bluuebunny/crossref_metadata_2025 huggingface dataset:
Immunomodulation by HDAC inhibition: Results from a phase I study with entinostat in combination with atezolizumab and bevacizumab in metastatic renal cell carcinoma patients.
Authors: Pili Roberto , Adra Nabil , Damayanti Nur , Logan Theodore F. , Narayan Vivek , Monk Paul , Dropcho S , Sego Lina M , Liu Hao , Althouse Sandra K. , Haas Naomi B.
Published: May 2020

5064

Background: Immunosuppressive regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) limit the efficacy of immunotherapies. We have previously reported that the HDAC inhibitor entinostat has synergistic antitumor effect in combination with immunotherapies in preclinical models by inhibiting Tregs and MDSCs function. The combination of atezolizumab (PD-L1 inhibitor) and bevacizumab (VEGF inhibitor) is active in renal cell carcinoma (RCC). Thus, we have conducted a Phase I study with entinostat, atezolizumab and bevacizumab in patients (pts) with metastatic RCC. Methods: The primary objective was to evaluate safety and tolerability. The phase I portion included 3 dose levels of entinostat (1 mg, 3 mg or 5 mg, PO weekly) and fixed, standard doses of atezolizumab (1200 mg IV every 21 days) and bevacizumab (15 mg/Kg IV every 21 days). Pts with any histological type and prior therapies were included. Results: Dose levels were completed with up to 1 DLT/dose level. 5 mg was the Phase II recommended dose for entinostat. DLTs included hypertension, encephalopathy, hyponatremia and pruritus. The most common resolved grade 3/4 toxicities were hypophosphatemia (33%), hypertension (17%), and pneumonitis (11%). We have enrolled 18 pts (17 evaluable for ORR by RECIST). 5 pts continue on treatment. 3 pts discontinued treatment because of adverse events, 9 pts for disease progression, and one pt for physician decision. Good risk and intermediate risk pts were 61% and 39%, respectively. Overall ORR was 47.1% (95% CI 23.0-72.2) and median PFS was 7.6 months (95% CI 1.6-16.3). In pts with no prior therapies (12) the ORR was 58.3% (95% CI 27.7-84.8) and median PFS was 13.4 months (95% CI 1.5-28.9). One additional PR was observed by ir-RC but was not confirmed within the data cut-off date of 11/11/19. In pts with prior immune checkpoint inhibitors (ICIs) (5) ORR was 20% (95% CI 0.5-71.6) and median PFS was 7.6 months (95% CI 1.3-NR). Preliminary data show a statistically significant lower % of circulating monocytic MDSC (HLADR−1CD11b+CD33highCD14+CD15−) and exhausted T cells (CD45+CD3+CD8+TIM3+) following treatment in pts (4) with objective responses as compared to pts (4) with progressive disease. Conclusions: The results from this phase I suggest that the combination of entinostat, atezolizumab and bevacizumab is relatively well tolerated and is active in renal cell carcinoma patients, in both ICIs naïve and resistant disease. A phase II portion of this study is currently accruing patients. Clinical trial information: NCT03024437 .
Quality-adjusted time without symptoms or toxicity (Q-TWiST) of lenvatinib plus everolimus versus everolimus monotherapy in patients with advanced renal cell carcinoma (RCC).
Authors: Lee Chung-Han , Wan Yin , Smith Alan D. , Xie RAN , Motzer Robert J.
Published: May 2020

5067

Background: In the primary analysis of Study 205 phase II trial (NCT01136733), lenvatinib+everolimus (vs everolimus) significantly prolonged progression-free survival (median PFS; 14.6 vs 5.5 months, HR = 0.40, 95% CI [0.24, 0.68]) in advanced RCC patients who received one prior anti-angiogenic therapy. Overall treatment differences were evaluated in a post hoc analysis using a quality-adjusted time without symptoms of disease or toxicity of treatment (Q-TWiST) methodology. Methods: Patients’ survival time was partitioned into three mutually exclusive health states: time spent with grade 3/4 toxicity (TOX), time prior to disease progression and without grade 3/4 toxicity (TWiST) and time post disease progression (REL). Mean time spent in each state was weighted by a health-state utility associated with that state and summed to calculate the Q-TWiST. Non-parametric bootstrapping method was used to generate 95% CI, which evaluates the between-treatment differences. At base case, utility for TWiST, TOX and REL were assigned as 1.0, 0.5 and 0.5, respectively. A sensitivity analysis was used, applying utilities across the range of 0 (similar to death) to 1.0 (perfect health). A relative gain in Q-TWiST of ≥10% and ≥15% has been established in previous literature as clinically important and clearly clinically important, respectively. Results: Patients receiving lenvatinib+everolimus (n = 51) vs everolimus (n = 50) had significantly longer mean time in TWiST (10.9 vs 6.4 months; difference 4.5 [95% CI: 1.4, 7.8]) and numerically longer in TOX (1.9 vs 0.7 months; difference 1.2 [95% CI: -0.3, 3.1]) but shorter in REL (5.8 vs 8.5 months; difference -2.8 [95% CI: -6.2, 0.6]). At base case, lenvatinib+everolimus patients had a significant mean Q-TWiST gain of 3.7 months (14.7 vs 11.0; 95% CI of difference [1.3, 6.3]), with a relative gain of 24% vs everolimus. In a sensitivity analysis using alternative utility values for TWiST (varied from 0.55 - 0.9) with utility of TOX and REL both set as 0.5, absolute mean Q-TWiST gain ranged from 1.7 to 3.3 months, with a relative gain ranging from 11.0% to 21.2% (all significant). With TWiST utility set as 1.0 and utility of TOX and REL varying from 0 to 1.0, Q-TWiST gain ranged from 1.7 to 5.8 months (mostly significant and became non-significant as the REL utility gets closer to 1.0 and TOX utility gets closer to 0). Conclusions: Within Study 205, lenvatinib+everolimus resulted in a statistically significant and clinically important gain in Q-TWiST vs everolimus alone. Clinical trial information: NCT01136733 .
Efficacy of immune-checkpoint inhibitors (ICI) in the treatment of older adults with metastatic renal cell carcinoma (mRCC): An international mRCC database consortium (IMDC) analysis.
Authors: Araujo Daniel Vilarim , Wells Connor , Hansen Aaron Richard , Dizman Nazli , Pal Sumanta K. , Beuselinck Benoit , Donskov Frede , Gan Chun Loo , Yan Flora , Tran Ben , Kollmannsberger Christian K. , de Velasco Guillermo , Yuasa Takeshi , Reaume M. Neil , Ernst D. Scott , Powles Thomas , Bjarnason Georg A. , Choueiri Toni K. , Heng Daniel Yick Chin , Dudani Shaan
Published: May 2020

