Cervix: Part 3

Cervical Cancer
Written By Sydney Oesch

Episode Notes

  1. Epidemiology of Cervical Cancer

    1. 4th most common cancer worldwide

    2. 4th most common cause of cancer death (in patients born with a uterus) worldwide

  2. Definitions

    1. Primary metastatic disease:

      1. Stage IVB: any spread to distant organs

      1. Stage IVA: invades mucosa of bladder or rectum still considered locally advanced disease

    2. Persistent disease: disease that does not resolve or respond to primary therapy

    3. Recurrent disease: disease that returns, either locally or metastatic, after an initial period of response to therapy

      1. 15-60% of patients with early or LACC will develop recurrent disease

  3. Epidemiology of Stage IVB Disease

    1. 5-15% of cases depending on geographic region

    2. In US, rate of primary diagnosis of stage IV disease is rising (coincides with rising rates of adenocarcinoma)

  4. NCCN General Recommendations

    1. Think about if disease is amenable to local treatment

      1. Surgical resection +/- EBRT

      2. Local ablative therapies +/- EBRT

      3. EBRT +/- concurrent platinum-agent

    2. If not amenable, consider systemic therapy and/or best supportive care

  5. Systemic Therapy for Metastatic or Recurrent disease

    1. Determined by PD-L1 status

      1. If positive → category 1: cisplatin or carboplatin + paclitaxel + pembrolizumab +/- bevacizumab

      2. If negative → cisplatin or carboplatin + paclitaxel + bevacizumab

  6. Trials That Support Systemic Therapy Recommendations

    1. GOG 169, 2004

      1. Phase III study, n = 264 with persistent, metastatic, or recurrent cervical cancer

      2. Cis/taxol vs Cis alone

      3. PFS improved from 2.8 to 4.8 mo in cis/taxol arm

      4. No difference in OS or QOL scores

      5. Toxicity w/ G3-4 neutropenia higher in cis/taxol arm

      6. Takeaway: combination improved PFS without significant detriment to QOL

    2. GOG 179, 2005

      1. Phase III study, n = 204

      2. Cis/topotecan vs cis alone

      3. PFS improved from 2.9 mo to 4.6 mo in cis/topo arm

      4. OS improved from 6.5 mo to 9.4 mo in cis/topo arm

      5. Takeway: first study to demonstrate OS advantage for combination therapy

        1. Cis/topo rather toxic and difficult to administer

    3. GOG 204, 2009

      1. Phase III study, n = 513 w/ metastatic or recurrent cervical cancer

      2. Cis/taxol vs cis/vinorelbine vs cis/gem vs cis/topo

      3. Closed early d/t futility analysis showing no better activity in experimental arms vs control arm of cis/taxol

    4. GOG 240, 2014

      1. Phase III study, n = 452 w/ persistent, metastatic, or recurrent cervical cancer

      2. 2x2 factorial design w/ total of 4 arms

        1. cis/taxol vs topo/taxol vs cis/taxol/bev vs topo/taxol/bev

      3. OS improved w/ addition of bev (13.3 mo to 16.8 mo)

      4. PFS improved w/ addition of bev (5.9 mo to 8.2 mo)

      5. Higher risk of progression for topo/taxol vs cis/taxol, but no difference in OS

      6. Higher rates of HTN, thromboembolic events, grade 3+ fistula in those receiving bev

      7. Takeaway: chemo in combo w/ bev as SOC 

        1. While cis/taxol are used, based on the results of this trial, if a patient cannot receive a platinum agent for some reason, then topo/taxol is a good alternative

    5. JCOG0505, 2015

      1. Phase III RCT, n = 253 w/ metastatic or recurrent cervical cancer

      2. Carbo/taxol vs cis/taxol

      3. Inclusion: <=1 platinum containing prior treatment, no prior taxane treatment

      4. Carbo/taxol was non-inferior to cis/taxol

        1. Patients in carbo/taxol arm had greater proportion of “non hospitalization periods” during treatment - authors used as QOL metric

