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摘要：膀胱癌的靶向治疗-2021 V3版NCCN指南内容节选（2021-05-18）
Targeted Therapies 【1】Platinum-based chemotherapy has been the standard of care in patients with metastatic disease with an OS of 9 to 15 months.194,207 However, in patients with disease that relapses after this type of chemotherapy, the median survival is reduced to 5 to 7 months.208 Several new agents, notably checkpoint inhibitors, have data supporting improved outcomes compared to standard therapies for metastatic urothelial carcinoma. Additionally, the FGFR inhibitor, erdafitinib, and the antibody-drug conjugate, enfortumab vedotin, have demonstrated effectiveness for the treatment of previously treated urothelial carcinoma. Cancers with higher rates of somatic mutations have been shown to respond better to checkpoint inhibitors.209-214 Data from the Cancer Genome Atlas rank bladder cancer as the third highest mutated cancer,190,191 suggesting that checkpoint inhibitors may have a substantial impact as a treatment option for this cancer. 【2】The FDA has approved the PD-L1 inhibitors atezolizumab and avelumab as well as the PD-1 inhibitors nivolumab and pembrolizumab for patients with urothelial carcinoma. Pembrolizumab, nivolumab, and avelumab are approved for the treatment of locally advanced or metastatic urothelial cell carcinoma that has progressed during or after platinum-based chemotherapy or that has progressed within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy, regardless of PD-L1 expression levels. Additionally, atezolizumab and pembrolizumab are approved as a first-line treatment option for patients with locally advanced or metastatic urothelial cell carcinoma who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or in patients who are not eligible for any platinumcontaining chemotherapy regardless of PD-L1 expression. Companion diagnostic tests have been approved by the FDA for measurement of PD-L1 expression.188,189 All of these approvals have been based on category 2 level evidence with the exception of pembrolizumab as a subsequent treatment option, which has category 1 level evidence supporting the approval.215 Pembrolizumab 【3】Pembrolizumab is a PD-1 inhibitor that has been evaluated as second-line therapy for patients with bladder cancer who previously received platinum-based therapy and subsequently progressed or metastasized.216 An open-label, randomized, phase III trial compared pembrolizumab to chemotherapy (paclitaxel, docetaxel, or vinflunine) in 542 patients with advanced urothelial carcinoma that recurred or progressed after platinum-based chemotherapy. Data from this trial showed a longer median OS for patients treated with pembrolizumab compared to chemotherapy (10.3 months vs. 7.4 months; P = .002). In addition, fewer grade 3, 4, or 5 treatment-related AEs occurred in the pembrolizumab-treated patients compared to those treated with chemotherapy (15.0% vs. 49.4%).217 Long-term results (>2 years’ follow-up) from this same phase III trial were consistent with earlier reports, with longer 1- and 2- year OS and PFS results for pembrolizumab compared to chemotherapy.218 The median DOR was not reached for pembrolizumab compared to 4.4 months for chemotherapy. Pembrolizumab also showed lower rates of any grade (62% vs. 90.6%) and grade ≥3 AEs (16.5% vs. 50.2%) compared to chemotherapy. Results from this phase 3 trial have led the NCCN Panel to assign pembrolizumab a category 1 recommendation as a secondline therapy. 【4】A single-arm, phase II trial evaluated pembrolizumab as a first-line therapy in 370 patients with advanced urothelial carcinoma who were ineligible for cisplatin-based therapy. Data from this study showed an ORR of 24%, with 5% of patients achieving a complete response. Grade 3 or higher treatment-related AEs occurred in 16% of patients treated with pembrolizumab at the time of data cutoff.219 In May 2018, the FDA issued a safety alert for the use of first-line pembrolizumab and atezolizumab, which warned that early reviews of data from 2 ongoing clinical trials (KEYNOTE-361 and IMvigor-130) showed decreased survival for patients receiving pembrolizumab or atezolizumab as firstline monotherapy compared to those receiving cisplatin- or carboplatinbased therapy.189 Based on these data, the pembrolizumab prescribing information was subsequently amended to restrict first-line use to patients who either 1) are not eligible for cisplatin-containingchemotherapy and whose tumors express PD-L1 as measured by a combined positive score (CPS) of at least 10; or 2) are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status.83 Atezolizumab 【5】Data from the two-cohort, multicenter, phase II IMvigor-210 trial evaluated atezolizumab in patients with metastatic disease. In cohort 1, atezolizumab was evaluated as a first-line therapy in 119 patients with locally advanced or metastatic urothelial carcinoma who were ineligible for cisplatin. Data from this study showed an ORR of 23% with 9% of patients showing a complete response. Median OS was 15.9 months. Grade 3 or 4 treatment-related AEs occurred in 16% of patients.220 In May 2018, the FDA issued a safety alert for the use of first-line pembrolizumab and atezolizumab, which warned that early reviews of data from 2 ongoing clinical trials (KEYNOTE-361 and