5068

Background: Anti-PD-1/PD-L1 immune-checkpoint inhibitors (ICI) are now a standard of care in metastatic renal cell carcinoma (mRCC). Older adults were underrepresented in registration trials and given that immunological senescence may affect the anti-tumor activity of ICIs, there is uncertainty about the efficacy of ICIs in this population. Here we provide real world data on outcomes of older adults with mRCC treated with ICIs. Methods: Patients with mRCC treated with a PD-1/PD-L1 ICI either as monotherapy or as a combination treatment from 2000 to 2019 were included. Older adult was defined as ≥ 70-years at the time of ICI treatment. Descriptive statistics were summarized in means, medians and proportions. Efficacy was assessed by survival analysis, including overall survival (OS), time to treatment failure (TTF), and overall response rate (ORR). Multivariate analyses adjusted for imbalances in IMDC risk factors. P < 0.05 was considered statistically significant. Results: Of 1427 patients, 397 (28%) were older adults. Mean age of older vs. younger adults was 74 (70-92) vs. 60 (22-69) years. Groups were comparable in terms of gender (Female 28.5% vs. 26.1%, p = 0.36), rates of nephrectomy (21% vs. 18.3%, p = 0.24) and presence of sarcomatoid features (12.3% vs. 17.8%, p = 0.14). Proportion of IMDC risk-groups between older vs. younger adults were as follows: 15.4% vs. 18.2% for favorable, 61.2% vs. 59.1% for intermediate, and 23.4% vs. 22.7% for poor; there was no statistical difference (p = 0.55). ICI was used as 1st line in 40%, 2nd line in 48.5% and 3rd line in 11.5% patients; older adults were less likely to be treated with ICI in 1st line (32.2% vs. 43%, p < 0.01). In terms of survival, older adults had poorer median OS (25.1m vs. 30.8m, p < 0.01) but similar median TTF (6.9m vs. 6.9m, p = 0.40) compared to younger adults. In multivariate analyses, older age was not a predictor of either worse OS (aHR = 1.02, p = 0.86) or TTF (aHR = 0.95, p = 0.59). Older adults had a lower ORR compared to younger (24% vs. 31%, p = 0.01), which was mainly driven by responses in 1st line (31% vs. 44%, p = 0.02) and not observed in 2nd/3rd line (20% vs. 20%, p = 0.86). Conclusions: On multivariate analyses, older adults with mRCC treated with ICI had no difference in OS and TTF when compared to younger adults, despite having lower ORR in 1st line. Our data supports that older age is not an independent risk factor for survival; thus, treatment selection should not be based solely on chronological age.
First-line pembrolizumab (pembro) monotherapy in advanced clear cell renal cell carcinoma (ccRCC): Updated follow-up for KEYNOTE-427 cohort A.
Authors: McDermott David F. , Lee Jae-Lyun , Bjarnason Georg A. , Larkin James M. G. , Gafanov Rustem , Kochenderfer Mark D. , Jensen Niels Viggo , Donskov Frede , Malik Jahangeer , Poprach Alexandr , Tykodi Scott S. , Alonso Gordoa Teresa , Cho Daniel C. , Geertsen Poul F. , Climent Duran Miguel Angel , Di Simone Christopher , Du Xiaoqi , Perini Rodolfo F. , Rodriguez-Lopez Karla , Atkins Michael B.
Published: May 2020

5069

Background: KEYNOTE-427 (NCT02853344), an open-label, single-arm, phase 2 study, showed clinical activity of first-line pembro monotherapy in patients (pts) with ccRCC (cohort A). Previous studies in RCC and immune-oncology suggest depth of response may correlate with long-term benefit. Association between depth of response and OS, along with updated efficacy and safety for cohort A of KEYNOTE-427, are presented. Methods: Pts with histologically confirmed ccRCC, measurable disease (RECIST v1.1), and no prior systemic therapy received pembro 200 mg IV Q3W for 2 y or until progressive disease, unacceptable toxicity, or withdrawal. End points: ORR (primary), DOR, and PFS (RECIST v1.1); OS, and safety. Association between depth of response (maximum reduction from baseline in the sum of target lesions) and OS was evaluated using Cox proportional hazards model with target lesion reduction group as time-varying covariate. Results: 110 pts enrolled; median time from enrollment to data cutoff was 23.1 (range, 16.7-27.5) mo. Overall, 38.2% of pts had favorable and 61.2% had intermediate/poor IMDC risk. ORR was 36.4% (95% CI, 27.4-46.1; 3 CRs, 37 PRs); median (range) DOR was not reached (2.3-23.5+ mo); 64.0% had a DOR ≥12 mo. Median PFS was 7.1 mo (95% CI, 5.6-11.0) and median OS was not reached; 18-mo PFS and OS rates were 26.6% and 80.0%, respectively. 69.1% had some reduction in target lesions. Pts with > 60% reduction in target lesions had a greater probability of survival than pts with a ≤60% reduction (Table). ORR observed in IMDC favorable and intermediate/poor risk was 31.0% and 39.7%, respectively; 18-mo OS rate was 95.2% for favorable and 70.5% for intermediate/poor IMDC risk. Treatment-related AEs (TRAEs) occurred in 81.8% of pts, primarily fatigue (29.1%) and pruritus (28.2%). Grade ≥3 TRAEs occurred in 29.1% of pts; 1 pt died of treatment-related pneumonitis. Conclusions: First-line pembro monotherapy was tolerable and showed promising antitumor activity in advanced ccRCC. In general, pts who had greater reductions in target lesions demonstrated a trend toward improved OS; pts with reduction of tumor burden ≥80% had comparable long term outcomes to those who achieved a RECIST 1.1 defined CR. Clinical trial information: NCT02853344 . [Table: see text]
Phase III trial of metronomic capecitabine maintenance after standard treatment in operable triple-negative breast cancer (SYSUCC-001).
Authors: Wang XI , Wang Shu-Sen , Huang Heng , Cai Li , Peng Rou-Jun , Zhao Li , Lin Ying , Zeng Jian , Zhang Le-Hong , Ke Yong-Li , Wang Xian-Ming , Liu Xin-Mei , Chen Qian-Jun , Zhang An-Qin , Pang Dan-Mei , Xu Fei , Huang Jia Jia , Shi Yanxia , Tang Jun , Yuan Zhongyu
Published: May 2020

