589 Background: Patients (pts) with human epidermal growth factor receptor 2 (HER2) positive (+) early breast cancer (EBC) receiving neoadjuvant systemic therapy (NAST) have poorer outcomes if they have residual disease (RD) after surgery. HER2 negative (-) RD has been reported in 1/3 of pts after NAST. The KATHERINE trial suggests that pts with HER2- RD (8%) have better invasive disease-free survival (IDFS) with adjuvant (adj) trastuzumab emtansine (T-DM1) versus trastuzumab (H) alone. However, only 18% of the pts enrolled in the trial received NAST with trastuzumab and pertuzumab (HP). We aimed to analyze IDFS and brain metastasis (BM) rates in pts with HER2+ EBC in a modern population homogenously treated with NAST. We also report the incidence of pts with HER2- RD and their outcomes. Methods: Clinicopathologic data for pts with HER2+ EBC who received NAST between 1 Jan 2019 and 31 Jan 2022 were reviewed. External assessment of HER2 status before NAST was allowed. HER2 status of the surgical specimens with RD were assessed internally at our center. IDFS was defined as the time from surgery until first occurrence of invasive cancer recurrence, distant recurrence, or death from any cause. Results: The total cohort was 594 pts. 456 (77%) and 138 (23%) received antracycline-taxane and taxane based chemotherapy, respectively during NAST. 587 (99%) received HP and 7 (1%) received H alone. NAST was completed by 566 (95%) of pts. pCR (ypT0/isN0) was achieved in 325 (55%) and RD was seen in 269 (45%) pts. In 269 pts with RD, 46 (17%) did not have HER2 retesting and were excluded from the final analysis. In the remaining 223 pts, 143 (64%) were HER2+ and 80 (36%) were HER2-. In the 143 pts with HER2+ RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 120 (84%), 16 (11%), 1 (1%) and 6 (4%) of pts, respectively. In the 80 pts with HER2- RD, adj TDM1, HP, H alone and no HER2 directed therapy were received by 44 (55%), 27 (34%), 3 (4%) and 6 (7%) of pts, respectively. With a median follow up of 24 months, 7 pts developed BM at initial recurrence, 3/325 (0.9%) with pCR and 4/143 (2.8%) with HER2+ RD. None of the pts who developed BM had HER2- RD. IDFS events occurred in 22/594 (3%) pts. RD pts had a higher likelihood of having an IDFS event, 14/269 (5%) in RD and 8/325 (2%) in pCR (p = 0.04). In the evaluable 223 pts with RD there was no difference in IDFS between 10/143 (7%) pts with HER2+ RD or 4/80 (5%) with HER2- RD (p = 0.10). Conclusions: At a single center, in pts who predominantly received HP with chemotherapy as NAST, pts with RD had higher IDFS events than those with pCR. In those with RD, 36% lost HER2+ status; IDFS events appeared similar in those with HER2+ RD versus those with HER2- RD. The HER2 loss rate is higher than reported in KATHERINE possibly due to majority of pts receiving dual HP as NAST. The BM events seen in those with RD and pCR highlights the need for more effective therapy in NAST and adj setting to minimize BM risk.

Aim: To characterise risk of anaphylaxis/hypersensitivity with intravenous pertu-zumab plus trastuzumab (PH IV), the fixed-dose combination of pertuzumab and trastuzumab for subcutaneous injection (PH FDC SC) or concomitant chemotherapy to support potential administration of PH FDC SC by healthcare professionals outside clinics.Methods: A cumulative search for anaphylaxis/hypersensitivity (Roche Standard Adverse Event Group Terms) was performed for all pivotal trials cited in the current EMA P IV/PH FDC SC summaries of product characteristics: MBC: NCT00567190, NCT02402712; EBC: NCT01358877, NCT00545688, NCT00976989, NCT02132949, NCT03493854 and NCT03674112. Occurrence, incidence and severity of events were analysed and a time-trend analysis (by cycle) was performed. Results: This analysis includes 4772 patients who received PH IV and/or PH FDC SC. Inci-dence of all-grade (grade >3) anaphylaxis/hypersensitivity events: 3-11% (<= 2%) for PH IV MBC trials; 1-13% (0-3%) for PH IV EBC trials; and 2-3% (<1% ; not related to PH FDC SC) for PH FDC SC EBC trials. Discontinuations due to anaphylaxis/hypersensitivity were rare for PH IV (generally <1% except two arms of TRYPHAENA: 1% and 3%); no dis-continuations of PH FDC SC have been recorded so far. Time-trend analysis showed that most events were reported during the first 6-8 cycles with concurrent chemotherapy, with a decrease in later cycles (except MetaPHER).Conclusion: PH IV and PH FDC SC were well tolerated, with few grade >3 anaphylaxis/hy-persensitivity events reported with PH IV and no grade >3 related events with PH FDC SC. Most events occurred during chemotherapy.(c) 2022 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Residual disease (RD) after NAC is a well-established risk factor for recurrence in patients (pts) with triple-negative breast cancer (TNBC) or high-risk hormone receptor-positive (HR+)/ HER2-negative (-) BC. Biologic and prognostic significance of HER2 gain on RD after NAC are unknown. We sought to determine invasive disease-free survival (IDFS) in patients with HER2 gain in a cohort of consecutive patients with HER2(-) BC treated with NAC. We identified pts with HER2(-) BC treated with NAC followed by surgery at our institution between 8/2019 and 12/2021. Pathologic complete response [pCR] (ypT0/is ypN0) rates and HER2 status pre- and post-NAC were assessed, the latter by 2018 ASCO/CAP guidelines. HER2-low was defined as IHC 1+ or IHC 2+, FISH non-amplified. IDFS was analyzed using the Kaplan-Meier method and differences assessed by log-rank