Melissa Plets

Effect of Intravesical Instillation of Gemcitabine vs Saline Immediately Following Resection of Suspected Low-Grade Non–Muscle-Invasive Bladder Cancer on Tumor Recurrence: SWOG S0337 Randomized Clinical Trial

Importance Low-grade non–muscle-invasive urothelial cancer frequently recurs after excision by transurethral resection of bladder tumor (TURBT). Objective To determine whether immediate post-TURBT intravesical instillation of gemcitabine reduces recurrence of suspected low-grade non–muscle-invasive urothelial cancer compared with saline. Design, Setting, and Participants Randomized double-blind clinical trial conducted at 23 US centers. Patients with suspected low-grade non–muscle-invasive urothelial cancer based on cystoscopic appearance without any high-grade or without more than 2 low-grade urothelial cancer episodes within 18 months before index TURBT were enrolled between January 23, 2008, and August 14, 2012, and followed up every 3 months with cystoscopy and cytology for 2 years and then semiannually for 2 years. Patients were monitored for tumor recurrence, progression to muscle invasion, survival, and toxic effects. The final date of follow-up was August 14, 2016. Interventions Participants were randomly assigned to receive intravesical instillation of gemcitabine (2 g in 100 mL of saline) (n = 201) or saline (100 mL) (n = 205) for 1 hour immediately following TURBT. Main Outcomes and Measures The primary outcome was time to recurrence of cancer. Secondary end points were time to muscle invasion and death due to any cause. Results Among 406 randomized eligible patients (median age, 66 years; 84.7% men), 383 completed the trial. In the intention-to-treat analysis, 67 of 201 patients (4-year estimate, 35%) in the gemcitabine group and 91 of 205 patients (4-year estimate, 47%) in the saline group had cancer recurrence within 4.0 years (hazard ratio, 0.66; 95% CI, 0.48-0.90; P<.001 by 1-sided log-rank test for time to recurrence). Among the 215 patients with low-grade non–muscle-invasive urothelial cancer who underwent TURBT and drug instillation, 34 of 102 patients (4-year estimate, 34%) in the gemcitabine group and 59 of 113 patients (4-year estimate, 54%) in the saline group had cancer recurrence (hazard ratio, 0.53; 95% CI, 0.35-0.81; P = .001 by 1-sided log-rank test for time to recurrence). Fifteen patients had tumors that progressed to muscle invasion (5 in the gemcitabine group and 10 in the saline group; P = .22 by 1-sided log-rank test) and 42 died of any cause (17 in the gemcitabine group and 25 in the saline group; P = .12 by 1-sided log-rank test). There were no grade 4 or 5 adverse events and no significant differences in adverse events of grade 3 or lower. Conclusions and Relevance Among patients with suspected low-grade non–muscle-invasive urothelial cancer, immediate postresection intravesical instillation of gemcitabine, compared with instillation of saline, significantly reduced the risk of recurrence over a median of 4.0 years. These findings support using this therapy, but further research is needed to compare gemcitabine with other intravesical agents. Trial Registration clinicaltrials.gov Identifier: NCT00445601

Abiraterone Acetate for Metastatic Prostate Cancer in Patients With Suboptimal Biochemical Response to Hormone Induction