507

Background: Triple-negative breast cancer (TNBC) has a relatively high relapse rate and poor outcome after standard therapy among all subtypes of breast cancer. Effective strategies to reduce risk of relapse and death are unmet medical needs. Methods: In this phase III trial, patients with operable TNBC were randomly assigned to receive metronomic capecitabine (650 mg/m2 twice daily continuously for one year) as maintenance therapy or observation after standard local and systemic treatment for curative intent. The primary end point was disease-free survival (DFS). Secondary end points included distant disease-free survival (DDFS), overall survival (OS) and safety. Results: A total of 434 patients were randomly assigned to capecitabine group (n = 221) or observation group (n = 213). At a median follow-up of 56.5 months, 5-year DFS was significantly better in capecitabine group than in observation group (83% vs. 73%, HR, 0.63; 95% CI, 0.42 to 0.96; p = 0.027). 5-year DDFS was also significantly better in capecitabine group than in observation group (85% vs. 76%, HR, 0.56; 95% CI, 0.37 to 0.90; p = 0.016). However, 5-year OS was not significantly different between two groups (85% vs. 81%, HR, 0.74; 95% CI, 0.47 to 1.18; p = 0.203). Two hundred and two (91.4%) of patients completed one year of capecitabine therapy as planned. The most common capecitabine-related adverse events were hand-foot syndrome (46%), leukopenia (24%), Hyperbilirubinemia (13%), gastrointestinal pain (7%) and elevated serum transaminases (5%). Conclusions: Maintenance therapy with metronomic capecitabine for one year following standard treatment significantly improved DFS in operable TNBC, which was safe and well tolerated. (SYSUCC-001, Clinical trial information: NCT01112826 .
Axitinib plus pembrolizumab in patients with advanced renal cell carcinoma: Long-term efficacy and safety from a phase Ib study.
Authors: Atkins Michael B. , Puzanov Igor , Plimack Elizabeth R. , Fishman Mayer N. , McDermott David F. , Cho Daniel C. , Vaishampayan Ulka N. , George Saby , Tarazi Jamal Christo , Duggan William , Perini Rodolfo F. , Fernandez Kathrine C. , Choueiri Toni K.
Published: May 2020

5080

Background: Axitinib (AXI) plus pembrolizumab (pembro) showed superior overall survival (OS), progression-free survival (PFS) and response rate compared with sunitinib in a randomized Phase 3 trial in advanced renal cell carcinoma (RCC). Here, we report long-term efficacy and safety data of the combination AXI/pembro from the Phase 1 trial, with almost 5 years of follow-up. Methods: 52 treatment-naïve patients with advanced RCC were enrolled between 23 September 2014 and 13 October 2015, and were treated with oral AXI 5 mg twice daily and intravenous pembro 2 mg/kg every 3 weeks. Planned treatment duration was 2 years for pembro and not limited for AXI. Based on International Metastatic Database Consortium (IMDC) criteria, 46.2%, 44.2% and 5.8% of patients were reported as having favourable, intermediate and poor risk. Results: At data cut-off date (July 3, 2019), median OS was not reached; 38 (73.1%) patients were alive. 14 (26.9%) patients had died, none were related to treatment. The probability of being alive was 96.1% (95% CI 85.2–99.0) at 1 year, 88.2% (95% CI 75.7– 94.5) at 2 years, 82.2 % (95% CI 68.5– 90.3) at 3 years, and 66.8 % (95% CI 49.1–79.5) at 4 years. Median PFS was 23.5 (95% CI 15.4–30.4) months. Median duration of response was 22.1 (95% CI 15.1–not evaluable) months. Median time on treatment with the combination AXI/pembro was 14.5 months (n=52), median time on pembro after AXI discontinuation was 9.0 months (n=10), and median time on AXI after pembro discontinuation was 7.5 months (n=11). After stopping study treatment, 22 patients received subsequent systemic therapy, including nivolumab and cabozantinib (n=6 each). Grade 3/4 AEs were reported in 38 (73.1%) patients. 20 (38.5%) patients discontinued either drug due to AEs: 17 (32.7%) patients discontinued AXI, and 13 (25.0%) patients discontinued pembro with 10 (19.2%) discontinuing both drugs. Dose reduction of AXI due to AEs was reported in 16 (30.8%) patients. The most common AEs reported were diarrhea (84.6%), fatigue (80.8%), hypertension (53.8%), cough (48.1%), and dysphonia (48.1%). Increased alanine aminotransferase and aspartate aminotransferase occurred in 44.2% and 36.5% of patients, respectively. With this longer follow-up, there were no cumulative AEs or new AEs. OS by IMDC risk group will be presented. Conclusions: In patients with advanced RCC with almost 5 years of follow-up, the combination of AXI/pembro continues to demonstrate clinical benefit with no new safety signals. Clinical trial information: NCT02133742 .
Patient preferences and expectations of systemic therapy in renal cell carcinoma.
Authors: Battle Dena , Bergerot Cristiane Decat , Msaouel Pavlos , Jonasch Eric , Zhang Tian , George Daniel J. , Staehler Michael D.
Published: May 2020

