Olwen Hahn

Impact of the Addition of Carboplatin and/or Bevacizumab to Neoadjuvant Once-per-Week Paclitaxel Followed by Dose-Dense Doxorubicin and Cyclophosphamide on Pathologic Complete Response Rates in Stage II to III Triple-Negative Breast Cancer: CALGB 40603 (Alliance)

PURPOSE One third of patients with triple-negative breast cancer (TNBC) achieve pathologic complete response (pCR) with standard neoadjuvant chemotherapy (NACT). CALGB 40603 (Alliance), a 2 × 2 factorial, open-label, randomized phase II trial, evaluated the impact of adding carboplatin and/or bevacizumab. PATIENTS AND METHODS Patients (N = 443) with stage II to III TNBC received paclitaxel 80 mg/m(2) once per week (wP) for 12 weeks, followed by doxorubicin plus cyclophosphamide once every 2 weeks (ddAC) for four cycles, and were randomly assigned to concurrent carboplatin (area under curve 6) once every 3 weeks for four cycles and/or bevacizumab 10 mg/kg once every 2 weeks for nine cycles. Effects of adding these agents on pCR breast (ypT0/is), pCR breast/axilla (ypT0/isN0), treatment delivery, and toxicities were analyzed. RESULTS Patients assigned to either carboplatin or bevacizumab were less likely to complete wP and ddAC without skipped doses, dose modification, or early discontinuation resulting from toxicity. Grade ≥ 3 neutropenia and thrombocytopenia were more common with carboplatin, as were hypertension, infection, thromboembolic events, bleeding, and postoperative complications with bevacizumab. Employing one-sided P values, addition of either carboplatin (60% v 44%; P = .0018) or bevacizumab (59% v 48%; P = .0089) significantly increased pCR breast, whereas only carboplatin (54% v 41%; P = .0029) significantly raised pCR breast/axilla. More-than-additive interactions between the two agents could not be demonstrated. CONCLUSION In stage II to III TNBC, addition of either carboplatin or bevacizumab to NACT increased pCR rates, but whether this will improve relapse-free or overall survival is unknown. Given results from recently reported adjuvant trials, further investigation of bevacizumab in this setting is unlikely, but the role of carboplatin could be evaluated in definitive studies, ideally limited to biologically defined patient subsets most likely to benefit from this agent.

Dynamic Contrast-Enhanced Magnetic Resonance Imaging Pharmacodynamic Biomarker Study of Sorafenib in Metastatic Renal Carcinoma

PURPOSE Sorafenib is an antiangiogenic agent with activity in renal cancer. We conducted a randomized trial to investigate dynamic contrast magnetic resonance imaging (DCE-MRI) as a pharmacodynamic biomarker. PATIENTS AND METHODS Patients were randomly assigned to placebo or 200 or 400 mg twice per day of sorafenib. DCE-MRI was performed at baseline and 4 weeks. DCE-MRI parameters, area under the contrast concentration versus time curve 90 seconds after contrast injection (IAUC(90)), and volume transfer constant of contrast agent (K(trans)) were calculated for a metastatic site selected in a blinded manner. Primary end point was change in K(trans). RESULTS Of the 56 assessable patients, 48 underwent two MRIs; 44 MRIs were assessable for study end points. Mean K(trans) log ratios were 0.131 (standard deviation [SD], 0.315), -0.148 (SD, 0.382), -0.271 (SD, 0.499) in placebo, 200- and 400-mg cohorts, respectively (P = .0077 for trend) corresponding to changes of +14%, -14%, and -24%. IAUC(90) log ratios were 0.041 (SD, 0.197), -0.040 (SD, 0.132), -0.356 (SD, 0.411), respectively (P = .0003 for trend), corresponding to changes of +4%, -4%, and -30%. Using a log-rank test, IAUC(90) and K(trans) changes were not associated with progression-free survival (PFS). Patients with high baseline K(trans) had a better PFS (P = .027). CONCLUSION IAUC(90) and K(trans) are pharmacodynamic biomarkers for sorafenib, but variability is high and magnitude of effect is less than previously reported. Changes in DCE-MRI parameters after 4 weeks of sorafenib are not predictive of PFS, suggesting that these biomarkers are not surrogate end points. The value of baseline K(trans) as a prognostic or predictive biomarker requires additional study.