test. Chi-square, Fisher’s exact, Wilcoxon rank sum test, and logistic regression were used to evalute baseline features associated with HER2 gain. Any p-value less than 0.05 was deemed to be statistically significant. We included 528 HER2(-) pts [274 (52%) HR+/HER2- and 252 (48%) TNBC]. Overall, pCR was achieved in 40% of TNBC and 9% of HR+/HER2(-). The median follow-up was 17.5 months (14.5-21.3). Among 401 pts with RD, the rate of HER2 gain was 5% (20/401) (Table). HER2-low and HR+ status assessed on initial biopsy were independently associated with HER2 gain on the surgery sample with OR=3.05 (95%CI:1.07-10.9) and OR=4.09 (95%CI: 1.02-27.5), respectively, while high grade was not (OR=0.68; 0.24-1.78). After surgery, all but two pts with HER2 gain received anti-HER2 therapy. The 2-year IDFS rate was 100% in pts with HER2 gain and 85% (95%CI: 81-90%) in pts with HER2(-) RD (p=0.07). HER2 gain after NAC was a rare event, more commonly occurring in pts with HR+/HER2(-) BC compared to TNBC, likely related to HER2 heterogeneity. Optimal adjuvant regimen remains to be established.Table: 291PDetails of patients with HER2 gainHR statusHER2 biopsyHER2 surgeryPost-NACPts(+/-)IHCF ratioF CNIHCF ratioF CNtherapy1-2+1.65.63+//TH2-1+//2+3.367.6Pembro/HP3+2+1.23.32+1.947.7AI4+1+//2+3.358.4V/HP, AI5+1+//2+2.65.4V/HP, AI6+1+//2+3.16.1HP/AI7+2+1.53.32+2.047.49THP8+1+//2+2.585.6T-DM19+1+//2+3.128.45Cape/HP10+2+1.23.442+2.275.17HP/AI11+0//2+3.727.67Carbo/HP, AI12+0//3+//HP/AI13+1+//2+1.86.3HP/AI14+0//3+//CMF/HP, OS/AI15+1+//2+2.74.14Cape/H, AI16+1+//3+//T-DM1, HP/AI17+2+1.75.42+25.4HP/AI18+2+1.52.92+2.96.1HP/AI/OS19+1+//2+2.36.2HP/AI/OS20+0//2+1.66.8AI/AbemaF: FISH test; CN: copy number; V: vinorelbine; T: paclitaxel. Open table in a new tab .

Purpose/Objective(s): The role of SBRT in the treatment of HCC is not well established. The hypothesis of this study was that overall survival (OS) would improve with SBRT followed by sorafenib (SBRT/S) vs. sorafenib alone (S), in patients with advanced HCC. Materials/Methods: Eligible patients had new or recurrent HCC, unsuitable for resection, transplant, ablation or TACE, with Zubrod performance status (PS) 0-2, Child-Pugh A, intermediate (B) or advanced (C) Barcelona Clinic Liver Cancer Stage (BCLC), ≤ 5 HCCs, sum of hepatic HCCs ≤ 20 cm, and sum of extrahepatic metastases ≤ 3 cm. Patients were randomized 1:1 to S 400 mg BID vs. SBRT (27.5- 50Gy in 5 fractions, with dose individualized based on mean liver dose and other dose constraints) followed by S 200 mg BID then increased to 400 mg BID after 28 days if appropriate. Primary endpoint was OS. Reported secondary endpoints were progression-free survival (PFS), time to progression (TTP), and adverse events (AEs - CTCAEv4). Planned sample size was 292 patients (238 OS events, HR=0.72, 80% power, 1-sided alpha=0.05). Accrual closed early, primarily due to a change in HCC standard of care systemic therapy. Statistics were amended to report data as of 7/1/2022, projecting 155 OS events providing 65% power for the original hypothesis, with the same alpha. OS and PFS were estimated by Kaplan-Meier and arms compared using log-rank test. Cox proportional hazards models were used to analyze treatment effect. TTP was estimated with cumulative incidence and arms compared using Gray ’ s test. Secondary endpoints were tested with 2-sided alpha=0.05. Results: Of 193 patients accrued from April 2013 to March 2021 from 23 sites, 177 eligible patients were randomized Purpose/Objective(s): There has been increased utilization of metastasis directed therapy (MDT) for oligometastatic prostate cancer. Despite data demonstrating the bene fi t of upfront hormone therapy (HT) and synergy between radiation and HT, there exists no randomized trials testing their combination. As it is accepted by most clinicians and men with prostate cancer that time off HT holds intrinsic value, we evaluated whether the addition of metastasis directed therapy (MDT) to intermittent HT in men with oligometastatic prostate cancer facilities time off HT by improving PFS and eugonad PFS. Materials/Methods: EXTEND (NCT03599765) is a phase II randomized basket trial for multiple solid tumors testing whether the addition of MDT improves PFS. The primary endpoint was pre-speci fi ed to be independently assessed and reported for the prostate intermittent HT basket at 41 events. Men with ≤ 5 metastases were randomized after ≥ 2 months of HT to con-tinuing HT with or without MDT. HT consisted of a luteinizing hormone- releasing hormone agonist/antagonist with or without a 2 nd generation androgen-receptor targeting agent (SART). The primary endpoint was pro- gression, de fi ned as death or radiographic, clinical, or biochemical progression. A planned HT break occurred 6 months after enrollment, after which HT was withheld until progression. The study was designed to have 80% power to detect an improvement in median PFS from 18 to 36 months, with a type I error of 0.1. Exploratory analysis included fl ow cytometry and TCR sequencing from peripheral blood at baseline and 3 months follow up. Results: Between Sept 2018 to Nov 2020, 87 men were randomized, 43 combined therapy and 44 to HT-only. Arms were well balanced. At a median follow-up of 22.1 months (range 13.0 Purpose/Objective(s): Upper abdominal / lower back pain characterizes pancreatic and other upper gastrointestinal malignancies; its satisfactory treatment is an unmet clinical need. We hypothesized that ablative radiation delivered to the celiac plexus would decrease