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Recent developments in gynae-oncology in 2020

Dr Priyanka Srivastava

MD. DNB Medical Oncology, Fellow Medical Oncology, PMCC, UOT, Canada. Consultant Medical Oncologist, M.S. Patel Cancer Center, Shreekrishna Hospital. Assistant Professor of Medicine, Pramukhswami Medical College, Bhaikaka University, Karamsad, Gujarat, 388325

Email: priyankasrivastavadr@gmail.com

The year 2020, year of COVID-19 pandemic has been a challenge for mankind. It posed a difficult time for scientific community also. Accrual in clinical trials were low and routine follow-up visits to hospital became a threat to patients. Ways of life changed substantially this year like telemedicine and virtual conferences. Despite all these challenges researchers continued their efforts to further refine their understanding of cancer care and bringing it to clinical practice. Following are some of the research papers published in the year 2020, in the field of gynae-oncology.

The American Cancer Society (ACS) published revised guidelines for cervical cancer screening. The updated recommendation is to initiate cervical cancer screening at age 25 years with primary human papillomavirus (HPV) testing every 5 years through age 65 years (preferred); if primary HPV testing is not available, then individuals aged 25 to 65 years should be screened with co-testing (HPV testing in combination with cytology) every 5 years or cytology alone every 3 years. The updated guidelines differ from 2012 recommendations in following four aspects:

  • 1. the preferred screening strategy is primary HPV testing every 5 years, however if US Food and Drug Administration (FDA) approved primary HPV testing is not yet available, then co-testing and cytology alone is acceptable;
  • 2. the recommended age to start screening is 25 years rather than 21 years;
  • 3. primary HPV testing, as well as co-testing or cytology alone when primary testing is not available, is recommended starting at age 25 years rather than age 30 years;
  • 4. the guideline is transitional, i.e., options for screening with co-testing or cytology alone are provided but should be phased out once full access to primary HPV testing for cervical cancer screening is available without barriers.1

The ACS also updated guidelines for human papilloma virus (HPV) vaccination. The ACS no longer endorses the 2019 Advisory Committee on Immunization Practices recommendation of shared clinical decision making for some adults aged 27 through 45 years who are not adequately vaccinated because of the low effectiveness and low cancer prevention potential of vaccination in this age group, the burden of decision making on patients and clinicians, and the lack of sufficient guidance on the selection of individuals who might benefit.2

In the field of ovarian cancer, some of the interesting and long-awaited data were presented this year. The role of secondary cytoreductive surgery in platinum sensitive recurrent ovarian cancer (PSROC) has been a matter of debate for long. The AGO DESKTOP III/ENGOT-ov20 is the first phase III study to show overall survival (OS) benefit in this group of patients. In this prospective randomised superiority trial, 407 patients were enrolled from 2010 to 2014. Inclusion criteria were first relapse after 6+ months platinum-free interval (TFIp) and a positive AGO-score (PS ECOG 0, ascites ≤500 ml, and complete resection at initial surgery). The treatment arm included cytoreductive surgery followed by the platinum-based combination chemotherapy vs. second-line chemotherapy alone in the control group. Primary endpoint analysis showed median overall survival (OS) of 53.7 months with and 46.2months without surgery hazard ratio (HR) 0.76, 95% confidence interval [CI] 0.59-0.97, p=0.03; median progression free survival (PFS) was 18.4 and 14 months (HR: 0.66, 95%CI 0.54-0.82, p<0.001), median time to start of first subsequent therapy (TFST) was 17.9 vs. 13.7 months in favour of the surgery arm (HR 0.65, 95%CI 0.52-0.81, p < 0.001). The patients who underwent complete resection (CR) were benefited most (median 60.7 vs. 46.2 months).3

The poly (ADP-ribose) polymerase inhibitors (PARPi’s) are being evaluated for multiple indications in gynaecological malignancies. The SOLO2/ENGOT-ov21 is a phase III trial, assessing maintenance olaparib in patients with PSROC and a BRCA mutation. In this trial patients who had received ≥2 lines of treatment and were in response to their most recent platinum-based chemotherapy received maintenance olaparib (300 mg bid tablets) or placebo. In a pre-planned final OS analysis, an unprecedented long-term treatment benefit was seen with olaparib vs placebo with an OS HR of 0.74 (95% CI 0.54–1.00) in the full analysis set (FAS; unadjusted for crossover; 38.4% of placebo patients crossed over to a PARPi). At 5 years: by Kaplan-Meier estimates, 28.3% of patients in the olaparib arm vs 12.8% of patients in the placebo arm were alive and had still not received subsequent treatment; 42.1% of olaparib patients vs 33.2% of placebo patients were alive.4