Cabozantinib Versus Sunitinib As Initial Targeted Therapy for Patients With Metastatic Renal Cell Carcinoma of Poor or Intermediate Risk: The Alliance A031203 CABOSUN Trial

Purpose Cabozantinib is an oral potent inhibitor of vascular endothelial growth factor receptor 2, MET, and AXL and is a standard second-line therapy for metastatic renal cell carcinoma (mRCC). This randomized phase II multicenter trial evaluated cabozantinib compared with sunitinib as first-line therapy in patients with mRCC. Patients and Methods Eligible patients had untreated clear cell mRCC and Eastern Cooperative Oncology Group performance status of 0 to 2 and were intermediate or poor risk per International Metastatic Renal Cell Carcinoma Database Consortium criteria. Patients were randomly assigned at a one-to-one ratio to cabozantinib (60 mg once per day) or sunitinib (50 mg once per day; 4 weeks on, 2 weeks off). Progression-free survival (PFS) was the primary end point. Objective response rate (ORR), overall survival, and safety were secondary end points. Results From July 2013 to April 2015, 157 patients were randomly assigned (cabozantinib, n = 79; sunitinib, n = 78). Compared with sunitinib, cabozantinib treatment significantly increased median PFS (8.2 v 5.6 months) and was associated with a 34% reduction in rate of progression or death (adjusted hazard ratio, 0.66; 95% CI, 0.46 to 0.95; one-sided P = .012). ORR was 33% (95% CI, 23 to 44) for cabozantinib versus 12% (95% CI, 5.4 to 21) for sunitinib. All-causality grade 3 or 4 adverse events were 67% for cabozantinib and 68% for sunitinib and included diarrhea (cabozantinib, 10% v sunitinib, 11%), fatigue (6% v 15%), hypertension (28% v 22%), palmar-plantar erythrodysesthesia (8% v 4%), and hematologic adverse events (3% v 22%). Conclusion Cabozantinib demonstrated a significant clinical benefit in PFS and ORR over standard-of-care sunitinib as first-line therapy in patients with intermediate- or poor-risk mRCC.

Stereotactic body radiotherapy for the treatment of oligometastatic renal cell carcinoma.

Objectives:Renal cell carcinoma (RCC) is considered radioresistant, but stereotactic radiosurgery can control intracranial metastases. Advances in radiotherapy, such as stereotactic body radiotherapy (SBRT), allow high-dose radiation delivery to extracranial sites. Herein, we report our experience treating oligometastatic RCC with SBRT. Methods:Patients with RCC and limited metastases were treated on a 3-fraction dose-escalation protocol (8 to 14 Gy/fraction) or off protocol with 10 fractions (4 to 5 Gy/fraction). Disease control was evaluated with serial imaging, and the Kaplan-Meier method was used to estimate lesion control (LeC), distant control, and survival. Results:Eighteen consecutively treated patients with 39 metastases were treated using SBRT; 12 underwent treatment for all metastatic sites. Median follow-up was 16.2 months. Treatment was well tolerated; the most common acute toxicity was fatigue (61.1%) and late toxicity was limited. At 2 years, LeC was 91.4% and overall survival was 85%. Those who underwent treatment for all metastatic sites had a 2-year LeC of 100% and distant control of 35.7%. A shorter interval from diagnosis to SBRT predicted for distant progression. Freedom from any post-SBRT therapy was 64.2% at 1 year. Conclusions:In metastatic RCC, SBRT produces promising LeC with minimal toxicity. Further study should be expanded beyond that of managing intracranial disease. Its selected use may delay the requirement for systemic therapies.

