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Clinical Trial
. 2023 Apr:171:141-150.
doi: 10.1016/j.ygyno.2023.01.010. Epub 2023 Mar 8.

Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study

Krishnansu S Tewari  1 , Michael W Sill  2 , Michael J Birrer  3 , Richard T Penson  4 , Helen Huang  5 , David H Moore  6 , Lois M Ramondetta  7 , Lisa M Landrum  8 , Ana Oaknin  9 , Thomas J Reid  10 , Mario M Leitao  11 , Helen E Michael  12 , Bradley J Monk  13
Affiliations
Clinical Trial

Final survival analysis of topotecan and paclitaxel for first-line treatment of advanced cervical cancer: An NRG oncology randomized study

Krishnansu S Tewari et al. Gynecol Oncol. 2023 Apr.

Abstract

Objective: To determine whether a non‑platinum chemotherapy doublet improves overall survival (OS) among patients with recurrent/metastatic cervical carcinoma.

Methods: Gynecologic Oncology Group protocol 240 is a phase 3, randomized, open-label, clinical trial that studied the efficacy of paclitaxel 175 mg/m2 plus topotecan 0.75 mg/m2 days 1-3 (n = 223) vs cisplatin 50 mg/m2 plus paclitaxel 135 or 175 mg/m2 (n = 229), in 452 patients with recurrent/metastatic cervical cancer. Each chemotherapy doublet was also studied with and without bevacizumab (15 mg/kg). Cycles were repeated every 21 days until progression, unacceptable toxicity, or complete response. The primary endpoints were OS and the frequency and severity of adverse effects. We report the final analysis of OS.

Results: At the protocol-specified final analysis, median OS was 16.3 (cisplatin-paclitaxel backbone) and 13.8 months (topotecan-paclitaxel backbone) (HR 1.12; 95% CI, 0.91-1.38; p = 0.28). Median OS for cisplatin-paclitaxel and topotecan-paclitaxel was 15 vs 12 months, respectively (HR 1.10; 95% CI,0.82-1.48; p = 0.52), and for cisplatin-paclitaxel-bevacizumab and topotecan-paclitaxel-bevacizumab was 17.5 vs 16.2 months, respectively (HR 1.16; 95% CI, 0.86-1.56; p = 0.34). Among the 75% of patients in the study population previously exposed to platinum, median OS was 14.6 (cisplatin-paclitaxel backbone) vs 12.9 months (topotecan-paclitaxel backbone), respectively (HR 1.09; 95% CI, 0.86-1.38;p = 0.48). Post-progression survival was 7.9 (cisplatin-paclitaxel backbone) vs 8.1 months (topotecan-paclitaxel backbone) (HR 0.95; 95% CI, 0.75-1.19). Grade 4 hematologic toxicity was similar between chemotherapy backbones.

Conclusions: Topotecan plus paclitaxel does not confer a survival benefit to women with recurrent/metastatic cervical cancer, even among platinum-exposed patients. Topotecan-paclitaxel should not be routinely recommended in this population. NCT00803062.

Keywords: Cervical Cancer; Paclitaxel; Platinum; Recurrent; Topotecan.

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Conflict of interest statement