      5. However! In patients who had not received prior cisplatin, OS significantly improved in cis/taxol arm vs carbo/taxol arm (23.2 mo vs 13 mo)

        1. NCCN Recs: Carbo/taxol as category 1 indication if patients have received prior cisplatin, but if they have not, then category 2A recommendation and cis/taxol is preferred

  7. Immunotherapy Monotherapy Trials

    1. KEYNOTE-028, 2017

      1. Phase IB basket trial of single-agent pembrolizumab (anti-PD-L1), n = 24 in cervical cancer cohort

        1. Advanced disease, 92% w/ prior radiation, 63% w/ 2+ lines of prior therapy (including bev)

      2. ORR 17%

      3. 75% w/ treatment-related adverse events

    2. KEYNOTE-158, 2019

      1. Phase II basket trial of single-agent pembrolizumab (anti-PD-L1), n = 98 in cervical cancer cohort

      2. 84% w/ PD-L1 positivity

      3. ORR 12.2%

        1. If PD-L1 positive → ORR 14.6%

    3. CHECKMATE 358, 2019

      1. Phase I/II trial of single-agent Nivolumab (anti-PD-1), n= 24 in gynecologic cancer cohort (metastatic, recurrent)

        1. 19 cervical, 2 vaginal, 3 vuvlar

      2. Most w/ stage IV disease

        1. ~80% w/ prior systemic therapy

      3. In cervical cancer cohort:

        1. ORR 26.3%

        2. Median duration of response NR at 19 mo

        3. Median OS: 21.9 mo

        4. Median PFS: 5.1 mo

        5. Adverse events of any grade: 63%

          1. 21% grade 2-4

    4. EMPOWER-CERVICAL, 2022

      1. Phase III trial of cemiplimab (anti-PD-1) vs single-agent chemo after progression on platinum-based therapy

      2. All patients previously received bev + paclitaxel

      3. OS improved from 8.5 to 12 mo

      4. PFS HR 0.75

      5. In initial sub-analysis:

        1. PD-L1 neg tumors did not have added benefit w/ use of the agent

        2. Limited by small sample sizes and short f/u

      6. In follow up sub-analysis:

        1. Increase in median OS from 7.7 mo to 10.8 mo in PD-L1 negative tumors

        2. Increase in median OS from 7.7 mo to 12.1 mo in PD-L1 positive tumors

  8. Immunotherapy Combination Trials

    1. KEYNOTE 826, 2021, 2023

      1. Phase III, n = 617 w/ persistent, metastatic, recurrent cervical cancer

      2. Of 617 included, 548 w/ PD-L1 positive, 317 w/ PD-L1 positive w/ CPS >= 10

      3. Randomized to pembro (200 mg q 3 wks) vs placebo in combo w/ chemotherapy +/- bevacizumab

      4. PFS: 8.2 mo vs 10.4 in favor of pembro

      5. OS at 24 mo: 40% vs 50% in favor of pembro

      6. In PD-L1 positive:

        1. ORR: 68% in pembro arm vs 50% in placebo

      7. Follow up Data:

        1. Improvement in PFS from 8.2 mo to 10.5 mo with pembro

        2. Improvement in OS from 16.5 om to 28.6 mo with pembro

      8. Takeaway: due to this study, the FDA approved the use of pembrolizumab in combination with chemotherapy +/- bev for PD-L1 positive persistent, metastatic, or recurrent cervical cancer

    2. BEATCC, 2024

      1. Phase III, n = 410, measurable stage IVB, persistent, or recurrent cervical cancer that was untreated and not amenable to curative surgery or radiation