pain. Following promis- ing results from a small pilot study (PMID 35257800), we sought to validate the results in a multi-institutional setting. Materials/Methods: An international single arm Phase II study. Inclusion criteria included average pain level of ≥ 5/11, ECOG 0-2, life expectancy ≥ 8 weeks and either pancreatic cancer or anatomical involvement of the celiac blood vessels. The intervention was a single fraction of 25Gy delivered to the celiac plexus, (surrogate marker the anterior & lateral aspects of aorta To assess if stereotactic for oligoprogressive metastatic lung or breast cancer prolongs progression- free survival (PFS), overall survival (OS), and alters circulating tumor Conclusion: This is the largest reported RCT of lung SBRT compared to a contemporary CRT control arm, with mature follow-up and the inclusion of patients with central tumors. There was an observed improvement of LC with SBRT compared to CRT, however, the trial was underpowered to con-fi rm this. No evidence of differences were observed in DFS and OS. Very few patients experienced severe late toxicities, including those with central tumors. This study con fi rms the ef fi cacy and safety of SBRT for both central and peripheral Stage I NSCLC (NCT01968941). Purpose/Objective(s): Retrospective studies demonstrate that ablative stereotactic MR-guided on-table adaptive radiation therapy (SMART) achieves favorable local control (LC) and overall survival (OS) with limited grade 3+ toxicity compared to historical non-ablative outcomes for locally advanced and borderline resectable pancreatic cancer (LAPC/BRPC). We conducted an international multi-center single-arm phase 2 trial of ablative 5-fraction SMART for LAPC/BRPC. Materials/Methods: Subjects were required to have biopsy-con fi rmed adenocarcinoma, receive ≥ 3 months of chemotherapy, have no distant metastasis months after iSRT) were observed in the iSRT+ADT than the iSRT arm (53.1% vs 70.5%; p=0.046). At 12 months ADT-related symptoms were more important in the iSRT+ADT arm (QLQ-PR25; p=0.04). At 24 months, no difference in QLQ-C30 or QLQ-PR25 analysis was reported. After an initial 25-fold decrease in blood testosterone level, all patients recovered to normal level 12 months after starting ADT. Conclusion: Despite the lack of differences in terms of EFS between the two arms, this study demonstrated that iSRT+ADT improved MFS without impaired quality-of-life for patients with persistently elevated PSA after RP.

Purpose/Objective(s) We hypothesize that there is an oligoprogressive state in metastatic cancer, in which disease control can be improved with local therapy to progressive lesions only. This study therefore evaluated the impact of stereotactic body radiotherapy (SBRT) to sites of oligoprogression in patients with metastatic non-small-cell lung cancer (NSCLC) and breast cancer with 1-5 progressive lesions. Materials/Methods We enrolled patients with metastatic NSCLC or breast cancer who received ≥ 1 line of systemic therapy and had oligoprogressive lesions amenable to SBRT. There was no upper limit of non-progressive lesions. Oligoprogression was defined as Response Evaluation or Positron Emission Tomography Response Criteria in Solid Tumors documented progression ≤ 5 individual lesions. Stratification factors included number of progressive sites (1 vs. 2-5), prior systemic therapy (immunotherapy vs. other), primary tumor (NSCLC vs. breast), and tumor marker status (driver mutation and hormone receptor status). Patients were randomized 1:1 between SBRT to all progressive sites plus palliative standard of care (SOC) vs. palliative SOC only. Systemic therapy was per physician's discretion. The primary endpoint was progression-free survival (PFS). We used a randomized phase II design with a one-sided alpha of 0.05 and a power of 0.80, yielding a target accrual of 160 patients. PFS was compared using one-sided stratified log-rank test. One interim analysis was planned. Results From January 2019 to May 2021, 102 patients were randomized - 58 NSCLC (30 in the SBRT arm) and 44 breast (22 in each arm). Median age was 67. Most patients (75%) had > 1 site of oligoprogression and 47% had > 5 total metastatic lesions. Fifty-five (54%) patients received immunotherapy. The majority of NSCLC (86%) did not harbor an actionable driver mutation and 32% of breast cancer were triple negative. Baseline factors were balanced between arms. At a median follow-up of 51 weeks, 71 patients progressed and 30 died. Median PFS was 22 weeks in the SBRT arm vs. 10 weeks in the palliative SOC arm (p=0.005). This was driven entirely by the PFS benefit from SBRT in the NSCLC patients (44 weeks with SBRT vs. 9 weeks with SOC; p=0.004). No difference in median PFS was seen in the breast cohort (18 weeks with SBRT vs. 17 weeks with SOC; p=0.5). In multivariable Cox model inclusive of stratification factors, age, sex, lines of systemic therapy, and change of systemic therapy, the PFS benefit of SBRT remained substantial in the NSCLC cohort (Hazard Ratio: 0.38; 95% CI: 0.18-77; p=0.007). Grade ≥2 adverse events occurred in 8 patients in the SBRT arm, including 1 grade 3 pneumonitis. Conclusion Inthis pre-planned interim analysis of the first and largest randomized trial of radiotherapy for oligoprogressive metastatic NSCLC and breast cancer, we demonstrated the benefit of SBRT to sites of oligoprogression on overall PFS, meeting the primary endpoint. The mechanism of the differential benefits between NSCLC and breast cohorts merits further evaluation.

