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Gem/Doce in 2024: What is Next?

Sequential intravesical gemcitabine and docetaxel (Gem/Doce) has been a notable advancement in the treatment of non-muscle invasive bladder cancer (NMIBC) since Michael O’Donnell developed this regimen in 2009.1 Following its initial publication in 2015, Gem/Doce has continued to gain traction in the urologic oncology community for various challenging situations.

This therapy began as a long-needed option for disease unresponsive to Bacillus Calmette-Guerin (BCG) and is now growing as an effective alternative first-line agent during chronic BCG shortages. As we move into an era of increasing therapy options for NMIBC, it is beneficial to evaluate the pros and cons of Gem/Doce, and what the future holds for this regimen.

When Gem/Doce was first utilized for treating disease refractory to bacillus Calmette-Guerin (BCG), it proved significantly more effective than available bladder-sparing alternatives of that time.1 A landmark multi-institutional analysis by Steinberg et al. in 2020 demonstrated that the 2-year recurrence-free survival (RFS) for patients with BCG-unresponsive NMIBC was 50%, a rate that remains superior to the currently FDA-approved and highly costly therapies such as Pembrolizumab, Adstiladrin, and Anktiva.2–5 This efficacy has been replicated in subsequent studies.6,7 Long-term evaluations have also shown that, compared to Adstiladrin, twice as many patients can avoid cystectomy at 5 years with Gem/Doce.8,9

As the ongoing BCG shortage persists, Gem/Doce has increasingly shown promise in the high-risk, BCG naïve setting. McElree et al. reported that a cohort of 107 patients receiving Gem/Doce for treatment-naïve high-risk NMIBC experienced a 2-year RFS of 82%.10 A follow-up comparative study revealed that Gem/Doce provided superior 2-year high-grade RFS (81% Gem/Doce versus 69% BCG), although the majority of patients who received BCG in that study received 1 year of maintenance.11 This result has been confirmed by other series and a prospective Phase II study of 25 patients who received Gem/Doce and had a 1-year RFS of 92%.12,13 The ongoing ECOG prospective BRIDGE trial, which aims to randomize 870 patients to either BCG or Gem/Doce, is embraced by the bladder cancer community and has already completed over 50% of its accrual.14

The use of Gem/Doce has continued to expand beyond high-grade NMIBC to include intermediate-risk and low-grade tumors. Initial and multi-institutional reports indicate that the overall 2-year RFS of Gem/Doce ranges from 70-80%.15,16  However, the regimen’s effectiveness decreases in patients with a history of recurrent disease or when maintenance therapy is not used.15 Furthermore, topical therapies have selectively been utilized for non-invasive completely ablated upper tract urothelial carcinoma (UTUC) or CIS of the upper tract.17 During the BCG shortage, Gem/Doce for UTUC was explored and appears to have equivalent safety and efficacy.18,19 Finally, the regimen has been tested in the context of resected prostatic urethral CIS, indicating its potential versatility in various bladder cancer scenarios.

Interestingly, the efficacy of Gem/Doce in treatment-naïve high-grade and low-grade NMIBC has been very comparable across studies.11,15 This consistency, along with the regimen’s favorable tolerance (<4% discontinuation), efficacy, low cost, and consistent availability, supports the argument for a non-risk adapted approach to its use.20 In oncology, non-risk adapted management strategies have been successfully employed in some contexts, such as the recent widespread adoption of non-risk adapted surveillance of clinical stage I germ cell tumors. However, the broader trend in oncology is moving towards precision medicine and tailored treatment approaches, which holds true for NMIBC as a myriad of promising biomarkers and targeted therapies are emerging. While non-risk adapted utilization may be optimal now, there will be a future need to integrate Gem/Doce into evolving precision treatment paradigms.