        1. 64% w/ prior chemoRT, 22% w/ stage IVB disease

      2. Cisplatin or carboplatin + paclitaxel + bevacizumab with vs without atezolizumab (anti-PD-L1)

      3. Median PFS improved from 10.4 mo to 13.7 mo (HR 0.62) w/ atezolizumab

      4. Median OS improved from 22.8 mo to 32.1 mo (HR 0.68) w/ atezolizumab

      5. Grade 3+ AEs in 79% w/ atezo vs 75% w/o atezo

      6. Subgroup analyses favored experimental group in all prespecified subgroup analyses

    3. CHECKMATE 358 - different arm, Oaknin 2024

      1. Combinations of ipilimumab (CTLA-4 inhibitor) with nivolumab (anti-PD-1)

      2. N = 176 w/ metastatic or recurrent cervical cancer

        1. 19 nivo alone

        2. 45 NIVO3 + IPI1

        3. 112 NIVO1 + IPI3

      3. 3 experimental arms: 

        1. Nivolumab alone at 240 mg every 2 weeks

        2. Nivolumab 3 mg/kg q2 wks + ipilimumab 1 mg/kg q6 wk (NIVO3 plus IPI1)

        3. Nivolumab 1 mg/kg q3 wks + ipilimumab 3mg/kg every 3 wks for 4 cycles then nivolumab 240 mg q2 wks (NIVO1 plus IPI3)

      4. ORR: 26% nivo alone, 31% NIVO3/IPI1, 38% NIVO1/IPI3

      5. Grade 3+ AEs: 16% nivo alone, 27% NIVO3/IPI1, 42% NIVO1/IPI3

      6. One treatment related death in NIVO/IPI3 group d/t immune mediated colitis

    4. O’Malley, 2922

      1. Phase II study, n = 155 w/ metastatic or recurrence after prior platinum therapy

      2. Dual PD-1 and CTLA-4 checkpoint blockade with balstilimab and falifrelimab

      3. ORR: 25.6%

        1. PD-L1 positive tumors with more robust response: 32.8% vs 9.1%

      4. Median DOR not reached

  9. Recurrent Disease Therapy

    1. PD-L1 positive, TMB-H, or MSI-H/dMMR tumors

      1. Single-agent pembrolizumab, nivolumab, or cemiplimab can be considered

      2. TBD weather re-treatment with checkpoint inhibitors is an effective strategy as they become more frequent in front-line treatment and whether dual-checkpoint inhibition increases efficacy

    2. Tisotumab-vedotin

      1. FDA granted full approval in 4/2024

      2. Antibody-drug conjugate which targets tissue factor (expressed in many solid tumors including cervical cancer)

        1. TF associated with worse clinical outcomes, increased risk of metastasis, may have a role in cancer progression

      3. Drug released (“payload”) is monomethyl auristatin E (MMAE), which disrupts the microtubule network of actively dividing cells

    3. InnovaTV-201, 2019

      1. Phase I/II trial, n = 147 w/ advanced, metastatic, or recurrent solid tumors (n = 55 for cervical cancer)

      2. No TF level required for inclusion

      3. Established treatment dose of 2 mg/kg

      4. Most common AEs: epistaxis (60%), fatigue, nausea, alopecia, conjunctivitis, anorexia, constipation, diarrhea

      5. ORR: 15.6% in all-comers

      6. Cervical cancer cohort

        1. ORR: 22%

        2. Median PFS: 4.1 mo

        3. Median DOR: 6 mo

    4. InnovaTV-204, 2021

      1. Phase II study, n = 102 w/ metastatic or recurrent cervical cancer who had progressed on systemic therapy

      2. ORR: 24%

        1. 7 pts w/ CR

      3. G3+ AEs in 28% of patients: neutropenia, fatigue, ulcerative keratitis, peripheral neuropathies

    5. InnovaTV-301, ESMO abstract 2023, NEJM 2024

      1. Phase III trial, n = 302

      2. Tisotumab-vedotin monotherapy vs investigator’s choice of single-agent chemotherapy

      3. 64% w/ prior bev, 27.5% w/ prior anti-PD-L1 therapy

      4. Tisotumab arm w/ 30% reduction in risk of death

        1. Median OS improved from 9.5 mo to 11.5 mo

      5. ORR improved from 5.2% to 17.8%

      6. Manuscript results confirmed abstract findings

      7. Toxicities lead to treatment discontinuation in 15% in tisotumab arm vs 4% in chemo arm

        1. Ocular toxicity and peripheral neuropathy responsible for majority of these

        2. QOL not affected

    6. DESTINY Pan TUMOR2 Trial, 2023

      1. Phase II study of trastuzumab-deruxtecan in pts with HER2 expressing (IHC HER2 2+ or 3+ using gastric cancer scoring criteria) progressive or recurrent solid tumors