5083

Background: In metastatic renal cell carcinoma, the systemic therapy landscape has expanded to include multiple VEGF inhibitors, immunotherapies, and combination therapy. Little is known about patient expectations and preferences when making decisions about systemic therapy. We sought to gather independent data from online kidney cancer patient communities to assess patient perspectives on what matters most when considering treatment options. Methods: The KCCure online survey was performed between August 1, and September 30, 2019. Patients were recruited via the KCCure website, social media channels (Twitter, Facebook) and through fliers distributed at cancer centers. Those who agreed to participate were surveyed for demographics (age, gender, race, income, country) and clinical characteristics (date of the diagnosis, disease stage, treatment history). Key questions focused on treatment selection and side effect management. Results: Out of 1,136 patients responding, 411 patients were on systemic therapy with a median age of 57 years (range 28-86). 223 (54%) of patients on systemic therapy were male. Patients were primarily from the U.S. (83%). Median duration on therapy was 24.7+/- 1.9 months. When asked to select the most important outcome for treatment selection, 58.8 % of patients chose complete response, followed by tumor control (10.2%), low risk of toxicity (5.7%) and the chance to discontinue therapy (3.7%). Patients ranked cost as the least important factor in selecting treatment (2.9%). 10.9% preferred infusion therapy and 42.1% oral therapy, whereas 47% were indifferent about the route of administration. Even if it would be safe to discontinue therapy, 62.8% of patients would be anxious about cancer progression. 23.2% would rather stay on treatment and 39.3% would want increased scanning intervals. Only 34.4% of patients would look forward to having more time off therapy. When asked to define treatment success, 86.3% selected reduction in tumor size, followed by stable disease (71.7%), freedom from symptoms (35.1%) and better quality of life (47.7%). Conclusions: Patients rank efficacy as the most important outcome when considering treatment options. Toxicity, time off therapy and cost are not significant priorities for patients. Further data is warranted investigating the impact of communicating treatment options, potential discontinuation of therapy and resulting expectations.
Role of intratumoral NK cells in triple-negative breast cancer in the FinXX trial and Mayo Clinic cohort.
Authors: Chumsri Saranya , Carter Jodi M , Ma Yaohua , Hinerfeld Douglas , Brauer Heather Ann , Warren Sarah , Nielsen Torsten O , Asleh Karama , Joensuu Heikki , Perez Edith A. , Leon-Ferre Roberto Antonio , Hillman David W. , Boughey Judy Caroline , Liu Minetta C. , Ingle James N. , Kalari Krishna R. , Couch Fergus , Knutson Keith L. , Goetz Matthew P. , Thompson E Aubrey
Published: May 2020

510

Background: Several studies have established the critical role of preexisting immune response in triple negative breast cancer (TNBC). Most studies evaluated the tumor infiltrating lymphocytes in stroma. However, limited data are available with regards to the importance of specific subtypes and spatial distribution of these immune infiltrates. Methods: NanoString IO360 gene expression analysis and Digital Spatial Profiling (DSP) were used. DSP was used to quantify 39 immune-related proteins in stromal and tumor-enriched segments from 44 TNBC samples from the FinXX trial (NCT00114816) and 335 samples from the Mayo Clinic (MC) cohort of centrally reviewed TNBC (Leon-Ferre BCRT 2018). In FinXX trial, 22 patients with recurrence and 22 patients without recurrence were included. In MC cohort, 217/335 patients received adjuvant chemotherapy while 118 patients had surgery only without adjuvant chemotherapy. Regions were segmented based on pancytokeratin staining. The general linear model was used for statistical analysis of differential expression with recurrence free survival (RFS) as a categorical variable (recur yes or no). Kaplan-Meier estimates and Cox regression models were also used for analysis. Results: In the FinXX trial, using global gene expression analysis with IO360, there was no signature significantly associated with RFS. However, using DSP, high protein expression of CD56 in the tumor-enriched segments was associated with significant improvement in RFS (HR 0.26, 95%CI 0.09-0.78, p 0.01). Nevertheless, CD56 expression in the stroma (HR 0.66, 95%CI 0.29-1.53, p 0.33) and all segments (HR 0.53, 95%CI 0.23-1.25, p 0.14) was not significantly associated with improved outcome. We further validated these findings in the MC TNBC cohort where intratumoral CD56 expression was associated with a significant improvement in RFS (HR 0.23, p 0.002) but not stromal CD56 (p 0.79). Interestingly, when evaluating the MC TNBC cohort according to receipt of chemotherapy, intratumoral CD56 was associated with improved outcome only in patients who received chemotherapy (p 0.02 vs. 0.07). In both cohorts, higher expressions of intratumoral PD-L1, HLA-DR, and CD8 were associated with improved outcome. Conclusions: Using an in-depth analysis with spatially defined context, we identify that intratumoral CD56-positive NK cells are associated with improved outcome in TNBC. Our study highlights the potential role of NK cells in TNBC and future implications for biomarkers and therapeutic targets.Support: W81XWH-15-1-0292, P50CA116201-9, P50CA015083. Clinical trial information: NCT00114816 .
Response to neoadjuvant chemotherapy and the 21-gene breast recurrence score in young women with estrogen receptor-positive early breast cancer.
Authors: Sella Tal , Gelber Shari I. , Poorvu Philip Daniel , Kim Hee Jeong , Guzman Arocho Yaileen D , Collins Laura C. , Ruddy Kathryn Jean , Tamimi Rulla M , Peppercorn Jeffrey M. , Schapira Lidia , Borges Virginia F. , Come Steven E. , Warner Ellen , Snow Craig , Jakubowski Debbie M , Russell Christy Ann , Winer Eric P. , Rosenberg Shoshana M. , Partridge Ann H.
Published: May 2020