Despite its advantages, Gem/Doce faces several challenges. The logistical demands of the regimen are cumbersome and financially burdensome, especially from the perspective of “tying up” rooms during dwell times. Additionally, most of the supportive data for Gem/Doce comes from retrospective studies, and prospective validation is needed for more contexts than the newly diagnosed high-grade setting, which is currently being evaluated by the BRIDGE trial. Several key questions remain about the optimal administration of Gem/Doce. For example, while the original protocol for Gem/Doce recommended 90-120 minute dwell time for each agent, recent studies have shown similar results using 1 hour dwell time for each.12 Furthermore, the ideal duration and role of maintenance need further investigation. While the original 2-year maintenance is effective and necessary for high-grade disease, this may be overtreatment for intermediate-risk disease.21 While there is a substantial ongoing body of research assessing predictors of response to BCG, similar efforts are needed for Gem/Doce to fully understand its mechanisms and optimization.

As we look to the future, Gem/Doce represents a promising treatment option for NMIBC, with ongoing studies and emerging data poised to further refine its role in bladder cancer management. The current enthusiasm for this regimen is tempered by practical challenges and unanswered questions. Novel research and future studies from the IBCG and others will be essential to address these questions and improve care for our patients. Much work remains to be done!

Written by: Vignesh Packiam, MD, Associate Professor, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ

  1. Steinberg RL, Thomas LJ, O’Donnell MA, Nepple KG. Sequential Intravesical Gemcitabine and Docetaxel for the Salvage Treatment of Non-Muscle Invasive Bladder Cancer. Bladder Cancer Amst Neth. 2015;1(1):65-72. doi:10.3233/BLC-150008
  2. Steinberg RL, Thomas LJ, Brooks N, et al. Multi-Institution Evaluation of Sequential Gemcitabine and Docetaxel as Rescue Therapy for Non-muscle Invasive Bladder Cancer. J Urol. 2020;203(5):902-909. doi:10.1097/JU.0000000000000688
  3. Balar AV, Kamat AM, Kulkarni GS, et al. Pembrolizumab monotherapy for the treatment of high-risk non-muscle-invasive bladder cancer unresponsive to BCG (KEYNOTE-057): an open-label, single-arm, multicentre, phase 2 study. Lancet Oncol. 2021;22(7):919-930. doi:10.1016/S1470-2045(21)00147-9
  4. Boorjian SA, Alemozaffar M, Konety BR, et al. Intravesical nadofaragene firadenovec gene therapy for BCG-unresponsive non-muscle-invasive bladder cancer: a single-arm, open-label, repeat-dose clinical trial. Lancet Oncol. Published online November 27, 2020. doi:10.1016/S1470-2045(20)30540-4
  5. Chamie K, Chang SS, Kramolowsky E, et al. IL-15 Superagonist NAI in BCG-Unresponsive Non–Muscle-Invasive Bladder Cancer. NEJM Evid. 2023;2(1). doi:10.1056/EVIDoa2200167
  6. Garneau CA, Marcotte N, Lacombe L, et al. Salvage therapy for BCG failure with intravesical sequential gemcitabine and docetaxel in patients with recurrent NMIBC. Can Urol Assoc J J Assoc Urol Can. 2024;18(2):33-40. doi:10.5489/cuaj.8341
  7. Yim K, Melnick K, Mott SL, et al. Sequential intravesical gemcitabine/docetaxel provides a durable remission in recurrent high-risk NMIBC following BCG therapy. Urol Oncol. 2023;41(11):458.e1-458.e7. doi:10.1016/j.urolonc.2023.06.018
  8. Chevuru PT, McElree IM, Mott SL, Steinberg RL, O’Donnell MA, Packiam VT. Long-term follow-up of sequential intravesical gemcitabine and docetaxel salvage therapy for non-muscle invasive bladder cancer. Urol Oncol. 2023;41(3):148.e1-148.e7. doi:10.1016/j.urolonc.2022.10.030
  9. Narayan VM, Boorjian SA, Alemozaffar M, et al. Efficacy of Intravesical Nadofaragene Firadenovec for Patients With Bacillus Calmette-Guérin-Unresponsive Non-muscle-Invasive Bladder Cancer: 5-Year Follow-Up From a Phase 3 Trial. J Urol. 2024;212(1):74-86. doi:10.1097/JU.0000000000004020
  10. McElree IM, Steinberg RL, Martin AC, et al. Sequential Intravesical Gemcitabine and Docetaxel for Bacillus Calmette-Guérin-Naïve High-Risk Non-muscle-Invasive Bladder Cancer. J Urol. 2022;208(3):589-599. doi:10.1097/JU.0000000000002740
  11. McElree IM, Steinberg RL, Mott SL, O’Donnell MA, Packiam VT. Comparison of Sequential Intravesical Gemcitabine and Docetaxel vs Bacillus Calmette-Guérin for the Treatment of Patients With High-Risk Non–Muscle-Invasive Bladder Cancer. JAMA Netw Open. 2023;6(2):e230849. doi:10.1001/jamanetworkopen.2023.0849
  12. Refugia JM, Roebuck E, Thakker P, et al. Sequential Intravesical Chemotherapy for Treatment Naïve, High-Risk Non-Muscle Invasive Bladder Cancer: Oncologic Outcomes, Tolerance, and Comparison to Contemporary Controls. Urology. Published online June 19, 2024:S0090-4295(24)00463-1. doi:10.1016/j.urology.2024.06.020
  13. Patel SH, Gabrielson AT, Chan S, et al. A Phase 2 Trial of Intravesical Gemcitabine and Docetaxel in the Treatment of Bacillus Calmette-Guérin‒Naïve Non-muscle-Invasive Urothelial Carcinoma of the Bladder. J Urol. 2024;212(1):95-103. doi:10.1097/JU.0000000000003977
  14. Kates M, Chu X, Hahn N, et al. Background and Update for ECOG-ACRIN EA8212: A Randomized Phase 3 Trial of Intravesical Bacillus Calmette-Guérin (BCG) Versus Intravesical Docetaxel and Gemcitabine Treatment in BCG-naïve High-grade Non-muscle-invasive Bladder Cancer (BRIDGE). Eur Urol Focus. 2023;9(4):561-563. doi:10.1016/j.euf.2023.06.006
  15. McElree IM, Orzel J, Stubbee R, et al. Sequential intravesical gemcitabine and docetaxel for treatment-naïve and previously treated intermediate-risk non-muscle invasive bladder cancer. Urol Oncol. 2023;41(12):485.e1-485.e7. doi:10.1016/j.urolonc.2023.06.017
  16. Tan WS, McElree IM, Davaro F, et al. Sequential Intravesical Gemcitabine and Docetaxel is an Alternative to Bacillus Calmette-Guérin for the Treatment of Intermediate-risk Non-muscle-invasive Bladder Cancer. Eur Urol Oncol. 2023;6(5):531-534. doi:10.1016/j.euo.2023.06.011
  17. Metcalf M, Pierorazio PM. Future strategies to enhance kidney preservation in upper urinary tract urothelial carcinoma. Transl Androl Urol. 2020;9(4):1831-1840. doi:10.21037/tau.2019.11.09
  18. McElree IM, Belzer A, Mott SL, Packiam VT, O’Donnell MA, Steinberg RL. Sequential endoluminal gemcitabine and docetaxel for the treatment of clinically non-invasive high-grade upper tract urothelial carcinoma. Urol Oncol. Published online October 5, 2023:S1078-1439(23)00289-2. doi:10.1016/j.urolonc.2023.08.013
  19. McElree IM, Mott SL, Hougen HY, Packiam VT, O’Donnell MA, Steinberg RL. Sequential endoluminal gemcitabine and docetaxel vs. Bacillus Calmette-Guérin for the treatment of upper tract carcinoma in situ. Urol Oncol. 2024;42(7):221.e9-221.e16. doi:10.1016/j.urolonc.2024.03.012
  20. Steinberg RL, O’Donnell MA, Packiam VT. Nonrisk-adapted Sequential Intravesical Gemcitabine and Docetaxel for Nonmuscle-invasive Bladder Cancer: The Time Is Now. J Urol. 2023;210(1):5-7. doi:10.1097/JU.0000000000003438
  21. Ben-David R, Tillu N, Alerasool P, et al. Induction and maintenance of sequential intravesical gemcitabine/docetaxel for intermediate and high-risk non-muscle invasive bladder cancer with different dosage protocols. World J Urol. 2024;42(1):315. doi:10.1007/s00345-024-04992-5
Adapted from the International Bladder Cancer Group (IBCG) Newsletter 2024 Vol 2
Written by: Vignesh Packiam, MD, Associate Professor, Rutgers Cancer Institute of New Jersey, New Brunswick, NJ
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