Abstract S5-01: Impact of the addition of carboplatin (Cb) and/or bevacizumab (B) to neoadjuvant weekly paclitaxel (P) followed by dose-dense AC on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC): CALGB 40603 (Alliance)

Background: Anthracycline- and taxane-based neoadjuvant chemotherapy (NAC) results in a pCR in 30-35% of TNBC patients (pts), which is associated with improved recurrence-free and overall survival (RFS/OS). Thus, pCR rates may be useful in evaluating novel regimens in TNBC. In advanced TNBC, platinum analogues like Cb are active and addition of B to chemotherapy increases response rates and time to progression. CALGB 40603 is a 2×2 randomized phase II study designed to determine if the addition of either Cb or B to standard NAC significantly increases pCR rates in TNBC. Methods: Pts had operable clinical stage II-III TNBC, defined as hormone receptors Results: 454 pts enrolled, median age 48, stage II 68%/stage III 32%. Of 354 pts with treatment data, 59 did not complete NAC, 30 withdrew due to AEs, more often with B vs. not (11.5% vs. 3.5%). B was discontinued in 23% of assigned pts vs. 6-13% for other agents. Grade 3-4 neutropenia (56% vs. 20%) and thrombocytopenia (22% vs. 4%) were more common with Cb vs. not, while grade 3 hypertension was more common with B vs. not (11% vs. There is no evidence of an interaction between the effects of Cb and B (p = 0.64 and 0.44, for breast and breast/axilla, respectively). Conclusions: Preliminary results suggest that adding Cb or B to standard NAC significantly increases pCR rates in stage II-III TNBC. These increases are additive, with pCR (breast) in 60.6% and pCR (breast/axilla) in 50% of pts who received both. Complete and confirmed results will be reported, including pCR rates for basal-like tumors vs. not. Pts will be followed for RFS/OS to assess the impact of pCR on these endpoints. Conduct of the trial was supported by grants from the NIH (ACTNOW and CA31946/CA33601), Genentech and the BCRF. Clinical trial information: NCT00861705. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr S5-01.

Phase III Trial Evaluating Letrozole As First-Line Endocrine Therapy With or Without Bevacizumab for the Treatment of Postmenopausal Women With Hormone Receptor-Positive Advanced-Stage Breast Cancer: CALGB 40503 (Alliance)

PURPOSE To investigate whether anti-vascular endothelial growth factor therapy with bevacizumab prolongs progression-free survival (PFS) when added to first-line letrozole as treatment of hormone receptor-positive metastatic breast cancer (MBC). PATIENTS AND METHODS Women with hormone receptor-positive MBC were randomly assigned 1:1 in a multicenter, open-label, phase III trial of letrozole (2.5 mg orally per day) with or without bevacizumab (15 mg/kg intravenously once every 3 weeks) within strata defined by measurable disease and disease-free interval. This trial had 90% power to detect a 50% improvement in median PFS from 6 to 9 months. Using a one-sided α = .025, a target sample size of 352 patients was planned. RESULTS From May 2008 to November 2011, 350 women were recruited; 343 received treatment and were observed for efficacy and safety. Median age was 58 years (range, 25 to 87 years). Sixty-two percent had measurable disease, and 45% had de novo MBC. At a median follow-up of 39 months, the addition of bevacizumab resulted in a significant reduction in the hazard of progression (hazard ratio, 0.75; 95% CI, 0.59 to 0.96; P = .016) and a prolongation in median PFS from 15.6 months with letrozole to 20.2 months with letrozole plus bevacizumab. There was no significant difference in overall survival (hazard ratio, 0.87; 95% CI, 0.65 to 1.18; P = .188), with median overall survival of 43.9 months with letrozole versus 47.2 months with letrozole plus bevacizumab. The largest increases in incidence of grade 3 to 4 treatment-related toxicities with the addition of bevacizumab were hypertension (24% v 2%) and proteinuria (11% v 0%). CONCLUSION The addition of bevacizumab to letrozole improved PFS in hormone receptor-positive MBC, but this benefit was associated with a markedly increased risk of grade 3 to 4 toxicities. Research on predictive markers will be required to clarify the role of bevacizumab in this setting.