      2. Cervical cancer cohort

        1. ORR: 50% in all comers

          1. IHC 3+: 75%

          2. IHC 2+: 40%

        2. Median PFS: 7 MO

          1. IHC 3+: NR

          2. IHC 2+: 4.8 mo

      3. Important to note that in cervical cancer, the rate of reported HER2 positivity is only 2-6%

    7. Other Targeted Therapies

      1. RET fusion mutation → consider selpercatinib

      2. NTRK fusion → consider larotrectinib and entrectinib

    8. Any Role for Surgery or Additional Radiation?

      1. Surgical resection with exenteration can be curative if isolated to the central pelvis

        1. Can assess margin status with intraoperative frozen section

        2. If margins anticipated to be positive beyond the possibility of surgical resection, intraoperative radiotherapy is an option (requires a lot of advanced planning)

      2. Most patients who recur will already have been treated with radiation

        1. Option if they have not

      3. Short course of palliative RT may provide relief of symptoms

      4. SBRT is an option for treatment of oligometastatic disease

Reference List

1. Frenel JS, Le Tourneau C, O’neil B, et al. Safety and Efficacy of Pembrolizumab in Advanced, Programmed Death Ligand 1-Positive Cervical Cancer: Results From the Phase Ib KEYNOTE-028 Trial. J Clin Oncol. 2017;35(36):4035-4041. doi:10.1200/JCO

2. Monk BJ, Colombo N, Tewari KS, et al. First-Line Pembrolizumab 1 Chemotherapy Versus Placebo 1 Chemotherapy for Persistent, Recurrent, or Metastatic Cervical Cancer: Final Overall Survival Results of KEYNOTE-826. J Clin Oncol. 2023;41(36):5505-5511. doi:10.1200/JCO.23.00914

3. Colombo N, Dubot C, Lorusso D, et al. Pembrolizumab for Persistent, Recurrent, or Metastatic Cervical Cancer. New England Journal of Medicine. 2021;385(20):1856-1867. doi:10.1056/nejmoa2112435

4. Chung HC, Ros W, Delord JP, et al. Efficacy and Safety of Pembrolizumab in Previously Treated Advanced Cervical Cancer: Results From the Phase II KEYNOTE-158 Study. J Clin Oncol. 2019;37(17):1470-1478. Accessed August 11, 2021. https://doi.org/10.

5. Oaknin A, Gladieff L, Martínez-García J, et al. Atezolizumab plus bevacizumab and chemotherapy for metastatic, persistent, or recurrent cervical cancer (BEATcc): a randomised, open-label, phase 3 trial. Published online 2024. doi:10.1016/S0140-6736(23)02405-4

6. Tewari KS, Monk BJ, Vergote I, et al. Survival with Cemiplimab in Recurrent Cervical Cancer. New England Journal of Medicine. 2022;386(6):544-555. doi:10.1056/NEJMOA2112187/SUPPL_FILE/NEJMOA2112187_DATA-SHARING.PDF

7. Naumann RW, Hollebecque A, Meyer T, et al. Safety and Efficacy of Nivolumab Monotherapy in Recurrent or Metastatic Cervical, Vaginal, or Vulvar Carcinoma: Results From the Phase I/II CheckMate 358 Trial. J Clin Oncol. 2019;37(31):2825-2834. doi:10.1200/JCO.19.00739

8. Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and Safety of Trastuzumab Deruxtecan in Patients With HER2-Expressing Solid Tumors: Primary Results From the DESTINY-PanTumor02 Phase II Trial. Journal of Clinical Oncology. 2024;42(1):47-58. doi:10.1200/JCO.23.02005