The chemotherapy-free regimen of niraparib and bevacizumab compared to niraparib alone in women with PSROC is being evaluated in randomized, open-label, phase 2 NSGO-AVANOVA2/ENGOT-OV24 study. Patients were included regardless of homologous recombination deficiency (HRD) status (MyChoice HRD), duration of chemotherapy-free interval (CFI) and number of previous lines of therapy. A total of 97 patients with measurable/evaluable, high-grade serous ovarian carcinoma (HGSOC) or endometrioid PSROC were randomized to niraparib 300 mg once daily (48 patients) or the combination of niraparib 300 mg once daily and bevacizumab 15 mg/kg IV (49 patients) every 3 weeks until disease progression. The recently published update consistently demonstrated that the niraparib-bevacizumab combination had clinically and statistically meaningful activity in PSROC with median PFS of 12.5 months vs. 5.5 months; HR adjusted for stratification factors 0.34; 95% CI [0.21 to 0.55]; P < 0.0001. The study was not powered to detect differences in OS or any other efficacy endpoints however TFST, PFS2 & TSST are significantly improved while there is a trend towards OS improvement with niraparib-bevacizumab combination. Patient-reported outcomes measured using EORTC QLQ-C30 and OV28 were similar for both treatment arms.5

Similarly, maintenance with olaparib + bevacizumab in patients with newly diagnosed advanced HGOC is being evaluated in the phase III PAOLA-1/ENGOT-ov25 trial. Total 537 patients were randomized to olaparib + bevacizumab and 269 to placebo + bevacizumab with median PFS2 follow-up of 35.5 and 36.5 months, respectively (data cut-off 22 March 2020). Patients with newly diagnosed, FIGO stage III -IV HGOC in response after platinum-based chemotherapy + bevacizumab were randomized to olaparib tablets (300 mg bid for 24 months) + bevacizumab (15 mg/kg q3w for 15 months) or placebo + bevacizumab. The final PFS2 data showed that Olaparib + bevacizumab provided a statistically significant reduction in the risk of second progression or death vs placebo + bevacizumab (Intention to treat ITT analysis; HR 0.78; 95% CI 0.64 -0.95; P=0.0125). A substantial PFS2 benefit was reported in tumour BRCAm (tBRCAm) and HRD-positive patients. HRs for PFS2 by biomarker status with olaparib + bevacizumab vs placebo + bevacizumab were 0.53 in patients with a tBRCAm, 0.56 in HRD-positive patients, 0.60 in HRD-positive patients without a tBRCAm and 1.04 in HRD-negative patients. TSST was longer with olaparib + bevacizumab vs placebo + bevacizumab (median 38.2 vs 31.5 months) (HR 0.78; 95% CI 0.64 -0.95; P=0.0115). 6 Professor Keiichi Fujiwara et al., reported the data from the Japanese subset of patients participating in the international phase III PAOLA-1/ENGOT-ov25 study with similar outcomes, with median PFS per investigator assessment being 27.4 months (95% CI 11.1–not reached) versus 19.4 months (95% CI 3.1–24.0) in the respective treatment arms (HR, 0.34; 95% CI, 0.11–1.00). Median PFS according to blinded independent central review (BICR) was 27.2 months versus 18.3 months, respectively (HR 0.40; 95% CI 0.13–1.23). The proportion of patients experiencing a Grade ≥3 AE was generally higher in the subset than in the overall population. 7

The adverse events with PARPi seen in Asian population are different from Caucasian population which requires frequent dosing modification. In phase III NORA trial X. Wuet et al., studied individualized starting dose of niraparib in Chinese patients with PSROC. This randomized, double-blind, placebo-controlled trial was conducted in 32 hospitals in China. Women with PSROC who had either germline BRCA mutation or high-grade serious histologic features and who had a complete or partial response after completion of the last round of platinum therapy were randomly allocated (2:1) to receive oral niraparib or placebo once daily. The starting dose was individualized (ISD) per baseline body weight and platelet count (200 mg for patients with baseline body weight < 77 kg or platelet count < 150,000/μL; otherwise, 300 mg). Total 265 patients were randomized to niraparib (n=177) or placebo (n=88); 16 patients received fixed starting dose of 300 mg and 249 patients received an ISD (300 mg, n=14; 200 mg, n=235) under the amended protocol. The median PFS was significantly longer for patients on niraparib versus placebo; 18.3 (95% CI, 10.9, not evaluable) versus 5.4 (95% CI, 3.7, 5.7) months (HR=0.32; 95% CI, 0.23–0.45; p <0.0001). Grade ≥3 treatment emergent adverse events (TEAE) occurred in 50.8% and 19.3% of patients in niraparib vs placebo arm respectively. The author concluded that ISD of niraparib is safe and effective in this population. 8