Abstract S2-05: Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance)

Background: CALGB (Alliance) 40603 measured the effects of adding carboplatin (Cb) and/or bevacizumab (Bev) to standard neoadjuvant chemotherapy (weekly paclitaxel x 12 then doxorubicin/cyclophosphamide every 2 weeks x 4) on pathologic complete response (pCR) rates in stage II-III triple-negative breast cancer (TNBC). As previously reported (Sikov et al, JCO 2015), pCR breast (ypT0/is) and pCR breast/axilla (pCR Br/Ax) (ypT0/isN0) rates increased from 46% to 60% and 41% to 54%, respectively, with Cb and from 48% to 59% and 44% to 52%, respectively, with Bev. Secondary endpoints included event-free survival (EFS) and overall survival (OS). Methods: EFS is measured from study entry to ipsilateral invasive breast or locoregional recurrence, distant recurrence or death from any cause and OS from study entry to death from any cause in all patients (pts) who started study treatment. Pts without an event were censored as of their last clinical assessment. Hazard ratios (HR) were calculated for pts who achieved pCR vs. not and for pts assigned to receive drug (Cb or Bev) vs. not. All p-values are 2-sided. Results: 443 pts started study treatment. Median follow-up was 39 months (range 28-66). 110 EFS events and 77 deaths have been reported. At 3 yrs, overall EFS was 74.1% and OS 83.2%. Pts who achieved pCR breast had 3-yr EFS of 84.8% vs. 61.8% for those who did not. Table 1 shows the association between pCR and pCR or minimal residual invasive disease (Residual Cancer Burden Class I (RCB I), Symmans et al, JCO 2007) and outcomes; p-values for all comparisons Pts assigned to Cb vs. not had 3-yr EFS 76.5% vs. 71.6% and OS 81.9% vs. 84.6%. Pts assigned to Bev vs. not had 3-yr EFS 75.5% vs. 72.9% and OS 85.5% vs. 80.9%. Table 2 shows HRs by assigned treatment: Conclusions: Pts with TNBC who achieved pCR with study treatment had significantly better EFS and OS than pts who did not, consistent with findings from a published meta-analysis (Cortazar et al, Lancet 2014); the addition of RCB I did not weaken this association. Our study was not powered to assess the impact of Cb or Bev on these endpoints. While our findings are consistent with predictions from the meta-analysis as to the impact of raising the pCR rate on EFS (Berry-Hudis, JAMA Oncology 2015), the wide confidence intervals illustrate the challenge of conclusively demonstrating a correlation between pCR increment and EFS benefit, especially as the control pCR rate rises. While the addition of Bev has failed to improve long-term outcomes in TNBC in large randomized adjuvant trials, our results support ongoing and planned neoadjuvant and adjuvant studies designed to further assess the value of Cb-containing regimens in stage II-III TNBC. Support: U10s - CA180821, CA180882, CA180820, CA076001, CA025224, CA180868, CA180888. Citation Format: Sikov WM, Berry DA, Perou CM, Singh B, Cirrincione CT, Tolaney SM, Somlo G, Port ER, Qamar R, Sturtz K, Mamounas E, Golshan M, Bellon JR, Collyar D, Hahn OM, Carey LA, Hudis CA, Winer EP. Event-free and overall survival following neoadjuvant weekly paclitaxel and dose-dense AC +/- carboplatin and/or bevacizumab in triple-negative breast cancer: Outcomes from CALGB 40603 (Alliance). [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr S2-05.

Randomized Controlled Trials and Comparative Effectiveness Research

Comparative effectiveness research (CER) has been promoted as a way to improve the translation gap between clinical research and everyday clinical practice as well as to deliver more cost-effective health care. CER will account for a significant portion of funding allocated by the US government for health care research. Oncology has a rich history of improving clinical outcomes and advancing research through randomized controlled trials (RCTs). In this article, we review the role of RCTs in achieving the goals of CER, with particular emphasis on the role of publicly funded clinical trials.