Importance Men with metastatic prostate cancer who have a poor response to initial androgen-deprivation therapy (ADT), as reflected by a prostate-specific antigen (PSA) level higher than 4.0 ng/mL after 7 months of ADT, have a poor prognosis, based on historical controls. Objective To determine the efficacy of abiraterone acetate with prednisone in these high-risk patients with a suboptimal response to hormonal induction. Design, Setting, and Participants A phase 2 single-arm study was conducted through the National Clinical Trials Network–Southwest Oncology Group. Eligible patients had metastatic prostate cancer and a PSA level higher than 4.0 ng/mL between 6 and 12 months after starting ADT. The PSA level could be rising or falling at the time of enrollment, but had to be higher than 4.0 ng/mL. No previous chemotherapy or secondary hormonal therapies were allowed, except in patients receiving a standard, first-generation antiandrogen agent with a falling PSA level at the time of enrollment; this therapy was continued in this cohort. Abiraterone acetate, 1000 mg, once daily with prednisone, 5 mg, twice daily was administered to all participants. A total of 41 men were enrolled between the trial’s activation on August 9, 2011, and closure on August 1, 2013. Data analysis was conducted from March 21 to November 29, 2016. Interventions Abiraterone acetate, 1000 mg, once daily by mouth with prednisone, 5 mg, by mouth twice daily. Main Outcomes and Measures The primary end point was a PSA level of 0.2 ng/mL or lower within 12 months of starting abiraterone acetate plus prednisone. A partial response (PR) was a secondary end point, defined as a PSA level reduction to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Results Of the 41 men enrolled, 1 did not receive any protocol treatment and was excluded from analysis. The median (range) age of the 40 participants was 66 (39-85) years. Five (13%) patients achieved a PSA level of 0.2 ng/mL or lower (95% CI, 4%-27%). Thirteen (33%) additional patients achieved a partial response, with a reduction in the PSA level to lower than 4.0 ng/mL but higher than 0.2 ng/mL. Sixteen (40%) patients had no PSA response and 6 (15%) were not assessable and assumed to be nonresponders. The median progression-free survival was 17.5 months (95% CI, 8.6-25.0 months) and the median overall survival was 25.8 months (95% CI, 15.7-25.8 months). There was 1 incident each of grade 4 adverse events of alanine aminotransferase level elevation and rectal hemorrhage. Eleven patients reported grade 3 adverse events. Conclusions and Relevance This study did not reach its prescribed level of 6 PSA responses of 0.2 ng/mL or lower, although 5 responses were observed. The overall survival and progression-free survival rates observed in this trial are encouraging compared with historical controls. The therapy was generally well tolerated, without any clear signal of any unexpected adverse effects.

Circulating microRNAs and treatment response in the Phase II SWOG S0925 study for patients with new metastatic hormone‐sensitive prostate cancer

Previous studies suggest circulating, blood‐based microRNAs (miRNAs) may serve as minimally invasive prostate cancer biomarkers, however there is limited data from prospective clinical trials. Here, we explore the role of candidate plasma miRNAs as potential biomarkers in the SWOG 0925 randomized phase II study of androgen deprivation combined with cixutumumab versus androgen deprivation alone in patients with new metastatic hormone‐sensitive prostate cancer.

Validation of the Association of RECIST Changes With Survival in Men With Metastatic Castration-Resistant Prostate Cancer Treated on SWOG Study S0421

Micro‐Abstract The association of Response Evaluation Criteria in Solid Tumors (RECIST) 1.0 changes within 120 days with survival in men with metastatic castration‐resistant prostate cancer receiving docetaxel was validated from a phase 3 trial. Given the limitations of prostate‐specific antigen and bone scan alterations to translate to improved survival, improved RECIST changes in phase 2 trials may be important before launching phase 3 trials. Background: Phase 2 trials evaluating new agents for metastatic castration‐resistant prostate cancer (mCRPC) have relied on bone scan and prostate‐specific antigen changes to assess activity. Given the increasing detection of measurable disease, Response Evaluation Criteria in Solid Tumors (RECIST) changes warrant consideration to evaluate activity. We validated the association of RECIST 1.0 changes with survival in men with mCRPC receiving docetaxel. Patients and Methods: Data for men with measurable disease from the Southwest Oncology Group (SWOG) S0421, a phase 3 trial in men with mCRPC receiving docetaxel and prednisone plus placebo or atrasentan, were used. Cox proportional hazards regression was used to evaluate the association of RECIST 1.0 outcomes within 120 days, ie, unconfirmed partial response (uPR), stable disease, and progressive disease (PD), with overall survival (OS) from day 120, adjusted for prognostic factors. Results: Overall, 326 men were evaluable for landmark analysis, of whom 23 had PD, 230 stable disease, and 73 uPR. OS beyond day 120 was significantly different (P = .004) among these subgroups, with median (95% confidence interval) OS of 7.1 (3.5‐8.8), 13.4 (11.4‐15.6), and 16.3 (10.0‐19.6) months for those with PD, stable disease, and uPR, respectively. In a multivariable model, the hazard ratio (95% confidence interval) for patients with PD was 2.47 (1.42‐4.29) compared to patients with an uPR (P = .002). Conclusion: The association of RECIST 1.0 changes with OS in men with mCRPC receiving docetaxel was validated. Given limitations of bone scan and prostate‐specific antigen alterations, improvements in objective RECIST 1.0 changes should be reported in phase 2 trials before launching phase 3 trials.