PH IV/PH FDC SC is standard of care for HER2-positive BC and usually given with chemotherapy, all of which can trigger anaphylaxis/hypersensitivity. In the US, PH FDC SC can be administered by healthcare professionals in patients’ (pts’) homes. There is a need to further characterise risk of anaphylaxis/hypersensitivity with PH IV/PH FDC SC to support safe administration outside of clinics. We assessed occurrence, incidence and severity of these events in key Roche clinical trials of PH IV/PH FDC SC, and did a time–trend analysis (by cycle) for metastatic BC (MBC) and early BC (EBC) studies.

RT was well-tolerated when given concurrently with either T-DM1 or H, regardless of fractionation. Local recurrences were unlikely, attesting to the efficacy of highly effective HER2-directed therapy with RT, and suggesting opportunities for future study of RT de-escalation.

BERENICE was designed to establish the cardiac safety of neoadjuvant pertuzumab/trastuzumab (PH) with anthracycline-containing chemotherapies (primary objective). Here we report the 5-year outcomes at end-of-study (clinical cut-off date: 25/08/2020), including additional safety and efficacy data (secondary objectives). BERENICE was a multicenter, open-label, non-comparative phase II trial. Patients with stage IIA to III HER2-positive breast cancer and a left ventricular ejection fraction (LVEF) ≥55% were allocated per physician's choice to cohort A (dose-dense doxorubicin/cyclophosphamide every 2 weeks [q2w] x 4 → paclitaxel q1w x 12) or cohort B (5-fluorouracil, epirubicin, cyclophosphamide q3w x 4 → docetaxel q3w x 4). PH q3w was initiated from the start of taxanes and continued after surgery for a total of 17 cycles. Intention-to-treat population comprised 199 patients in cohort A and 201 in cohort B, with a median follow-up of 64.5 months. No new cardiac safety issues were seen, with few events occurring in the treatment-free period and a low incidence of class III/IV congestive heart failure (Table). Event-free survival (EFS) rates at 5 years were 90.8% (95% CI, 86.5-95.2) and 89.2% (84.8-93.6) in cohorts A and B, respectively. Overall survival rates at 5 years were 96.1% (93.3-98.9) and 93.8% (90.3-97.2) in cohorts A and B, respectively. According to PAM50 classification, available for 339 patients, most patients had HER2-enriched tumors (51.6%), with 5-year EFS rates of 93.1% (87.2-98.9) in cohort A and 88.3% (81.8-94.8) in cohort BTable: 43OSafety populationCohort A (N=199)Cohort B (N=198)*No. of patients with at least one LVEF decrease to ≥10% points from baseline to an LVEF <50% (whole study) No. during the treatment-free follow-up period27 (13.6%) 12 (6.0%)24 (12.1%)7 (3.5%)No. of patients with New York Heart Association class III/IV congestive heart failure (whole study)No. during the treatment-free follow-up period3 (1.5%)02 (1.0%)1 (0.5%)*3 patients without safety data available Open table in a new tab . *3 patients without safety data available The final analysis of BERENICE showed sustained cardiac safety and favorable long-term efficacy outcomes, further supporting neoadjuvant/adjuvant PH with standard anthracycline-containing therapies in patients with early stage HER2-positive breast cancer.