The advent of immunotherapy has changed treatment of cancer dramatically. Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo-controlled randomised phase III trial of bevacizumab-containing therapy +/- atezolizumab for newly diagnosed stage III/IV ovarian cancer (OC) was reported by Kathleen Moore et al. This study enrolled 1301 patients with newly diagnosed untreated stage III/IV OC who underwent either primary cytoreductive surgery (PCS) with gross residual disease or neoadjuvant chemotherapy (NACT) and interval surgery. Patients were randomised 1:1 to atezolizumab 1200 mg or placebo cycles 1–22, with paclitaxel 175 mg/m2 + carboplatin AUC6 cycles 1–6 + bevacizumab 15 mg/kg cycles 2–22 (PCS pts), omitting peri-operative bevacizumab in NACT patients. Cycles were repeated q3w. There was no statistically significant PFS improvement in either the ITT population (HR 0.92 [95% CI 0.79–1.07]; median 18.4 months with placebo vs 19.5 months with atezolizumab) or the PD-L1+ population (HR 0.80 [0.65–0.99], median 18.5 vs 20.8 months, respectively) although exploratory PFS analyses in the PD-L1 IC ≥5% subgroup showed a trend favouring atezolizumab. Also, first interim OS results did not show significant benefit from atezolizumab. Further biomarker subgroup analysis might show benefits in particular group in future.9

Another newer IO agent under evaluation in ovarian cancer is dostarlimab. It’s an anti–PD-1 humanized monoclonal antibody. L.M. Randall et al., are evaluating the efficacy and safety of combination of niraparib and dostarlimab in patients with platinum-resistant ovarian cancer in a phase II, open-label, single-arm study.10 Mirvetuximab Soravtansine (MIRV), is a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC). As part of the Phase 1b FORWARD II trial (NCT02606305), the combination of MIRV with bevacizumab was evaluated in patients with FRα-positive (medium/high expression; ≥ 50%/ ≥75% of cells with PS2+ staining intensity), platinum agnostic ovarian cancer. Objective responses were seen in 26 patients for a confirmed overall response rate (ORR) of 43% (95% CI, 31, 57). The most common treatment related AEs (percent all grade/grade 3+) were diarrhoea (65/2), blurred vision (62/3), nausea (55/0), and fatigue (55/5). The most common treatment related grade 3+ AEs were hypertension and neutropenia, (10% each); all other grade 3+ events occurred in ≤ 5% of patients.11

