 0.42-0.83; P =.003).
In an experimental comparison, PFS was significantly longer with durvalumab-olaparib than with durvalumab (HR, 0.78; 95% CI, 0.61-0.99), and there was a trend toward improved OS with durvalumab-olaparib (HR, 0.77; 95% CI, 0.53-1.10).
Grade 3 or higher AEs occurred in 56.4% of patients in the placebo-chemotherapy arm, 54.9% of those in the durvalumab-chemotherapy arm, and 67.2% of those in the durvalumab-olaparib-chemotherapy arm. There were 8 fatal AEs in the placebo arm, 4 in the durvalumab arm, and 5 in the durvalumab-olaparib arm.
“These data confirm the clinical benefit of integrating immunotherapy into first-line chemotherapy and are the first to indicate that the addition of a PARP inhibitor may offer further benefit in this setting,” the study authors wrote in the Journal of Clinical Oncology, where this study was published to coincide with the ESMO presentation.7
Disclosures: KEYNOTE-A18 was supported by Merck Sharp & Dohme LLC. The innovaTV 301 trial was supported by Genmab and Seagen Inc. The FLAMES trial was supported by IMPACT Therapeutic, Inc. AtTEnd was supported by F. Hoffmann-La Roche Ltd. DUO-E was supported by AstraZeneca. Some study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original references for a full list of disclosures.
References
1. McCormack M, Gallardo Rincón D, Eminowicz G, et al. A randomised phase III trial of induction chemotherapy followed by chemoradiation compared with chemoradiation alone in locally advanced cervical cancer: The GCIG INTERLACE trial. Presented at ESMO Congress 2023. Oct 20-24, 2023. Madrid, Spain. Abstract LBA8.
2. Lorusso D, Xiang Y, Hasegawa K, et al. Pembrolizumab plus chemoradiotherapy for high-risk locally advanced cervical cancer: A randomized, double-blind, phase III ENGOT-cx11/GOG-3047/KEYNOTE-A18 study. Presented at ESMO Congress 2023. Oct. 20-24, 2023. Madrid, Spain. Abstract LBA38.
3. Vergote IB, Gonzalez Martin A, Fujiwara K, et al. innovaTV 301/ENGOT-cx12/GOG-3057: A global, randomized, open-label, phase III study of tisotumab vedotin vs investigator’s choice of chemotherapy in 2L or 3L recurrent or metastatic cervical cancer. Presented at ESMO Congress 2023. Oct 20-24, 2023. Madrid, Spain. Abstract LBA9.
4. Wu X, Liu J, Wang X, et al. Efficacy and safety of senaparib as maintenance treatment in patients with newly diagnosed advanced ovarian cancer (FLAMES study): A randomized, double-blind, placebo-controlled, phase III trial. Presented at ESMO Congress 2023. Oct. 20-24, 2023. Madrid, Spain. Abstract LBA36.
5. Colombo N, Harano K, Hudson E, et al. Phase III double-blind randomized placebo controlled trial of atezolizumab in combination with carboplatin and paclitaxel in women with advanced/recurrent endometrial carcinoma. Presented at ESMO Congress 2023. Oct. 20-24, 2023. Madrid, Spain. Abstract LBA40.
6. Westin SN, Moore KN, Chon HS, et al. Durvalumab (durva) plus carboplatin/paclitaxel (CP) followed by maintenance (mtx) durva ± olaparib (ola) as a first-line (1L) treatment for newly diagnosed advanced or recurrent endometrial cancer (EC): Results from the phase III DUO-E/GOG-3041/ENGOT-EN10 trial. Presented at ESMO Congress 2023. Oct. 20-24, 2023. Madrid, Spain. Abstract LBA41.
7. Westin SN, Moore KN, Chon HS, et al. Durvalumab plus carboplatin/paclitaxel followed by maintenance durvalumab with or without olaparib as first-line treatment for advanced endometrial cancer: The phase III DUO-E trial. J Clin Oncol. Published online October 21, 2023. doi:10.1200/JCO.23.02132