Young age has been associated with worse overall survival (OS) in breast cancer patients. While the cause of this is likely multi-factorial, this has been in part attributed to the higher prevalence of the aggressive triple-negative disease in younger cohorts. However, it remains unclear if younger age predicts for worse survival in patients with TNBC. In this study we aimed to assess the impact of age on survival in women with stage I-III TNBC. Women with stage I-III TNBC diagnosed between 2004-2014 were identified in the National Cancer Data Base. Patients with male sex, in situ disease, metastatic disease, or incomplete information were excluded from the analysis. We analyzed demographic factors as well as disease- and treatment-related factors by age group. Statistical analyses including Kaplan-Meier estimates and Cox proportional hazards were calculated for treatment- and disease-related factors. Patients were divided into 4 age-based groups for this analysis, age <36, 36-50, 51-65, and >65. A total of 48,248 women (range 18-90, median 57) were identified in the database with median follow-up of 38 months (range 0.1 to 86.67 months). On univariate analysis, women age <36 did not have a statistically significant difference in OS when compared to women age 36-50 (HR = 0.949, 95% CI 0.841-0.1071, p = 0.3979) or women age 51-65 (HR = 1.078, 95% CI 0.958-1.212, p = 0.2142). Women age >65 had a statistically significant decrease in OS in comparison with women age <36 (HR = 2.030, 95% CI 1.804-2.284, p = <0.0001) in univariate analysis. Increasing T and N stages were associated with decreased OS in all patients except in the T2 stage group (HR = 0.984, 95% CI 0.889-1.091, p = 0.7640) when compared with the T1 and N1 stage groups. However, the different cohorts had similar distribution of stage I, II and III patients. Multivariable Cox proportional hazards model did not demonstrate an increased mortality in the younger patients in comparison with the older patients. When compared to older cohorts, virtually all younger patients underwent chemotherapy and had higher levels of neoadjuvant and combined neoadjuvant and adjuvant chemotherapy, higher rates of mastectomy, and higher rates of post-mastectomy radiation (chi-squared p-value = <0.0001 for all comparisons). These data demonstrate that stage-matched younger patients with TNBC do not have a decreased OS when compared to their older counterparts. However, younger patients tended to have more aggressive chemotherapy and surgery which likely underlies the lack of difference in survival in the younger age groups compared to the older age groups. Thus, younger women do not have worse survival, but may continue to require more aggressive treatment to achieve similar survival rates to their older counterparts.

In KEYNOTE-010, pembro improved OS vs doce as 2L+ therapy for advanced NSCLC with PD-L1 TPS ≥1% and ≥50%. KEYNOTE-010 did not enroll any pts from mainland China, which has high NSCLC mortality. KEYNOTE-033 (NCT02864394) evaluates pembro vs doce in pts with previously treated advanced NSCLC with PD-L1 TPS ≥1%, with most pts enrolled in mainland China. Eligible pts (≥18 y) were randomized to pembro 2 mg/kg Q3W (35 cycles) or doce 75 mg/m2 Q3W (per local standard of care), stratified by TPS (≥50% vs 1–49%). Response was assessed Q9W per RECIST v1.1 by BICR. PD-L1 expression was assessed centrally (PD-L1 IHC 22C3 pharmDx assay). OS and PFS (primary objectives) were evaluated sequentially using stratified log-rank tests, first in pts with TPS ≥50% and then in pts with TPS ≥1% (1-sided α=0.025). 425 pts were enrolled. At data cutoff (Sep 9, 2019), median follow-up was 18.8 (range, 0.2-38.8) mo, and 291 (68%) pts had died. Pembro numerically improved OS in all groups analyzed, but did not achieve predefined statistical significance in pts with PD-L1 TPS ≥50% (Table); thus, sequential testing of OS and PFS ceased. HR for OS in TPS ≥1% pts from mainland China (n=311) was 0.68 (95% CI, 0.51–0.89). In all treated pts, incidence of treatment-related AEs was lower with pembro vs doce (any grade, 70% vs 88%; grade 3-5, 11% vs 47%).Table:PembroDocePD-L1 TPS ≥50%N=114N=113OSMedian (95% CI), mo12.3 (10.0-16.3)10.9 (8.3-13.1)HR (95% CI)0.83 (0.61-1.14)P0.1276PFSMedian (95% CI), mo4.0 (2.1-8.0)2.5 (2.1-4.2)HR (95% CI)0.76 (0.54-1.07)ORR% (95% CI)28.1 (20.1-37.3)7.1 (3.1-13.5)PD-L1 TPS ≥1%N=213N=212OSMedian (95% CI), mo12.9 (10.3-16.5)10.6 (8.7-12.5)HR (95% CI)0.75 (0.60-0.95)PFSMedian (95% CI), mo3.3 (2.1-4.1)3.0 (2.3-4.0)HR (95% CI)0.84 (0.66-1.08)ORR% (95% CI)20.7 (15.4-26.7)5.7 (3.0-9.7) Open table in a new tab While pembro did not meet statistical significance for OS in pts with PD-L1 TPS ≥50%, HRs for OS and PFS numerically favored pembro and ORR was higher with pembro in both the PD-L1 TPS ≥50% and ≥1% groups. Toxicity was consistent with the established pembro safety profile. These data support the value of pembro for previously treated advanced NSCLC in China.