IMvigor-130) showed decreased survival for patients receiving pembrolizumab or atezolizumab as first-line monotherapy compared to those receiving cisplatin- or carboplatin-based therapy.189 Based on these data, the atezolizumab prescribing information was subsequently amended to restrict first-line use to patients who either 1) are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 as measured by PD-L1–stained tumor-infiltrating immune cells covering at least 5% of the tumor area; or 2) are not eligible for any platinumcontaining chemotherapy regardless of the level of tumor PD-L1 expression.221 【6】Atezolizumab has also been investigated for patients with metastatic urothelial carcinoma post-platinum treatment, although it is no longer FDA-approved or recommended by the NCCN in that setting. Cohort 2 of the IMvigor 210 trial enrolled 310 patients with metastatic urothelial carcinoma post-platinum treatment and showed a significantly improved ORR compared to historical controls (15% vs. 10%; P = .0058).222 【7】Follow-up to date suggests these responses may be durable with ongoing responses recorded in 38 (84%) of 45 responders with a median follow-up of 11.7 months. At the investigator’s discretion, patients on this trial could continue atezolizumab beyond RECIST progression.223 An analysis of post-progression outcomes showed that those who continued atezolizumab had longer post-progression OS (8.6 months) compared to those who received a different treatment (6.8 months) and those who received no further treatment (1.2 months). 【8】The multicenter, randomized phase III IMvigor-211 study compared atezolizumab to chemotherapy (vinflunine, paclitaxel, or docetaxel) in 931 patients with locally advanced or metastatic urothelial carcinoma following progression with platinum-based chemotherapy.224 The primary endpoint of this study, median OS in patients with IC2/3 PD-L1 expression levels (n = 234), showed no significant difference between atezolizumab and chemotherapy (11.1 months vs. 10.6 months; P = .41). Likewise, confirmed ORR was similar between atezolizumab and chemotherapy treatments in this group of patients (23% vs. 22%). While atezolizumab was not associated with significantly longer OS compared to chemotherapy, the safety profile of atezolizumab was favorable, with 20% of patients experiencing grade 3 or 4 adverse effects compared to 43% with chemotherapy. 【9】The phase IIIb SAUL study and another expanded access study of atezolizumab evaluated the safety and efficacy of atezolizumab in patients who more closely resembled the real-world population, including those ineligible for IMvigor-211. 225,226 These studies reported similar efficacy and safety results compared to the pivotal clinical trial. 【10】In March 2021, the makers of atezolizumab voluntarily withdrew its indication for patients with locally advanced or metastatic urothelial carcinoma that was previously treated with a platinum based chemotherapy.227 This withdrawal was based on the IMvigor211 trial failing to meet its primary endpoint of improved OS. Therefore, the NCCN Panel does not recommend atezolizumab as an option following platinum-based first-line therapy, although it is still recommended in its first-line indication. Nivolumab 【11】Data from a phase II trial in patients with locally advanced or metastatic urothelial carcinoma who progressed after at least one platinum-containing regimen reported an ORR in 52 of 265 patients (19.6%; 95% CI, 15.0–24.9) following treatment with nivolumab that was unaffected by PD-1 tumor status.228 Out of the 270 patients enrolled in the study, grade 3 or 4 treatment-related AEs were reported in 18% of patients. Three patient deaths were the result of treatment.228 The median OS was 8.74 months (95% CI, 6.05–not yet reached). Based on PD-L1 expression of less than 1% and 1% or greater, OS was 5.95 months to 11.3 months, respectively. These data are comparable to the phase I/II data that reported an ORR of 24.4% (95% CI, 15.3%–35.4%) that was unaffected by PD-1 tumor status. Out of the 78 patients enrolled in this study, 2 experienced grade 5 treatment-related AEs, and grade 3 or 4 treatment-related AEs were reported in 22% of patients.229 An extended follow-up of this same phase I/II study (minimum follow-up of 37.7 months) reported a similar ORR of 25.6% (95% CI, 16.4%– 36.8%) for nivolumab monotherapy, with a median DOR of 30.5 months.230 Avelumab 【12】Avelumab is another PD-L1 inhibitor currently in clinical trials to evaluate its activity in the treatment of bladder cancer. Results from the phase 1b trial for 44 patients with platinum-refractory disease demonstrated an ORR of 18.2% that consisted of 5 complete responses and 3 partial responses following treatment with avelumab. The median PFS was 11.6 weeks and the median OS was 13.7 months with a 54.3% OS rate at 12 months. Grade 3 or 4 treatment-related AEs occurred in 6.8% of patients treated with avelumab.231 A pooled analysis of two expansion cohorts of the same trial reported results for 249 patients with platinum-refractory metastatic urothelial carcinoma or who were ineligible for cisplatin-based chemotherapy. Of the 161 postplatinum patients with at least 6 months of follow-up, the ORR as determined by independent review was 17%, with 6% reporting complete responses and 11% reporting