In field of endometrial cancer (EC), some encouraging data were published this year. Combination of antiangiogenic drugs and immunotherapy is being utilized to reprogram tumour microenvironment with increased antitumor activity. KEYNOTE-146/Study 111 is an ongoing multinational, open-label, single-arm study (ClinicalTrials.gov identifier: NCT02501096) of lenvatinib + pembrolizumab in patients with selected solid tumors including EC. Vickey Makker et al., reported primary efficacy analysis results for a patients cohort with advanced EC. Patients took lenvatinib 20 mg once daily orally plus pembrolizumab 200 mg intravenously once every 3 weeks, in 3-week cycles. The primary end point was objective response rate (ORR) at 24 weeks (ORRWk24). Total 108 patients with previously treated EC were enrolled, with a median follow-up of 18.7 months. The ORRWk24 was 38.0% (95% CI, 28.8% to 47.8%). Among subgroups, the ORRWk24 (95% CI) was 63.6% (30.8% to 89.1%) in patients with microsatellite instability (MSI)–high tumours (n = 11) and 36.2% (26.5% to 46.7%) in patients with microsatellite-stable tumours (n = 94). 12 Another, 2:1 randomized phase 2 trial compared the combination of cabozantinib and nivolumab (Arm A) versus nivolumab (Arm B) in recurrent EC. Primary endpoint was PFS assessed by RECIST 1.1. Cabozantinib was given at 40 mg daily (Arm A) and nivolumab at 240 mg, on D1 and D15 of a 28-day cycle for four cycles, followed by 480 mg every four weeks (Arms A & B). Patients with carcinosarcoma or prior IO were enrolled in an exploratory cohort and received combination treatment (Arm C). Total 76 evaluable patients were enrolled (Arm A: 36, Arm B: 18, Arm C: 9 carcinosarcoma, and 20 post IO. The Kaplan-Meier estimated median PFS was 5.3 (95% CI: 3.5-9.5) months in Arm A and 1.9 (95% CI: 1.6-3.8) months in Arm B, with a log-rank p = 0.07. Objective response rate (ORR) was 25% for Arm A and 16.7% for Arm B; stable disease (SD) was seen in 44.4% vs 11.1%, respectively. Clinical benefit (ORR+SD) was significantly higher in arm A vs B (p < 0.001). In Arm C-carcinosarcoma, one patient had a partial response (11.9 months duration) and four SD. In Arm C-prior IO, six patients responded and eight had SD. 13 NSGO-PALEO / ENGOT-EN3 trial is a randomized double-blind placebo-controlled phase II trial of palbociclib combined with letrozole in patients with oestrogen receptor-positive (ER+) advanced/recurrent EC. Patients were randomised 1:1 to receive L 2.5 mg OD orally d1–28 with either palbociclib 125 mg or placebo OD orally d1–21 in a 28-d cycle until progression. Tumours were assessed every 12 weeks. The primary endpoint was PFS. Letrozole + palbociclib significantly improved PFS compared with letrozole + placebo: median 8.3 vs. 3.0 months, respectively; HR 0.56 (95% CI 0.32 to 0.98; p0.041). Disease control rate at 24 weeks: 64% vs. 38%. Treatment-emergent grade 3/4 adverse events were significantly more frequent with letrozole + palbociclib (anaemia 8% vs 3%; neutropenia 42% vs 0%).14 There has been a relative paucity of newer treatment options in field of cervical cancer. Currently, newer agents are under evaluation in clinical trials. ENGOT-cx11/KEYNOTE-A18, is a phase III, randomised, double-blind study evaluating pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.15 Bintrafusp-α is a first-in-class bifunctional fusion protein composed of the extracellular domain of the TGF-bRII receptor (a TGF-b “trap”) fused to a human IgG1 mAb blocking PD-L1. A single-arm phase II study is assessing the clinical activity and safety profile of bintrafusp-α in platinum-experienced cervical cancer.16 Africa, China and India are the worst affected with cervical cancer, which is a leading cause of cancer related mortality in this region. While western researchers mainly focusing on ovarian cancer and EC, there remains an unmet need of research in the field of cervical cancer.