Background: Breast cancer (BC) treatment, including surgery, can impact not only short-term health outcomes but may also affect longer term health-related and psychosocial quality of life (QOL). We sought to describe the impact of BC surgery on QOL among breast cancer survivors followed in a large randomized trial. Methods: The ECOG-ACRIN protocol E5103 was a phase III trial that randomized BC patients (pts) who had undergone definitive BC surgery to receive adjuvant doxorubicin, cyclophosphamide, and paclitaxel with either bevacizumab (bev) or placebo. Telephone based surveys were administered to all pts enrolled between 01/Jan/10 and 08/Jun/10 as part of a Decision-Making/QOL component until 18 mos post enrollment. Functional/psychosocial QOL domains were assessed by the EQ-5D-3L and the FACT B+G. Fisher9s exact test compared categorical and Wilcoxon rank sum test compared continuous variables between subgroups. Multivariable regression was used to evaluate factors in addition to primary surgery at enrollment (age, race, ER/PgR status, tumor size, nodal status) associated with overall FACT score at 18 mos. Results: Patient reported outcomes at 18 mos were available from 89.6% (465/519) pts. At enrollment, 57% (266/465) had a mastectomy; 43% (199/465) breast conserving surgery (BCS). Median age at enrollment was 52 (range: 25-76) years. There were no differences in QOL between bev vs placebo treatment arms (EQ-5D-3L Index Score p=0.65; FACT B+G Score p=0.23) at 18 mos so groups were combined. Using EQ-5D-3L, over half of the pts (58%) reported at least some pain/discomfort; 38% symptoms of anxiety/depression. A higher proportion of mastectomy pts reported problems with usual activities compared to BCS pts (Table). Compared to BCS pts, mastectomy pts had lower average EQ5D-3L scores 0.80 vs. 0.84, p=0.04 and FACT B+G scores 109 vs. 114, p=0.01, indicating worse QOL. In univariate analyses, non-white race (p=0.03), ER/PgR+ status (p=0.04) and mastectomy as primary surgery (p=0.01) were significantly associated with worse QOL (lower FACT B+G scores). In multivariable analyses, non-white race (p=0.02) and ER/PgR+ status (p=0.05) remained associated with worse QOL; mastectomy was borderline significant (p=0.06). Conclusions: Among women participating in a contemporary adjuvant BC chemotherapy trial, a substantial proportion of survivors experience symptoms that may be amenable to intervention, including referral to physical rehabilitation, especially among pts undergoing more extensive surgery. Attention to psychosocial health is also essential both during and after completion of active treatment to optimize QOL outcomes. Citation Format: Rosenberg SM, O9Neill A, Sepucha K, Miller KD, Dang CT, Northfelt DW, Sledge GW, Schneider BP, Partridge AH. The impact of breast cancer surgery on quality of life: Long term results from E5103 [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS6-05.

BACKGROUNDPrevious data suggest that the immune microenvironment plays a critical role in human epidermal growth factor receptor 2 (HER2) -positive breast cancer; however, there is little known about the immune profiles of small HER2-positive tumors. In this study, we aimed to characterize the immune microenvironment of small HER2-positive breast cancers included in the Adjuvant paclitaxel and trastuzumab for node-negative, HER2-positive breast cancer (APT) trial and to correlate the immune markers with pathological and molecular tumor characteristics.PATIENTS AND METHODSThe APT trial was a multicenter, single-arm, phase II study of paclitaxel and trastuzumab in patients with node-negative HER2-positive breast cancer. The study included 406 patients with HER2-positive, node-negative breast cancer, measuring up to 3 cm. Exploratory analysis of tumor infiltrating lymphocytes (TIL), programmed death-ligand 1 (PD-L1) expression (by immunohistochemistry), and immune gene signatures using data generated by nCounter PanCancer Pathways Panel (NanoString Technologies, Seattle, WA), and their association with pathological and molecular characteristics was carried out.RESULTSOf the 406 patients, 328 (81%) had at least one immune assay carried out: 284 cases were evaluated for TIL, 266 for PD-L1, and 213 for immune gene signatures. High TIL (≥60%) were seen with greater frequency in hormone-receptor (HR) negative, histological grades 2 and 3, as well in HER2-enriched and basal-like tumors. Lower stromal PD-L1 (≤1%) expression was seen with greater frequency in HR-positive, histological grade 1, and in luminal tumors. Both TIL and stromal PD-L1 were positively correlated with 10 immune cell signatures, including Th1 and B cell signatures. Luminal B tumors were negatively correlated with those signatures. Significant correlation was seen among these immune markers; however, the magnitude of correlation did not indicate a monotonic relationship between them.CONCLUSIONImmune profiles of small HER2-positive breast cancers differ according to HR status, histological grade, and molecular subtype. Further work is needed to explore the implication of these findings on disease outcome.CLINICAL TRIAL REGISTRATIONclinicaltrials.gov identifier: NCT00542451.