partial responses. Grade 3 or 4 treatment-related AEs occurred in 8% of patients and, likewise, 8% of patients had a serious AE related to treatment with avelumab.232 【13】Avelumab is also recommended as a maintenance therapy following first-line platinum-containing treatment. For this setting, see Chemotherapy for Metastatic Disease, above. Erdafitinib 【14】Erdafitinib is a pan-FGFR inhibitor that has been evaluated in a global,open-label phase II trial of 99 patients with a prespecified FGFR alteration who had either previously received chemotherapy or who were cisplatin ineligible, chemotherapy naïve. Of these patients, 12% were chemotherapy naïve and 43% had received 2 or more prior lines of therapy. The confirmed ORR was 40% (95% CI, 31%–50%), consisting of 3% complete responses and 37% partial responses. Among patients who had previously received immunotherapy, the confirmed ORR was 59%. Median PFS was 5.5 months and the median OS was 13.8 months. Grade ≥3 treatment-related AEs were reported in 46% of patients and 13% of patients discontinued treatment due to AEs.233 Based on these data, the FDA has approved erdafitinib for patients with locally advanced or metastatic urothelial carcinoma that has progressed during or after platinum-based chemotherapy and whose tumors have susceptible FGFR3 or FGFR2 genetic alterations.234 Enfortumab Vedotin 【15】Enfortumab vedotin is a Nectin-4-directed antibody–drug conjugate that has been evaluated in a global, phase II, single-arm study of 125 patients with metastatic urothelial carcinoma who had previously received both a platinum-containing chemotherapy regimen and a PD1/PD-L1 checkpoint inhibitor. The confirmed ORR was 44% (95% CI, 35.1%–53.2%), including 12% complete responses. Similar response rates were seen in subgroups of patients with liver metastases and in those with no response to prior checkpoint inhibitor therapy. The median DOR was 7.6 months. Grade ≥3 treatment-related AEs were reported in 54% of patients and treatment-related AEs lead to dose reductions or discontinuation of therapy in 32% and 12% of patients, respectively.235 NCCN Recommendations for Targeted Therapies 【16】Based on these data, the NCCN Panel recommends pembrolizumab,nivolumab, avelumab, or erdafitinib as preferred second-line systemic therapy options after platinum-based therapy. Atezolizumab and pembrolizumab are also recommended as preferred first-line therapy options for patients who are not eligible for cisplatin-containing chemotherapy and whose tumors express PD-L1 or in patients who are not eligible for any platinum-containing chemotherapy regardless of PDL1 expression for locally advanced or metastatic disease. Avelumab is also recommended as maintenance therapy following treatment with a first-line platinum-containing regimen. In addition to chemotherapy options, erdafitinib is also recommended for second-line systemic therapy following a first-line checkpoint inhibitor and as a third- or subsequent-line therapy option for patients who have already received both a platinum-containing therapy and a checkpoint inhibitor, if eligible on the basis of FGFR3 or FGFR2 genetic alterations. Enfortumab vedotin is also recommended as a preferred subsequent-line systemic therapy option. See the Principles of Systemic Therapy within the algorithm for more information on these recommendations. With the exception of pembrolizumab as a second-line, post-platinum treatment option (category 1), the use of targeted therapies are all category 2A recommendations. Targeted Therapies Not Recommended 【17】Early results from a phase I/II multicenter study of durvalumab for 61 patients with PD-L1–positive inoperable or metastatic urothelial bladder cancer that progressed following a platinum-based regimen showed that 46.4% of patients who were PD-L1 positive had disease that responded to treatment; no response was seen in patients who were PD-L1 negative.236 A 2017 update on this study (N = 191) showed an ORR of 17.8% and a median OS of 18.2 months, with 55% of patients surviving at 1 year.237 In May 2017, the FDA granted accelerated approval to durvalumab based on these initial results.238 Subsequently, in February 2021, the makers of durvalumab voluntarily withdrew this indication based on negative results from the phase III DANUBE trial.239 DANUBEevaluated the use of durvalumab, with or without tremelimumab, compared to chemotherapy for first-line treatment of advanced urothelial carcinoma.240 The trial did not meet its primary endpoints as both durvalumab alone and in combination with tremelimumab failed to improve overall survival compared to chemotherapy. 【18】Likewise, in March 2021, the makers of atezolizumab voluntarily withdrew its indication for patients with locally advanced or metastatic urothelial carcinoma that was previously treated with a platinum-based chemotherapy.227 This withdrawal was based on the IMvigor211 trial failing to meet its primary endpoint of improved OS. More information and the data from this trial is described above in the Atezolizumab section. 【19】In response to these voluntary withdrawals,, the NCCN Panel voted to remove atezolizumab and durvalumab as a treatment options for patients with metastatic urothelial carcinoma in the post-platinum setting. |
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