514

Background: The 21- gene Breast Recurrence Score predicts benefit from adjuvant chemotherapy in estrogen receptor positive (ER+), HER-2 negative (-) breast cancer (BC). We aimed to examine whether the 21-gene assay predicts response to neoadjuvant chemotherapy (NAC). Methods: We identified patients with stage I-III ER+/HER2− BC treated with NAC from the Young Women's Breast Cancer Study, a prospective cohort of women diagnosed with BC at age ≤ 40 years. The 21-gene assay was performed on tumor specimens removed prior to NAC either as part of clinical care or retrospectively for research. Pathologic complete response (pCR) was defined as no residual invasive tumor (ypT0/is ypN0). The relationship between Recurrence Score result (RS) and pCR was evaluated using logistic regression modeling. Results: 76 women in the cohort had undergone NAC for ER+, HER2- BC and were eligible for this analysis: 5 had undergone clinical 21-gene assay testing, 71 had banked specimens retrospectively tested. Median age at diagnosis was 36.7 (24.3-40). Most tumors were of ductal histology (78%), high grade (51%), progesterone receptor (PgR) positive (86%), ≥T2 (88%), clinically node positive (74%), and anthracycline and taxane containing protocols were administered in 86% of cases. RS ranged between 5-75 with 50% > 25 and only 4 < 11. Mean RS was significantly higher among tumors achieving pCR vs. non-pCR response (51.9 vs. 26.6, pwilcoxon= 0.0005). pCR rate in patients with RS > 25 was 21% (8/38) vs. 5% in patients with RS < 25 (2/38), with both pCRs in the <25 group in patients with RS 21-25. In univariable analysis, PgR negativity (odds ratio (OR) 5.62, 95% confidence interval (CI) 1.27-24.89, p = 0.02), high grade (OR 9.03, 95%CI 1.07-76.32, p = 0.04) and higher RS as a continuous variable (OR 1.08, 95%CI 1.04-1.13, p = 0.0003) were associated with a greater likelihood of pCR. In multivariable analysis only RS remained significantly associated with pCR (OR: 1.07, 95%CI 1.01-1.12, p = 0.01): a 7% increase in the odds of pCR for every 1-point increase in RS. Conclusions: In young women with ER+, HER2- BC who received NAC, higher pretreatment RS was associated with an increased likelihood of pCR. Genomic expression profiling assays may have a role in decision-making in young women in need of neoadjuvant therapy. For women with low likelihood of benefiting from NAC, alternative approaches are clearly warranted. Given the demonstrated efficacy of neoadjuvant endocrine therapy in post-menopausal women, further evaluation in young women should be pursued.
GAIN-2: Neo-/adjuvant phase III trial to compare intense dose-dense chemotherapy (CT) to tailored dose-dense CT in patients (pts) with high risk early breast cancer (EBC): Results on safety and interim invasive disease-free survival (iDFS).
Authors: Moebus Volker , Lueck Hans-Joachim , Ladda Ekkehart , Klare Peter , Schmidt Marcus , Schneeweiss Andreas , Untch Michael , Marmé Frederik , Huober Jens Bodo , Stickeler Elmar , Reinisch Mattea , Link Theresa , Sinn Bruno Valentin , Furlanetto Jenny , Reimer Toralf , Solbach Christine , Schmatloch Sabine , Rey Julia , Burchardi Nicole , Loibl Sibylle
Published: May 2020

516

Background: GAIN-2 (NCT01690702) compared efficacy and safety of intense, dose-dense epirubicin, nab-paclitaxel, and cyclophosphamide (iddEnPC) vs dose-dense, dose-tailored epirubicin/ cyclophosphamide followed by dose-dense, dose-tailored docetaxel (dtEC-dtD) as adjuvant or neoadjuvant CT for node-positive or high risk node-negative EBC. Here, we report safety results and interim analysis (IA) of the primary endpoint iDFS. Methods: Pts (luminal A ≥N2; luminal B N+; HER2+ and TNBC) were randomized between iddEnPC (E 150 mg/m2, nP 330 mg/m2, C 2000 mg/m2, all q2w x 3) or dtEC-dtD (dtEC q2w x 4 followed after 1 week rest by dtD q2w x 4). Primary objective was to compare iDFS. 797 events are needed to detect a hazard ratio of 0.819 with a 2-sided log-rank-test with 80% power and α=0.05. The IA of iDFS was planned after 50% of the events have occurred. Safety and compliance were secondary objectives. Results: Between 10/2012 and 09/2018, 2887 pts were randomized and 2857 started treatment (iddEnPC 1429; dtEC-dtD 1428). Median age was 51 (range 18-75) years. Overall, 18.1% were luminal A, 31.5% luminal B/HER2-, 18.8% hormone-receptor (HR)+/HER2+, 8.5% HR-/HER2+ and 23.2% TNBC. Overall, 88.1% of pts completed all treatment in both arms. 66.8% with iddEnPC vs 58.8% with dtEC-dtD delayed CT dose (p<0.001). Grade 3-4 non-hematological adverse events (AEs) were more frequent with iddEnPC (iddEnPC 50.8% vs dtEC-dtD 45.1%, p=0.002). Grade 3-4 leukopenia, neutropenia, febrile neutropenia, arthralgia, and peripheral sensory neuropathy were significantly higher with iddEnPC. There were 1464 serious AEs (iddEnPC 870 vs dtEC-dtD 594) and 26 (9 vs 17) predefined AEs of special interest (anaphylaxis, any AE affecting cranial nerves, macula edema). Two deaths occurred during dtEC-dtD. After a median follow-up of 45.8 months, there was no difference in iDFS between arms (log-rank p=0.9102, hazard ratio iddEnPC vs dtEC-dtD 1.01, 95% CI 0.83-1.23). Conclusions: No new safety concerns were observed. Use of both iddEnPC and dtEC-dtD appears feasible in the (neo)adjuvant treatment of high risk EBC. Clinical trial information: NCT01690702 .
HER2 status and prediction of extended endocrine benefit with breast cancer index (BCI) in HR+ patients in the adjuvant tamoxifen: To offer more? (aTTom) trial.
Authors: Bartlett John , Sgroi Dennis C. , Treuner Kai , Zhang Yi , Piper Tammy , Salunga Ranelle C. , Ahmed Ikhlaaq , Doos Lucy , Thornber Sarah , Taylor Karen J. , Brachtel Elena F. , Pirrie Sarah , Schnabel Catherine A. , Rea Daniel William
Published: May 2020

