Neoadjuvant Atezolizumab/Chemo Shows Encouraging Efficacy in Muscle-Invasive Bladder Cancer

Samuel A. Funt, MD

The addition of atezolizumab (Tecentriq) to neoadjuvant gemcitabine and cisplatin (GC) generated a high rate of non–muscle-invasive downstaging following radical cystectomy, which correlated with improved relapse-free survival (RFS) and overall survival (OS) in patients with muscle-invasive bladder cancer (MIBC), according to data from a phase 2 trial (NCT02989584) published in the Journal of Clinical Oncology.¹

Results showed that 27 of 39 evaluable patients had a non–muscle-invasive downstaging rate of 69.2% (95% CI, 55.0%-79.0%), which was defined as the absence of muscle-invasive disease (< pT2) and lymph node metastases (N0) within the TC-PLND specimen, meeting the primary end point of the research. Moreover, Forty-one percent of those patients (n = 16) experienced pathologic complete response (pCR).

At a median follow-up of 16.5 months (range, 7.0-33.7), no patients with <pT2N0 relapsed, although relapse was observed in 4 patients (11%) with ≥ pT2N0. At a median follow-up from time of treatment start of 23.6 months (range, 12.0-38.2), the median RFS and OS were not reached among 39 patients evaluable for response.

“The 69% < pT2N0 and 41% pT0N0 rates observed with GC plus atezolizumab compare favorably to those reported for GC and dd-MVAC [dose-dense methotrexate, vinblastine, doxorubicin, cisplatin], which are the neoadjuvant regimens preferred by the National Comprehensive Cancer Network,” lead study author Samuel A. Funt, MD, of Memorial Sloan Kettering Cancer Center, and colleagues, wrote in the paper. “Several large retrospective analyses of neoadjuvant GC have reported < pT2N0 rates of 36%-46% and pT0N0 rates of 21%-31%.”

Most patients with MIBC develop metastases following radical cystectomy and pelvic lymph node dissection,² though neoadjuvant cisplatin-based chemotherapy has demonstrated improvement in long-term survival vs surgery alone.³ Past studies have also shown non–muscle-invasive downstaging (< pT2) and negative lymph nodes (N0) at the time of radical cystectomy and pelvic lymph node dissection have led to improved survival.⁴

However, only 36% to 49% of patients with MIBC achieve non–muscle-invasive downstaging with GC alone, which is widely used as a neoadjuvant regimen.This trial aimed to weigh the efficacy and safety of atezolizumab in combination with the standard GC therapy.

This nonrandomized, single-arm trial enrolled patients who were eligible for radical cystectomy and pelvic lymph node dissection and had cT2N0M0 or cT4aN0M0 disease, determined by cystoscopy and transurethral resection of the bladder tumor (TURBT) within 60 days of treatment initiation. Patients also required a computed tomography scan of the chest, abdomen, and pelvis using intravenous (IV) contrast within 30 days of treatment initiation. Notably, TURBT was not mandated at enrolling sites, though pathologic confirmation of MIBC was required.

Cisplatin eligibility required an estimated glomerular filtration rate of ≥ 50mL/min per 1.73m². Other eligibility criteria included a ECOG performance status of 0 or 1; no preexisting grade 2 or higher peripheral neuropathy or hearing impairment; and no New York Heart Association class 3 or 4 heart failure, or recent cardiovascular event. Major exclusion criteria included active infection, prior use of immune checkpoint blockade, and autoimmune disease.

All enrolled patients received a lead-in dose of atezolizumab, followed 2 weeks later by 4, 21-day cycles of GC with atezolizumab on day 8. One additional dose of atezolizumab was administered 3 weeks after the conclusion of chemotherapy. Atezolizumab was delivered in a flat 1200 mg IV dose once every 3 weeks. Furthermore, gemcitabine was given at 1000 mg/m² IV once on days 1 and 8 of each cycle, and cisplatin was administered as either 70 mg/m² IV on day 1 or 35 mg/m² IV on days 1 and 8. Split-dose cisplatin was recommended if the estimated glomerular filtration was 50 to < 60, or by physician’s digression.

Notably, dexamethasone was given as either 12 mg IV on day 1 and 4 mg orally on day 2 for patients who received cisplatin 70 mg/m², or as 12 mg IV on days 1 ad 8 for patients who were administered split-dose cisplatin.

Imaging was performed at the completion of protocol therapy, and radical cystectomy and pelvic lymph node dissection were recommended approximately 4 to 8 weeks following the last dose of chemotherapy. Any postoperative complications up to 90 days following surgery were retrospectively recorded.

The primary end point of the trial was non–muscle-invasive downstaging, defined by the absence of muscle-invasive disease (< pT2) and lymph node metastases (N0), as assessed by institutional pathologists using the American Joint Committee on Cancer 7th edition criteria. Secondary end points included pCR, safety, time to cystectomy, OS, and RFS.