9. Santin AD, Deng W, Frumovitz M, et al. Phase II evaluation of nivolumab in the treatment of persistent or recurrent cervical cancer (NCT02257528/NRG-GY002). Gynecol Oncol. 2020;157(1):161-166. doi:10.1016/j.ygyno.2019.12.034

10. Tewari KS, Sill MW, Penson RT, et al. Bevacizumab for advanced cervical cancer: final overall survival and adverse event analysis of a randomised, controlled, open-label, phase 3 trial (Gynecologic Oncology Group 240). Lancet. 2017;390(10103):1654-1663. doi:10.1016/S0140-6736(17)31607-0

11. Kitagawa R, Katsumata N, Shibata T, et al. Paclitaxel Plus Carboplatin Versus Paclitaxel Plus Cisplatin in Metastatic or Recurrent Cervical Cancer: The Open-Label Randomized Phase III Trial JCOG0505. J Clin Oncol. 2015;33:2129-2135. doi:10.1200/JCO.2014.58.4391

12. Monk BJ, Sill MW, Scott D, et al. Phase III Trial of Four Cisplatin-Containing Doublet Combinations in Stage IVB, Recurrent, or Persistent Cervical Carcinoma: A Gynecologic Oncology Group Study. J Clin Oncol. 27:4649-4655. doi:10.1200/JCO.2009.21.8909

13. Moore DH, Blessing JA, McQuellon RP, et al. Phase III study of cisplatin with or without paclitaxel in stage IVB, recurrent, or persistent squamous cell carcinoma of the cervix: a gynecologic oncology group study. J Clin Oncol. 2004;22(15):3113-3119. doi:10.1200/JCO.2004.04.170

14. Long HJ, Bundy BN, Grendys EC, et al. Randomized phase III trial of cisplatin with or without topotecan in carcinoma of the uterine cervix: a Gynecologic Oncology Group Study. J Clin Oncol. 2005;23(21):4626-4633. doi:10.1200/JCO.2005.10.021

15. de Bono JS, Concin N, Hong DS, et al. Tisotumab vedotin in patients with advanced or metastatic solid tumours (InnovaTV 201): a first-in-human, multicentre, phase 1-2 trial. Lancet Oncol. 2019;20(3):383-393. doi:10.1016/S1470-2045(18)30859-3

16. Gemelli A, Rome I, Coleman RL, et al. Efficacy and safety of tisotumab vedotin in previously treated recurrent or metastatic cervical cancer (innovaTV 204/ GOG-3023/ENGOT-cx6): a multicentre, open-label, single-arm, phase 2 study. Articles Lancet Oncol. 2021;22:609-628. doi:10.1016/S1470-2045(21)00056-5

17. Vergote IB, GMA, FK, SB. LBA9 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. Ann Onc. 2023;34(2):S1276-S1277.

18. Vergote I, González-Martín A, Fujiwara K, et al. Tisotumab Vedotin as Second- or Third-Line Therapy for Recurrent Cervical Cancer. New England Journal of Medicine. 2024;391(1):44-55. doi:10.1056/nejmoa2313811

19. O’malley DM, Neffa M, Monk BJ, et al. Dual PD-1 and CTLA-4 Checkpoint Blockade Using Balstilimab and Zalifrelimab Combination as Second-Line Treatment for Advanced Cervical Cancer: An Open-Label Phase II Study. J Clin Oncol. 2021;40:762-771. doi:10.1200/JCO.21

20. Oaknin A, Moore K, Meyer T, et al. Nivolumab with or without ipilimumab in patients with recurrent or metastatic cervical cancer (CheckMate 358): a phase 1–2, open-label, multicohort trial. Lancet Oncol. 2024;25(5):588-602. doi:10.1016/S1470-2045(24)00088-3

Sydney Oesch
Previous

Radiation: The fundamentals
Next

Cervix Part 2