522

Background: BCI is a validated gene expression-based assay that stratifies patients based on risk of overall (0-10y) and late (post-5y) distant recurrence (DR) and predicts likelihood of benefit from extended endocrine therapy (EET). The Trans-aTTom study established Level1B validation for BCI (H/I) to predict benefit from EET.1 In this updated Trans-aTTom analysis including HER2 status, BCI (H/I) and prediction of endocrine benefit were further characterized. Methods: Centralized HER2 was determined for all cases according to current ASCO/CAP guidelines. Kaplan-Meier and Cox proportional hazards regression were conducted to assess primary and secondary endpoints of Recurrence-Free Interval (RFI) and Disease-Free Interval (DFI), respectively. A three-way interaction using likelihood ratio testing, which included treatment, BCI (H/I) and HER2, was performed to assess the effect of HER2 on BCI (H/I) prediction of EET benefit. Results: Of 789 N+ patients, 90% (N = 711) and 9% (N = 72) were HR+/HER2- and HR+/HER2+, respectively. In the HER2- subset, BCI (H/I)-High (48%) showed significant benefit from 10y vs. 5y of tamoxifen (9.4% RFI: HR = 0.35 [95% CI 0.15-0.81]; P = 0.047) while BCI (H/I)-Low patients did not (-2.1% RFI; HR = 1.15 [95% CI 0.78-1.69]; P = 0.491). For DFI, BCI (H/I)-High patients also showed significant benefit (10.3% DFI; HR = 0.41 [95% CI 0.18-0.91]; P = 0.047) while BCI (H/I)-Low patients did not (-1.7% DFI; HR = 1.10 [95% CI 0.75-1.62] P = 0.612). As demonstrated in the overall N+ cohort, significant interaction between BCI (H/I) and treatment was shown in the HER2- subset (RFI P = 0.045; DFI P = 0.044). Notably, three-way interaction evaluating BCI (H/I), treatment and HER2 status was not statistically significant (P = 0.85), indicating the ability of BCI (H/I) to predict benefit of EET activity was not significantly affected by HER2 status. Conclusions: In this updated Trans-aTTom analysis with HER2 data, BCI (H/I) showed similar predictive performance for EET response in the HER2- subset when compared to the overall N+ cohort. These data further support the clinical utility of BCI (H/I) as a predictive biomarker for informing EET benefit in HR+/HER2- and HR+/HER2+ disease. Clinical trial information: NCT00003678 . [Table: see text]
Genome-wide association study of steady-state letrozole concentration in patients with breast cancer.
Authors: Hertz Daniel Louis , Douglas Julie , Kidwell Kelley M. , Gersch Christina L , Desta Zeruesenay , Storniolo Anna Maria , Stearns Vered , Skaar Todd C. , Hayes Daniel F. , Henry Norah Lynn , Rae James M.
Published: May 2020

538

Background: Letrozole is a non-steroidal aromatase inhibitor (AI) used to treat hormone receptor positive (HR+) breast cancer. Variability in letrozole efficacy and toxicity may be partially attributable to variable systemic drug exposure, which may be influenced by germline variants in the enzymes responsible for letrozole metabolism, including CYP2A6. The objective of this genome-wide association study (GWAS) was to identify genetic variants that affect steady state letrozole concentrations. Methods: The Exemestane and Letrozole Pharmacogenetics (ELPh) Study randomized 503 post-menopausal patients with HR+ non-metastatic breast cancer to exemestane or letrozole treatment. Germline DNA was collected pre-treatment and blood samples were collected after 1 or 3 months of treatment to measure steady-state letrozole concentration via HPLC/MS. Genome-wide genotyping was conducted on the Infinium Global Screening Array to the Haplotype Reference Panel ( > 2 million variants). The association of each polymorphism with square-root transformed letrozole concentration was tested in self-reported white patients via linear regression using the standard alpha for genome-wide significance (α = 5x10−8) assuming an additive genetic model and correcting for age and body mass index. Results: 228 patients met inclusion criteria and had all necessary data. Each variant allele of rs7937 a patient carried increased their letrozole concentration ~22.9 ng/mL (standard error = 4.01, p = 3.51x10−8, Table) and this variant explained 13% of the variability in letrozole concentrations. rs7937 is located ~50 kB upstream of CYP2A6, and has previously been identified in GWAS of CYP2A6-related phenotypes, including nicotine metabolism and lung cancer. Conclusions: This GWAS confirmed that steady-state letrozole concentrations are partially determined by germline polymorphisms affecting CYP2A6 activity. If letrozole concentrations affect treatment efficacy or toxicity, CYP2A6 genetics may be useful to individualize letrozole dosing to improve clinical outcomes in patients with HR+ breast cancer. [Table: see text]
PD-1 protein and gene expression in early breast cancer: Prognostic implications.
Authors: Zerdes Ioannis , Matikas Alexios , Lövrot John , Sifakis Emmanouil G. , Richard François , Sotiriou Christos , Rassidakis George Z. , Bergh Jonas C. S. , Valachis Antonios , Foukakis Theodoros
Published: May 2020

545

Background: We have previously shown the prognostic value of PD-L1 protein and gene expression in early breast cancer (BC), however, the prognostic role of PD-1 expression remains unclear. Methods: The prognostic value of PD-1 in early BC was investigated using three different approaches: i) evaluation of PD-1 at the protein (IHC, immunohistochemistry in tissue microarrays) and mRNA levels in a retrospective patient cohort of 586 patients treated for early BC in Stockholm, Sweden between 1997-2005, ii) systematic review and trial-level meta-analysis of studies published in Medline, Embase, Cochrane Library and Web of Science Core Collection libraries on the prognostic value of PD-1 IHC expression, and iii) pooled analysis of transcriptomic data from 39 publicly available datasets for the prognostic capacity of PD-1 gene expression. Univariate and multivariable Cox regression models were used. Results: In the retrospective study cohort, PD-1 protein was significantly associated with biologically high-risk characteristics. PD-1 protein, but not gene expression, was correlated with improved overall survival (OS) (adjusted HR = 0.73, 95% CI 0.55 – 0.96, p = 0.023 and adjusted HR = 0.88, 95% CI 0.68 – 1.13, p = 0.307, respectively). In the trial-level meta-analysis, 4736 entries were initially identified and 15 studies, including our original cohort, fulfilled the predefined eligibility criteria. PD-1 IHC expression was not prognostic in unselected patients. However, a significant correlation to improved disease-free survival was seen within the triple-negative subtype (pooled multivariate HR = 0.57, 95% CI 0.29 – 0.90, p = 0.02). In the pooled gene expression analysis, PD-1 gene expression was associated with improved OS in the entire population (adjusted HR = 0.89, 95% CI 0.80 – 0.99, p = 0.025) and in basal-like (adjusted HR = 0.77, 95% CI 0.63 – 0.95, p = 0.014) tumors. Conclusions: PD-1 expression at the RNA and protein levels represent promising prognostic factors, especially in the triple-negative and basal-like subtypes. Standardization and further validation are needed prior to clinical implementation.
Results of a phase II trial of intense androgen deprivation therapy prior to radical prostatectomy (RP) in men with high-risk localized prostate cancer (PC).
Authors: McKay Rana R. , Xie Wanling , Fennessy Fiona M. , Zhang Zhenwei , Lis Rosina , Rathkopf Dana E. , Laudone Vincent Paul , Bubley Glenn , Einstein David Johnson , Chang Peter , Wagner Andrew , Preston Mark A. , Kilbridge Kerry L. , Chang Steven Lee , Choudhury Atish Dipankar , Pomerantz Mark , Trinh Quoc-Dien , Kibel Adam S. , Taplin Mary-Ellen
Published: May 2020