Declaration of Competing Interest Dr. Tewari reports receiving honoraria for lectures, presentations, speakers' bureaus for Merck, Astra Zeneca, Eisai, Seagen, Tesaro and Clovis. He also reports serving on Data Safety Monitoring Board/Advisory Board for Iovance. Dr. Penson reports grants received from Array BioPharma Inc., AstraZeneca, Eisai Inc., Genentech, Inc., Regeneron, Sanofi-Aventis US LLC, Tesaro Inc. and Vascular Biogenics Ltd. Dr. Penson also reports receiving consulting fees from AstraZeneca, Eisai, GSK Inc., ImmunoGen Inc., Merck & Co, Mersana, Novacure, Roche Pharma, Sutro Biopharma, and Vascular Biogenics Ltd. and reports participating on Advisory Boards for AstraZeneca and Roche Pharma. Dr. Oaknin reports grants to her institution from the following: Abbvie Deutschland Gmbh & Co Hg, Ability Pharmaceuticals, Advaxis, Agenus, Aprea Therapeutics AB, AstraZeneca AB, BeiGene USA, Inc., Belgian Gynecological Oncology Group (BGOG), Bristol-Myers Squibb International Corporation (BMSM Clovis Oncology, Corcept Therapeutics, Eisai, F. Hoffmann-La Roche, Grupo Española de Investigación en Cáncer de Ovario (GEICO)), Immunogen, Iovance Biotherapeutics, Lilly, Medimmune, Merck Healthcare, Merck Sharp & Dohme, Millennium Pharmaceuticals, Unipharm Research, Novartis Farmacéutica, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem, Regeneron Pharmaceuticals, Seagen, Seattle Genetics, Sutro Biopharma, Tesaro, University Health Network, and Werastem. Dr. Oaknin also reports receiving consulting fees from: Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs, and Sutro Biopharma, Inc., and GEICO. Dr. Oaknin reports personally receiving honoraria for lectures, presentations and Speakers bureaus from ESMO, Edizioni Minerva Medica SpA, Doctaforum Servicios S.L and received support for travel from Roche, AstraZeneca, PharmaMar as well as Clovis. Dr. Oaknin participated on Data Safety Monitoring Board/Advisory Board for Agenus, AstraZeneca Clovis Oncology, Inc., Corcept Therapeutics, Deciphera Pharmaceutical, Eisai Europe Limited, EMD Serono, Inc., F. Hoffmann-La Roche, GlaxoSmithKline, GOG, Immunogen, KL Logistics, Medison Pharma, Merck Sharp & Dohme de España, Mersana Therapeutics, Novocure GmbH, Pharma Mar, prIME Oncology, ROCHE FARMA, Sattucklabs and Sutro Biopharma. Dr. Leitao reports receiving consulting fees from Medtronic, honoraria for lectures from Intuitive Surgical, Inc. as an Ad-hoc Speaker and participating on an Advisory Board for JnJ/Ethicon. Dr. Monk reports receiving consulting fees from the following: Acrivon, Adaptimune, Agenus, Akeso Bio, Amgen, Aravive, AstraZeneca, Bayer, Clovis, Easai, Elevar, EMD Merck, Genmab/Seagen, GOG Foundation, Gradalis, Heng Rui, UmmunoGen, Karyopharm, Iovance, Laekna, Macrogenics, Merck, Mersana, Myriad, Novartis, Novocure, OncoC4, Panavance, Pleris, Pfizer, Puma, Regeneron, Roche/Genentech, Sorrento, Tesaro/GSK, US Oncology Research, VBL, Verastem and Zentalis. He also reports receiving honoraria from: AstraZeneca, Merck, Myriad, Tesaro/GSK, Roche/Genentech, Clovis and Easai. All other authors had no conflicts of interest to disclose with regard to this Study.