References
  • 1. Fontham ET, Wolf AM, Church TR, Etzioni R, Flowers CR, Herzig A, Guerra CE, Oeffinger KC, Shih YC, Walter LC, Kim JJ. Cervical cancer screening for individuals at average risk: 2020 guideline update from the American Cancer Society. CA: A Cancer Journal for Clinicians. 2020 Sep;70(5):321-46.
  • 2. Saslow D, Andrews KS, Manassaram‐Baptiste D, Smith RA, Fontham ET, American Cancer Society Guideline Development Group. Human papillomavirus vaccination 2020 guideline update: American Cancer Society guideline adaptation. CA: A Cancer Journal for Clinicians. 2020 Jul;70(4):274-80.
  • 3. Du Bois A, Sehouli J, Vergote I, Ferron G, Reuss A, Meier W, Greggi S, Jensen PT, Selle F, Guyon F, Pomel C. Randomized phase III study to evaluate the impact of secondary cytoreductive surgery in recurrent ovarian cancer: Final analysis of AGO DESKTOP III/ENGOT-ov20.
  • 4. Poveda A, Floquet A, Ledermann JA, Asher R, Penson RT, Oza AM, Korach J, Huzarski T, Pignata S, Friedlander M, Baldoni A. Final overall survival (OS) results from SOLO2/ENGOT-ov21: A phase III trial assessing maintenance olaparib in patients (pts) with platinum-sensitive, relapsed ovarian cancer and a BRCA mutation.
  • 5. Mirza MR, Nyvang GB, Lund B, Christensen RD, Werner TL, Malander S, Bjørge L, Birrer MJ, Anttila M, Lindahl G, Hietanen S. Final survival analysis of NSGO-AVANOVA2/ENGOT-OV24: Combination of niraparib and bevacizumab versus niraparib alone as treatment of recurrent platinum-sensitive ovarian cancer—A randomized controlled chemotherapy-free study.
  • 6. Martín AG, Tazi Y, Heitz F, Montane L, Gargiulo P, Berger R, Yonemori K, Vergote I, Bologna A, Maenpaa J, Costan C. LBA33 Maintenance olaparib plus bevacizumab (bev) in patients (pts) with newly diagnosed advanced high‐grade ovarian carcinoma (HGOC): Final analysis of second progression-free survival (PFS2) in the phase III PAOLA-1/ENGOT-ov25 trial. Annals of Oncology. 2020 Sep 1;31:S1163-4.
  • 7. 236O – Fujiwara K, Fujiwara H, Yoshida H, et al. Olaparib (ola) plus bevacizumab (bev) as maintenance (mx) therapy in patients (pts) with newly diagnosed advanced ovarian carcinoma (OC): Japan subset of the PAOLA-1 trial. ESMO Asia Virtual Congress 2020 (20-22 November).
  • 8. Wu X, Zhu J, Yin R, Yang J, Liu J, Wang J, Wu L, Liu Z, Gao Y, Wang D, Lou G. LBA29 Individualized starting dose of niraparib in Chinese patients with platinum-sensitive recurrent ovarian cancer (PSROC): A randomized, double-blind, placebo-controlled, phase III trial (NORA). Annals of Oncology. 2020 Sep 1;31:S1160-1.
  • 9. Moore KN, Bookman M, Sehouli J, Miller A, Anderson C, Scambia G, Myers T, Taskiran C, Robison K, Maenpaa J, Willmott LJ. LBA31 Primary results from IMagyn050/GOG 3015/ENGOT-OV39, a double-blind placebo (pbo)-controlled randomised phase III trial of bevacizumab (bev)-containing therapy+/-atezolizumab (atezo) for newly diagnosed stage III/IV ovarian cancer (OC). Annals of Oncology. 2020 Sep 1;31:S1161-2.
  • 10. Randall LM, O'Malley DM, Monk BJ, Coleman RL, O'Cearbhaill RE, Gaillard S, Adams S, Cappuccini F, Huang M, Chon HS, Secord AA. 883TiP MOONSTONE/GOG-3032: A phase II, open-label, single-arm study to evaluate the efficacy and safety of niraparib+ dostarlimab in patients with platinum-resistant ovarian cancer. Annals of Oncology. 2020 Sep 1;31:S646-7.
  • 11. Gilbert L, Oaknin A, Matulonis UA, Mantia-Smaldone G, Lim PC, Castro CM, Provencher DM, Memarzadeh S, Wang J, Esteves B, Zweidler-McKay PA. Mirvetuximab soravtansine, a folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC), in combination with bevacizumab in patients (pts) with platinum-agnostic ovarian cancer.
  • 12. Makker V, Taylor MH, Aghajanian C, Oaknin A, Mier J, Cohn AL, Romeo M, Bratos R, Brose MS, DiSimone C, Messing M. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. Journal of clinical oncology. 2020 Sep 10;38(26):2981.
  • 13. Lheureux S, Matei D, Konstantinopoulos PA, Block MS, Jewell A, Gaillard S, McHale MS, McCourt CK, Temkin S, Girda E, Backes FJ. A randomized phase II study of cabozantinib and nivolumab versus nivolumab in recurrent endometrial cancer.
  • 14. Mirza MR, Bjørge L, Marmé F, Christensen RD, Gil-Martin M, Auranen A, Ataseven B, Rubio MJ, Salutari V, Lund B, Runnebaum I. LBA28 A randomised double-blind placebo-controlled phase II trial of palbociclib combined with letrozole (L) in patients (pts) with oestrogen receptor-positive (ER+) advanced/recurrent endometrial cancer (EC): NSGO-PALEO/ENGOT-EN3 trial. Annals of Oncology. 2020 Sep 1;31:S1160.
  • 15. Lorusso D, Colombo N, Coleman RL, Randall LM, Duska LR, Xiang Y, Hasegawa K, Rodrigues AN, Cibula D, Mirza MR, You B. ENGOT-cx11/KEYNOTE-A18: A phase III, randomized, double-blind study of pembrolizumab with chemoradiotherapy in patients with high-risk locally advanced cervical cancer.
  • 16. Birrer MJ, Mileshkin LR, Fujiwara K, Ray-Coquard I, Alexandre J, Okamoto A, et al. 879TiP Phase II study of bintrafusp alfa, a bifunctional fusion protein targeting TGF-β and PD-L1, in platinum-experienced advanced cervical cancer. Annals of Oncology. 2020 Sep;31:S644–5.

Courtesy - Indian Journal of Medical and Paediatric Oncology (IJMPO)
Editor-in-Chief - Dr. Padmaj Kulkarni