5503

Background: Patients with high-risk localized PC have an increased risk of recurrence and death despite treatment. Abiraterone acetate (AA), a potent CYP17 inhibitor, and apalutamide, a next generation anti-androgen, have each demonstrated improved overall survival in metastatic PC. In this multicenter randomized phase II trial we investigate the impact of intense androgen deprivation on RP pathologic response (NCT02903368). Methods: Eligible patients had a Gleason score ≥4+3=7, PSA >20 ng/mL or T3 disease (by prostate MRI) and lymph node <20 mm. During Part 1 of the study, patients were randomized 1:1 to AA + prednisone + apalutamide + leuprolide (APAL) or AA + prednisone + leuprolide (APL) for 6 cycles (1 cycle=28 days) followed by RP. All RPs underwent central pathology review. The primary endpoint was the rate of a pathologic complete response (pCR) or minimum residual disease (MRD, tumor ≤5 mm). Secondary endpoints include PSA response, surgical staging at RP, positive margin rate, and safety. Results: 118 patients were enrolled at four sites. Median age was 61 (range 46-72) years. The majority of patients had NCCN high-risk disease [n=111, 94%; T3 n=73 (62%), Gleason 8-10 n=84 (71%), PSA >20 ng/mL n=28 (24%)]. 114 (97%) patients completed 6 therapy cycles followed by RP. Median PSA nadir was <0.01 versus 0.02 ng/mL and time to nadir was 4.2 versus 4.6 months in the APAL and APL arms, respectively. RP outcomes are displayed in Table. The combined pCR or MRD rate was 21.8% in the APAL arm and 20.3% in the APL arm (p=0.85). 13 (11%) patients (8 in APAL; 5 in APL) experienced grade 3 treatment-related adverse events (TrAEs). The most common grade 3 TrAEs were hypertension (5%), elevated ALT (3%) and elevated AST (3%). No grade 4 or 5 TrAE was reported. Conclusions: Intense neoadjuvant hormone therapy followed by RP in men with high-risk PC resulted in favorable pathologic responses (<5 mm residual tumor) in 21% of patients. Pathologic responses were similar between the treatment arms. Follow-up is necessary to evaluate the significance of a pathologic response on recurrence rates. Part 2 of this trial will investigate the impact of an additional 12 months of APAL post-RP on biochemical recurrence. A phase 3 trial investigating neoadjuvant apalutamide + leuprolide prior to RP is ongoing. Clinical trial information: NCT02903368 . [Table: see text]
Neoadjuvant apalutamide (APA) plus leuprolide (LHRHa) with or without abiraterone (AA) in localized high-risk prostate cancer (LHRPC).
Authors: Efstathiou Eleni , Boukovala Myrto A , Spetsieris Nicholas , Wen Sijin , Hoang Anh , Weldon Justin Alexander , Tidwell Rebecca , Davis John W. , Chapin Brian Francis , Corn Paul Gettys , Subudhi Sumit Kumar , Aparicio Ana , Pettaway Curtis Alvin , Pisters Louis L. , Papadopoulos John N. , Adibi Mehrad , Wang Jennifer , Zurita Amado J. , Logothetis Christopher , Troncoso Patricia
Published: May 2020

5504

Background: Novel androgen signaling inhibitors (ASI) with medical castration may improve outcomes in LHRPC. We previously reported relapse free survival association with pathologic measures of tumor regression. However a wide range of persistent cancers was recorded. To build on our findings and test candidate predictors of outcome, we conducted a study examining APA effect in LHRPC. Methods: This is a phase II neoadjuvant study of 6 months APA+LHRHa +/- AA (randomized 1:1) in LHRPC (≥ cT2 + Gleason Score ≥ 8 or ≥ cT2b + Gleason ≥ 7 + PSA > 10 ng/mL) followed by radical prostatectomy (RP). We studied treatment effect by pathology measures [path. stage, tumor volume (TV), tumor cellularity % (TC), tumor epithelial volume (TEV: TC x TV)]. Tumor expression of candidate markers of outcome was assessed in the diagnostic biopsy by IHC [AR signaling (AR-N, ARC19, ARV7, PSA), PTEN, glucocorticoid receptor (GR), Ki67, p53, RB] and DNA/RNA seq. A previously identified candidate predictive molecular signature (AR-N overexpression, nARV7 absence, no GR overexpression, Ki67 ≤10%) was tested. Univariate (Fisher’s exact, Wilcoxon) and multivariate (logistic, linear models) analyses employed. Results: Sixty three -of 65 pts enrolled- had RP. PS-ECOG 0, median age 65 (43-77). Treatment was well tolerated with Grade 3 hypertension in 7 (2 APA + LHRHa). Presurgical PSA was ≤0.1 in 62/63 (98%). Organ confined disease (≤ypT2N0) found in 13/32(41%) APA+LHRHa vs. 12/31 (39%) APA+AA+LHRHa treated. 2 (3%) had pathologic complete remission (APA+AA+LHRHa), 6 (10%) minimal residual disease (5 on APA +LHRHa). Despite uniformity in PSA response, we recorded heterogeneity in measures of tumor viability: TV (0-11.5cc), TC (1-80%), TEV (0-6.1cc). ≤ypT2N0 associates with diagnostic biopsy positivity for the prespecified molecular signature (p <0.0001), PTEN expression (p: 0.004), absence of cribriform/ intraductal spread (p 0.002) but not with Gleason Score. On multivariate analysis only the prespecified biopsy signature associates with outcome (p 0.003). Findings were replicated when analyzed by TV, TC and TEV measures. Conclusions: Neoadjuvant Apalutamide plus LHRHa is tolerable and results in tumor regression in a subset of LHRPC patients. Dual ASI treatment does not further improve outcomes. Biopsy positive for a prespecified molecular signature, associated with response. Study results emphasize the need to consider biologic heterogeneity and pursue validation of predictors of response in order to improve therapeutic outcomes in LHRPC. Clinical trial information: NCT03279250 .
TRANSFORMER: Bipolar androgen therapy (BAT) versus enzalutamide (E) for castration-resistant metastatic prostate cancer (mCRPC).
Authors: Denmeade Samuel R. , Wang Hao , Cao Harry , Fu Wei , Wang Ting , Abdallah Rehab , Bolejack Vanessa , Agarwal Neeraj , Smith David C. , Schweizer Michael Thomas , Stein Mark N. , Assikis Vasily J. , Flaig Thomas W. , Szmulewitz Russell Zelig , Holzbeierlein Jeffrey , Paller Channing Judith , Carducci Michael Anthony , Markowski Mark Christopher , Eisenberger Mario A. , Antonarakis Emmanuel S.
Published: May 2020