Notably, all patients with PD-L1­–positive tumors (n = 4) achieved < pT2N0. In patients with PD-L1 low and negative tumors (n = 34), 68% reached < pT2N0, and 32% were ≥ pT2N0 (P = .3).

The median age of the 39 evaluable patients was 65 years (range, 58-69), and 84.6% were male. Additionally, 64.1% were current or former smokers. The majority of patients were clinical TNM stage T2 (79.5%). Furthermore, 61.5% of patients had urothelial carcinoma that was not otherwise specified, and other histology included urothelial carcinoma with squamous cell carcinoma (23.1%), urothelial carcinoma with nested features (5.1%), urothelial carcinoma with glandular differentiation (5.1%), urothelial carcinoma with micropapillary features (2.6%), or urothelial carcinoma with focal plasmacytoid features (2.6%).

Additionally, 30.8% of patients presented with hydronephrosis, and most patients had an estimated glomerular filtration rate of ≥ 60 mL/min per 1.73 m² (84.6%). The majority of patients had an ECOG performance status of 0 (59%), and most had a PD-L1 score less than 5 (89.7%). Finally, the median hemoglobin was 13.90 (interquartile range [IQR], 12.50-14.60), and the median albumin was 4.20 (IQR, 4.00-4.45).

Among patients evaluable for safety (n = 44), 98% experienced treatment-related adverse effects (TRAEs), and 59% encountered a TRAE of grade 3 or higher. The most common TRAEs of any grade were neutropenia (59%), fatigue (55%), anemia (55%), and nausea (50%). The most common grade 3 or 4 TRAEs was neutropenia (36%), though no patients developed neutropenic fever.

Three patients experienced treatment-related venous thromboembolic effects. One patient had grade 2 upper-extremity deep vein thrombosis, and 2 patients had grade 3 pulmonary embolus. Additionally, 2 patients encountered a treatment-related arterial thromboembolic effect, with both experiencing a grade 2 stroke. Additionally, grade 3 immune-related AEs occurred in 11% of patients, with 1 incidence of hepatitis, asymptomatic elevation in lipase during treatment and nephritis after RC-PLND, pancreatitis, rash, and asymptomatic elevations in amylase/lipase each reported.

Among the 39 response-evaluable patients, 67% required dose modifications, with the most common reasons including neutropenia (30.7%), creatinine increase (15.4%), and thrombocytopenia (10.3%). Notably, 92% of patients received 4 cycles of GC, and 74% were administered all 6 doses of atezolizumab. Two patients discontinued GC after experiencing grade 2 stroke, and 1 patient discontinued GC after grade 2 creatinine increase.

All evaluable patients underwent radical cystectomy and pelvic lymph node dissection, and none failed to undergo surgery due to AEs. The median time from last chemotherapy to radical cystectomy was 7.8 weeks (range, 5.1-17.0). Two patients had delays in surgery beyond 12 weeks due to chemotherapy, though neither was because of AEs.

The efficacious results of adding immune checkpoint blockade to chemotherapy has prompted further investigation with a variety of agents. Ongoing phase 3 trials are exploring GC with and without pembrolizumab (Keytruda), nivolumab (Opdivo) with or without linrodostat (BMS-986205), and durvalumab (Imfinzi).

“These phase 3 trials include adjuvant therapy irrespective of the pathologic response at the time of [radical cystectomy and pelvic lymph node dissection], which data from our study and from studies of neoadjuvant cisplatin-based chemotherapy suggest may be overtreatment for those patients with non–muscle-invasive downstaging. Furthermore, as novel therapies become incorporated into the perioperative treatment armamentarium for patients with MIBC, a prospective biomarker-based approach to identify those patients most likely to benefit from these therapies is crucial.

References

1. Funt SA, Lattanzi M, Whiting K, et al. Neoadjuvant atezolizumab with gemcitabine and cisplatin in patients with muscle-invasive bladder cancer: a multicenter, single-arm, phase 2 trial. J Clin Oncol. Published online January 28, 2022. Accessed February 7, 2022. doi:10.1200/JCO.21.01485
2. Stein JP, Lieskovsky G, Cote R, et al. Radical cystectomy in the treatment of invasive bladder cancer: long-term results in 1,054 patients. J Clin Oncol. 2001;19(3):666-75. doi:10.1200/JCO.2001.19.3.666
3. Grossman HB, Natale RB, Tangen CM, et al. Neoadjuvant chemotherapy plus cystectomy compared with cystectomy alone for locally advanced bladder cancer. N Engl J Med. 2003;349(9):859-66. doi:10.1056/NEJMoa022148
4. Dash A, Pettus JA, Herr HW, et al. A role for neoadjuvant gemcitabine plus cisplatin in muscle-invasive urothelial carcinoma of the bladder: a retrospective experience. Cancer. 2008;113(9):2471-7. doi:10.1002/cncr.23848