Cabozantinib versus sunitinib as initial therapy for metastatic renal cell carcinoma of intermediate or poor risk (Alliance A031203 CABOSUN randomised trial): Progression-free survival by independent review and overall survival update

Background: The randomised phase 2 CABOSUN trial comparing cabozantinib with sunitinib as initial therapy for advanced renal cell carcinoma (RCC) of intermediate or poor risk met the primary end-point of improving progression-free survival (PFS) as assessed by investigator. We report PFS by independent radiology review committee (IRC) assessment, ORR per IRC and updated overall survival (OS). Patients and methods: Previously untreated patients with advanced RCC of intermediate or poor risk by IMDC criteria were randomised 1:1 to cabozantinib 60 mg daily or sunitinib 50 mg daily (4 weeks on/2 weeks off). Stratification was by risk group and presence of bone metastases. Results: A total of 157 patients were randomised 1:1 to cabozantinib (n = 79) or sunitinib (n = 78). Median PFS per IRC was 8.6 months (95% confidence interval [CI] 6.8—14.0) versus 5.3 months (95% CI 3.0—8.2) for cabozantinib versus sunitinib (hazard ratio [HR] 0.48 [95% CI 0.31—0.74]; two-sided p = 0.0008), and ORR per IRC was 20% (95% CI 12.0—30.8) versus 9% (95% CI 3.7—17.6), respectively. Subgroup analyses of PFS by stratification factors and MET tumour expression were consistent with results for the overall population. With a median follow-up of 34.5 months, median OS was 26.6 months (95% CI 14.6—not estimable) with cabozantinib and 21.2 months (95% CI 16.3—27.4) with sunitinib (HR 0.80 [95% CI 0.53—1.21]. The incidence of grade 3 or 4 adverse events was 68% for cabozantinib and 65% for sunitinib. Conclusions: In this phase 2 trial, cabozantinib treatment significantly prolonged PFS per IRC compared with sunitinib as initial systemic therapy for advanced RCC of poor or intermediate risk.

Abstract S4-05: Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc

Background: Adding either Cb or Bev to standard NACT significantly increases pCR rates in TNBC (Sikov et al, SABCS 2013). Genomic analysis may help us to identify determinants of response within this clinical phenotype. Methods: Patients (pts) with clinical stage II-III TNBC received weekly paclitaxel x 12 followed by ddAC x 4 +/- Cb and/or Bev. Pre-treatment biopsies were collected in formalin, RNAlater and OCT; residual disease at surgery was biopsied when possible. Illumina mRNA sequencing (RNAseq) was performed. Gene expression values were normalized to a TCGA subset of clinically TNBC samples prior to downstream analysis. pCR was defined as the absence of residual invasive cancer in the breast (ypT0/is). For each molecular signature, prognostic (effect on pCR in the overall study population) and predictive (effect of the addition of Cb or Bev, separately, on pCR) relationships were explored with logistic regression models. Results: PAM50 subtype analysis was performed on 367 pre-treatment samples (of 443 pts who started NACT); pCR results were available for 360, comprising the analysis subset. 87% of these displayed a basal-like gene expression pattern, 2% claudin-low, 4% HER2-enriched, Conclusions: Selection criteria led to accrual of a high % of pts with basal-like tumors, limiting our ability to assess prognostic or predictive impact of intrinsic subtype on pCR. Given that limitation, the magnitude of pCR benefit with Cb was consistent across subtypes, while a basal-like pattern was predictive of greater pCR increment with Bev. Ongoing studies will test a large number of other gene signatures and biomarkers, including the Lehmann et al subtypes. Recognition of clinically relevant subpopulations within TNBC may distinguish pts likely to achieve a pCR from those for whom an investigational approach might be considered. Citation Format: William M Sikov, William T Barry, Katherine A Hoadley, Brandelyn N Pitcher, Baljit Singh, Sara M Tolaney, Charles S Kuzma, Timothy J Pluard, George Somlo, Elisa R Port, Mehra Golshan, Donald A Berry, Olwen M Hahn, Lisa A Carey, Charles M Perou, Clifford A Hudis, Eric P Winer. Impact of intrinsic subtype by PAM50 and other gene signatures on pathologic complete response (pCR) rates in triple-negative breast cancer (TNBC) after neoadjuvant chemotherapy (NACT) +/- carboplatin (Cb) or bevacizumab (Bev): CALGB 40603/150709 (Allianc [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr S4-05.