5517

Background: Rapid cycling between high and low testosterone (T) (i.e BAT) produces tumor response in mCRPC, and may overcome resistance to newer AR therapies. Here we report a randomized study comparing BAT to E in men with mCRPC progressing on abiraterone (A). Methods: In this phase 2 trial, men received either T cypionate 400mg IM (BAT) once every 28 days or daily oral E 160mg. Primary endpoint was clinical/radiographic PFS; crossover was permitted at progression. Secondary endpoints were OS, PSA progression to primary and crossover therapy, PSA and objective responses (OR), time to PSA progression from randomization through crossover (PFS2), quality of life (QoL), and AEs. Results: 195 men were randomized (94 to BAT, 101 to E). Results are presented in table. Although diametrically opposed therapies, median PFS and PSA response in the intent-to-treat (ITT) population was not significantly different between BAT and E. OR and OS favored BAT. For those who received BAT and then crossed over to E the PSA50 response was 77.8% and time to PSA progression was 10.9 mo compared to 25.3% and 3.8 mo for those receiving E immediately after A. The sequence of treatment had a significant effect on median PSF2 which was 28.2 mo for men receiving BAT→E vs. 19.6 m for E→BAT. For men who crossed over from BAT to E, OS was 37.3 mo vs. 28.6 months for those receiving E without crossover. AEs were primarily grade 1-2 in the BAT arm and included fatigue, generalized pain, and lower extremity edema. BAT improved QoL (fatigue, physical functioning, sexual function) vs. E. Conclusions: BAT could be safely administered to asymptomatic men with mCRPC. BAT produced a comparable PFS to E in A-refractory mCRPC pts. However, PSA50 and OR after crossover, as well as PFS2, were significantly improved in men who received BAT→E versus E→BAT. OS in men receiving BAT→E was 37.3 mo, exceeding historical expectations. These results support the hypothesis that treatment with BAT is safe, has efficacy and can restore sensitivity to antiandrogens. Clinical trial information: NCT02286921 . [Table: see text]
Biomarker analysis from the KEYNOTE-199 trial of pembrolizumab in patients (pts) with docetaxel-refractory metastatic castration-resistant prostate cancer (mCRPC).
Authors: Antonarakis Emmanuel S. , Piulats Rodriguez Jose Maria M. , Gross-Goupil Marine , Goh Jeffrey C. , Vaishampayan Ulka N. , De Wit Ronald , Alanko Tuomo , Fukasawa Satoshi , Tabata Kenichi , Feyerabend Susan , Berger Raanan , Wu Haiyan , Kim Jeri , Schloss Charles , Qiu Ping , Suttner Leah , Cristescu Razvan , Marton Matthew John , De Bono Johann S.
Published: May 2020

5526

Background: In the phase II KEYNOTE-199 study (NCT02787005), pembrolizumab monotherapy demonstrated antitumor activity in pts with docetaxel-refractory mCRPC (n = 258). Here we evaluated the association between prespecified molecular biomarkers and clinical outcomes. Methods: Cohorts 1 (C1) and 2 (C2) enrolled pts with RECIST-measurable PD-L1–positive (combined positive score [CPS] ≥1 using immunohistochemistry) and PD-L1–negative (CPS <1) disease, respectively. C3 enrolled pts with nonmeasurable, bone-predominant disease, irrespective of PD-L1 status. Biomarkers evaluated in this analysis were tumor mutational burden ([TMB; mutations/exome] n = 155), PD-L1 CPS (n = 255), tumor microenvironment–based 18-gene RNA expression profile ([GEP] n = 196), and microsatellite instability ([MSI] as determined by Promega PCR analysis; n = 147). Outcomes evaluated for C1 and C2 (n = 200) were ORR, disease control rate (DCR), and radiographic PFS (rPFS) per blinded, independent central review per PCWG-modified RECIST v1.1. Outcomes evaluated for C1-C3 (n = 258) were prostate-specific antigen (PSA) response, time to PSA progression, and OS. Significance of continuous biomarkers (CPS; TMB; GEP) was prespecified at 0.05 for one-sided P values from logistic (ORR; DCR; PSA response) and Cox proportional hazard regression (rPFS; OS; PSA progression) adjusted for Eastern Cooperative Oncology Group performance status. Binary biomarkers (MSI) were analyzed using Fisher’s exact test (ORR; DCR; PSA response). Clinical data cutoff date: Jun 24, 2019. Results: Median TMB was 53.0 (interquartile range [IQR], 40.5 to 78.0), median CPS was 1 (IQR, 0 to 5), and median GEP was –0.64 (IQR, –0.88 to –0.46); 6 pts (2.3%) had MSI-high tumors. In C1-C3, TMB was associated with PSA response (one-sided nominal P = 0.0016) and time to PSA progression (one-sided nominal P = 0.00092). In C1-C3, PD-L1 CPS was associated with PSA response (one-sided nominal P = 0.046) and time to PSA progression (one-sided nominal P = 0.021). In C1-C3, GEP was not significantly associated with response. In C1-C3, MSI was associated with PSA response (one-sided nominal P = 0.019). Conclusions: In this biomarker analysis from KEYNOTE-199 C1-C3, TMB and PD-L1 CPS were associated with better PSA response; however, small pt numbers limit definitive conclusions on ORR, DCR, and OS. Further evaluation of molecular biomarkers in pts with mCRPC treated with pembrolizumab is warranted. Clinical trial information: NCT02787005 .