Background: Pembro significantly improved OS vs chemo as first-line therapy in pts with PD-L1–positive locally advanced/metastatic NSCLC without EGFR/ALK alterations after median follow-up of 12.8 mo based on interim analysis of KEYNOTE-042 (NCT02220894). We present the final protocol-specified analysis with an additional 6 mo of follow-up. Methods: Pts were randomized 1:1 to 35 cycles of pembro 200 mg Q3W or chemo (6 cycles of paclitaxel/pemetrexed [pem] + carboplatin with optional pem maintenance [nonsquamous only]), stratified by region (east Asia/non-east Asia), ECOG PS (0/1), histology (squamous/nonsquamous), and PD-L1 tumor proportion score (TPS; ≥50%/1%–49%). No α was allocated to OS in this analysis as the primary hypotheses for OS were met at the interim analysis. PFS differences (secondary endpoints) were assessed sequentially in pts with TPS ≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P = 0.01977, 0.02022, and 0.02065, respectively). Other secondary endpoints were ORR and safety. Duration of response (DOR) was an exploratory endpoint. Results: 1274 pts were randomized, 637 per arm. As of September 4, 2018 (median follow-up, 14 mo), 6% were receiving pembro and 3% were receiving pem maintenance. OS benefit with pembro vs chemo was maintained with longer follow-up (Table). PFS was not significantly improved with pembro vs chemo in pts with TPS ≥50%, therefore secondary efficacy hypotheses were not formally tested beyond TPS ≥50%. DOR was longer with pembro vs chemo (Table). Grade 3–5 treatment-related AEs were less frequent with pembro (18%) vs chemo (41%).Table102O OS, PFS, and DOR by PD-L1 TPSnOSPFSDORMedian, mo (95% CI)HR (95% CI)Median, mo (95% CI)HR (95% CI)P*PFS differences were assessed sequentially in pts with TPS≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P=0.01977, 0.02022, and 0.02065, respectively).Responders, n (95% CI)Median, mo (range)PD-L1 TPS ≥50%Pembro29920.0 (15.9–24.2)0.70 (0.58–0.86)6.5 (5.9–8.5)0.83 (0.69–1.00)0.026011722.0 (–2.1+ to 36.5+)Chemo30012.2 (10.4–14.6)6.4 (6.2–7.2)9610.8 1.8+ to 30.4+)PD-L1 TPS ≥20%Pembro41318.0 (15.4–21.9)0.77 (0.65–0.91)6.2 (5.1–7.4)0.94 (0.80–1.10)–13720.2 (2.1+ to 36.5+)Chemo40513.0 (11.6–15.3)6.7 (6.3–8.0)11710.8 (1.8+ to 30.4+)PD-L1 TPS ≥1%Pembro63716.4 (14.0–19.7)0.82 (0.71–0.93)5.4 (4.3–6.2)1.05 (0.93–1.19)–17320.2 (2.1+ to 37.0+)Chemo63712.1 (11.3–13.3)6.6 (6.3–7.3)1698.4 (1.8+ to 30.4+)PD-L1 TPS 1%–49%†Exploratory analysis.Pembro33813.4 (10.7–16.9)0.91 (0.77–1.09)4.2 (4.1–5.2)1.27 (1.08–1.50)–5617.4 (2.2 to 37.0+)Chemo33712.1 (11.0–14.0)7.0 (6.4–8.1)738.1 (1.9+ to 28.2)* PFS differences were assessed sequentially in pts with TPS≥50%, ≥20%, and ≥1% using the stratified log-rank test (one-sided P = 0.01977, 0.02022, and 0.02065, respectively).† Exploratory analysis. Open table in a new tab Conclusions: With an additional 6 mo follow-up, pembro demonstrated continued OS benefit vs chemo as first-line therapy in pts with locally advanced/metastatic PD-L1–positive NSCLC without EGFR/ALK alterations. Clinical trial identification: NCT02220894. Editorial acknowledgement: Medical writing and editorial assistance was provided by Rozena Varghese, PharmD, of C4 MedSolutions, LLC (Yardley, PA), a CHC Group company. This assistance was funded by Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Legal entity responsible for the study: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Funding: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Disclosure: T.S.K. Mok: Grants or research support: AstraZeneca, Bristol-Myers Squibb, Clovis Oncology, Merck Sharp & Dohme, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery; Speakers' fees: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Sharp & Dohme, Novartis, Bristol-Myers Squibb, Taiho, Takeda Oncology; Honoraria: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Bristol-Myers Squibb, OncoGenex Pharmaceuticals, Inc., Celgene, Ignyta, Inc., Fishawack Facilitate Ltd, Takeda Oncology, Janssen; Major stockholder: Sanomics Ltd.; Advisory board member: AstraZeneca, Roche/Genentech, Pfizer, Eli Lilly, Boehringer Ingelheim, Clovis Oncology, Merck Serono, Merck Sharp & Dohme, Novartis, SFJ Pharmaceuticals, ACEA Biosciences, Inc., Vertex Pharmaceuticals, Bristol-Myers Squibb, geneDecode Co., Ltd., OncoGenex Technologies Inc., Celgene, Ignyta, Inc., Cirina, Fishawack Facilitate Ltd., Janssen, Takeda, ChiMed. Y-L. Wu: Honoraria: AstraZeneca, Eli Lilly, Roche, Pierre Fabre, Pfizer, Sanofi; Consulting, advisory role: AstraZeneca, Roche, Merck, Boehringer Ingelheim; Research funding to institution: Boehringer Ingelheim, Roche. B.C. Cho: Honoraria: AstraZeneca, Roche, Boehringer Ingelheim; Consultant/advisor: AstraZeneca, Roche, Boehringer Ingelheim; Speakers' bureau: AstraZeneca, BMS, Merck Sharp & Dohme, Novartis; Research funding: Bayer, AstraZeneca, Yuhan, Novartis. G. de Castro Jr: Consulting, advisory role: AstraZeneca, MSD, BMS, Roche, Novartis, Boehringer Ingelheim; Speakers' bureau: MSD, BMS, Novartis, AstraZeneca; Travel, accommodation, expenses: MSD, BMS, Roche, Bayer, Novartis, Boehringer Ingelheim, AstraZeneca. K. Kubota: Research funding: Boehringer Ingelheim, Taiho, Ono; Speakers' fees: Chugai, Taiho, MSD, Boehringer Ingelheim, AstraZeneca, BMS, Eli-Lilly, Daiichi Sankyo, Novartis, Ono, Dainippon-Sumitomo, Kyowa-Kirin, Eisai; Advisory role: Taiho. C. Caglevic: Consultant/advisor: BMS, MSD, Bayer, AZ; Speakers' bureau: BMS, MSD, Bayer, Lilly, Roche; Research funding: MSD, Boehringer Ingelheim, GSK, Bayer, AZ, Medivation, Astellas Pharma, BMS; Travel, accommodation expenses: Boehringer Ingelheim, MSD. T. Dang, L. Yin, J. Penrod: Employee: Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. G. Lopes: Research funding to institution: Merck & Co., Inc., EMD Serono, AstraZeneca. All other authors have declared no conflicts of interest.