Figures

Fig. 1.
Fig. 1.
Kaplan-Meier curves comparing protocol-specified Final Overall Survival, updated Progression-Free Survival, and Post-Progression Survival between the cisplatin-containing chemotherapy backbone and the topotecan-containing chemotherapy backbone. Panel A: Final OS for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab. Panel B: Updated PFS for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab. Panel C: Final OS comparing cisplatin-paclitaxel without bevacizumab to topotecan-paclitaxel without bevacizumab. Panel D: Final OS comparing the cisplatin-paclitaxel-bevacizumab triplet to the topotecan-paclitaxel-bevacizumab triplet. Panel E: Final OS among the cohort of patients who previously were exposed to cisplatin for treatment of locally advanced disease using chemoradiation: cisplatin-paclitaxel with and without bevacizumab vs topotecan-paclitaxel with and without bevacizumab. Panel F: Final OS among the cohort of patients who were radiation naïve (i.e., presented with FIGO stage IVB disease): cisplatin-paclitaxel with and without bevacizumab vs topotecan-paclitaxel with and without bevacizumab. Panel G: Post-Progression Survival for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab.
Fig. 1.
Fig. 1.
Kaplan-Meier curves comparing protocol-specified Final Overall Survival, updated Progression-Free Survival, and Post-Progression Survival between the cisplatin-containing chemotherapy backbone and the topotecan-containing chemotherapy backbone. Panel A: Final OS for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab. Panel B: Updated PFS for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab. Panel C: Final OS comparing cisplatin-paclitaxel without bevacizumab to topotecan-paclitaxel without bevacizumab. Panel D: Final OS comparing the cisplatin-paclitaxel-bevacizumab triplet to the topotecan-paclitaxel-bevacizumab triplet. Panel E: Final OS among the cohort of patients who previously were exposed to cisplatin for treatment of locally advanced disease using chemoradiation: cisplatin-paclitaxel with and without bevacizumab vs topotecan-paclitaxel with and without bevacizumab. Panel F: Final OS among the cohort of patients who were radiation naïve (i.e., presented with FIGO stage IVB disease): cisplatin-paclitaxel with and without bevacizumab vs topotecan-paclitaxel with and without bevacizumab. Panel G: Post-Progression Survival for the overall population comparing cisplatin-paclitaxel with and without bevaciaumab vs topotecan-paclitaxel with and without bevacizumab.
Fig. 2.
Fig. 2.
Prognostic factors and Health-Related Quality of Life. Panel A: Forest plot of prognostic factors depicting distribution of the hazard of death for the experimental regimen (i.e., topotecan-paclitaxel chemotherapy backbone) and the control regimen (i.e., cisplatin-paclitaxel chemotherapy backbone).
Fig. 3.
Fig. 3.
Exploratory analyses comparing the Final Overall Survival and Progression-Free Survival of the cisplatin-containing chemotherapy backbone to the topotecan-containing chemo-therapy backbone. Panel A: Moore High-Risk clinical prognostic scoring system. Panel B: Moore Mid-Risk clinical prognostic scoring system. Panel C: Moore Low-Risk clinical prognostic scoring system. Panel D: Adenocarcinoma histology. Panel E: Adenocarcinoma plus Adenosquamous histology. Panel F: Squamous cell carcinoma histology. Panel G: Squamous cell carcinoma plus Adenosquamous histology. Panel H: Pre-Cycle 1 Low Circulating Tumor Cells Final OS. Panel I: Pre-Cycle 1 High Circulating Tumor Cells Final OS. Panel J: Pre-Cycle 1 Low Circulating Tumor Cells PFS. Panel K: Pre-Cycle 1 High Circulating Tumor Cells PFS. Panel L: Post-Cycle 1 Low Circulating Tumor Cells Final OS. Panel M: Post-Cycle 1 High Circulating Tumor Cells Final OS. Panel N: Post-Cycle 1 Low Circulating Tumor Cells PFS. Panel O: Post-Cycle 1 High Circulating Tumor Cells PFS.
Fig. 3.
Fig. 3.
Exploratory analyses comparing the Final Overall Survival and Progression-Free Survival of the cisplatin-containing chemotherapy backbone to the topotecan-containing chemo-therapy backbone. Panel A: Moore High-Risk clinical prognostic scoring system. Panel B: Moore Mid-Risk clinical prognostic scoring system. Panel C: Moore Low-Risk clinical prognostic scoring system. Panel D: Adenocarcinoma histology. Panel E: Adenocarcinoma plus Adenosquamous histology. Panel F: Squamous cell carcinoma histology. Panel G: Squamous cell carcinoma plus Adenosquamous histology. Panel H: Pre-Cycle 1 Low Circulating Tumor Cells Final OS. Panel I: Pre-Cycle 1 High Circulating Tumor Cells Final OS. Panel J: Pre-Cycle 1 Low Circulating Tumor Cells PFS. Panel K: Pre-Cycle 1 High Circulating Tumor Cells PFS. Panel L: Post-Cycle 1 Low Circulating Tumor Cells Final OS. Panel M: Post-Cycle 1 High Circulating Tumor Cells Final OS. Panel N: Post-Cycle 1 Low Circulating Tumor Cells PFS. Panel O: Post-Cycle 1 High Circulating Tumor Cells PFS.
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