PNFLBA-10 A PHASE III BLINDED STUDY OF IMMEDIATE POST-TURBT INSTILLATION OF GEMCITABINE VERSUS SALINE IN PATIENTS WITH NEWLY DIAGNOSED OR OCCASIONALLY RECURRING GRADE I/II NON-MUSCLE INVASIVE BLADDER CANCER: SWOG S0337

following genes were queried: VHL, PBRM1, SETD2, BAP1, KDM5C, KIT, NFE2L2, MET, TP53, CDKN2A, FGFR3, PIK3CA, BRAF, MUC4. Criteria for calling mutations included adequate frequency by overall count and percentage of reads, identification in all overlapping sequences, and presence of buffy coat for comparison with <0.5% containing the mutation. RESULTS: Thirty preoperative test patients with RCC and 32 healthy controls were analyzed using the gene panel. Of the 32 patients analyzed in the healthy control cohort, 27 (84%) failed to yield sequence of the genes of interest. Of the pre operative RCC patients, 20/30 (67%) had detectable somatic mutations, resulting in nonsynonymous, frameshift, stopgain, or splice site mutations, compared to 1/32 (3.1%) controls. Mutations were detected in both early and advanced stage disease, including a patient with a 1.1 x 0.7 x 0.5 cm tumor. Mutations were seen in all genes assayed. CONCLUSIONS: These data demonstrate feasibility of genespecific whole exome sequencing of ctDNA for diagnosis of RCC in patients with solid renal tumors. The majority of RCC patients of various stages and histology had ctDNA detected in a single preoperative blood sample. A single control gave a positive test. Non invasive detection of RCC shows promise for not only initial diagnosis but also disease monitoring and guidance of targeted therapies throughout a wide spectrum of disease severity, including small lesions.

Parallel (Randomized) Phase II Evaluation of Tivantinib (ARQ197) and Tivantinib in Combination with Erlotinib in Papillary Renal Cell Carcinoma: SWOG S1107

Background: Papillary renal cell carcinoma (pRCC) is associated with EGFR expression and activation of MET signaling pathway. A randomized multicenter parallel two-stage phase II trial of MET inhibitor tivantinib alone or in combination with EGFR inhibitor erlotinib was conducted in patients with pRCC. Methods: Patients with advanced pRCC and 0-1 prior systemic therapy were randomly assigned to tivantinib 360 mg BID (Arm 1) or tivantinib 360 mg BID plus erlotinib 150 mg daily (Arm 2). Target max accrual was 70 patients (35 per arm) with interim analysis planned after enrollment of 20 patients per arm. Results: Six % of patients had type 1 pRCC, 42% had type 2, and 52% had no subtype assigned. The study was closed after the first stage when both arms yielded RR of 0%. Median progression free survival (PFS) was 2.0 and 3.9 months, and OS was 10.3 and 11.3 months in Arms 1 and 2 respectively. Treatment was well tolerated. Exome of tumor tissue from 16 patients were successfully sequenced using Agilent SureSelect probes. Only 1 of 16 samples harbored MET mutation. Other mutations associated primarily with type 2 pRCC were noted and included CDKN2A, PBRM1, SETD2, KDM6A, FAT1 and NF2. Conclusions: Tivantinib - either alone or in combination with erlotinib has no clinical activity in patients with advanced pRCC. The S1107 cohort had a low proportion of patients with MET alterations. MET remains a reasonable therapeutic target in pRCC, but selection of patient subsets exhibiting MET activation may be required to better benefit from therapy with MET inhibitors.

Validation of the association of RECIST 1.0 changes with survival in men with metastatic castration-resistant prostate cancer (mCRPC) treated on SWOG Study S0421.

5079Background: Prostate specific antigen (PSA) and bone scan changes are often used as components of primary endpoints in phase II trials of mCRPC. However, they do not reliably capture drug activ...