In the global, open-label KEYNOTE-042 study (NCT02220894), pembrolizumab significantly improved OS vs chemotherapy in PD-L1–positive locally advanced/metastatic NSCLC without targetable EGFR/ALK aberrations (HRs: TPS ≥50%, 0.69; ≥20%, 0.77; and ≥1%, 0.81). We present the very first results for Chinese patients enrolled in the KEYNOTE-042 global and China extension (NCT03850444) studies. The global and extension studies were designed identically. Patients were randomized 1:1 (stratified by ECOG PS 0/1, squamous/nonsquamous histology, and TPS ≥50%/1‒49%) to up to 35 cycles of pembrolizumab 200 mg Q3W or up to 6 cycles of paclitaxel/pemetrexed + carboplatin with optional pemetrexed maintenance (nonsquamous only). Primary endpoints were OS in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1%. No alpha was allocated to the China extension analysis. Overall, ∼350 patients from China will be enrolled including 140 patients with TPS ≥50%, to determine the OS effect of pembrolizumab and consistency across outcomes in Chinese patients. As of September 4, 2018, 262 Chinese patients with PD-L1–positive (TPS ≥1%) NSCLC were enrolled (global, n=92; China extension, n=170) and randomized to pembrolizumab (n=128) or chemotherapy (n=134). 146 patients (55.7%) had PD-L1 TPS ≥50%; 204 (77.9%) had PD-L1 TPS ≥20%. After median (range) follow-up of 11.3 (0.1‒23.2) months, 32 patients (25.0%) were still receiving pembrolizumab and 6 (4.8%) were receiving pemetrexed maintenance. Pembrolizumab improved OS vs chemotherapy in patients with PD-L1 TPS ≥50%, ≥20%, and ≥1% (Table). Among patients who received ≥1 dose of pembrolizumab (n=128) or chemotherapy (n=125), grade 3–5 drug-related AEs occurred in 17% vs 68%, respectively.Tabled 1nOverall SurvivalMedian (95% CI), moHR (95% CI)PD-L1 TPS ≥50%Pembrolizumab7220.0 (15.5–NR)0.62 (0.38–1.00)Chemotherapy7414.0 (10.0–17.9)PD-L1 TPS ≥20%Pembrolizumab10120.0 (17.4–NR)0.62 (0.41–0.95)Chemotherapy10313.7 (10.1–17.9)PD-L1 TPS ≥1%Pembrolizumab12820.0 (17.4–NR)0.65 (0.45–0.94)Chemotherapy13413.7 (10.1–17.9)PD-L1 TPS 1–49%aPembrolizumab5619.9 (11.9–NR)0.69 (0.40–1.20)Chemotherapy6010.7 (8.3–20.9)NR, not reached. aExploratory analysis. Open table in a new tab NR, not reached. aExploratory analysis. Pembrolizumab monotherapy improved OS with a favorable safety profile vs platinum-based chemotherapy as first-line therapy in Chinese patients with locally advanced/metastatic NSCLC without sensitizing EGFR/ALK aberrations and a PD-L1 TPS ≥1%. Findings are consistent with the global study primary endpoints, supporting first-line use of pembrolizumab for PD-L1–expressing advanced/metastatic NSCLC in China.

Abstract Background: In CALGB 40601 (Alliance, NCT00770809), a neoadjuvant phase III trial of paclitaxel and trastuzumab with or without lapatinib for 12 weeks for patients with HER2-positive breast cancer, 33% of pretreatment tumors were Luminal A subtype, however, 69% of post-treatment samples with residual disease were Luminal A subtype. In addition, 71% of Luminal B (12/17) and 67% of HER2-Enriched (6/9) tumors changed into Luminal A, while 80% of Luminal A (20/24) remained Luminal A (Carey et al. J Clin Oncol. 2016). It is not known whether this shift to Luminal A was transient or permanent. Methods: We selected matched pairs of pre- and post-treatment 40601 samples with tumor purity >10% based upon DNA analyses to ensure all samples contained tumor. PAM50 intrinsic subtyping was applied to the 40601 samples gene expression data using a two-step normalization process based on The Genome Cancer Atlas, and PAM50 training set. In addition, a HER2-enriched expression subtype patient-derived xenograft (PDX) tumor called WHIM35, was studied and was either untreated (n=10), or treated with lapatinib at 220 mg/kg for 1 week (wk) (n=5), for 2 wks (n=8), or for 3 wks (n=4). We also treated WHIM35 tumors with lapatinib for 2 wks (on) and then removed laptinib for 1 wk (off) (n=6), or for 2 wks on and 2-4 wk off (n=6), and finally for 3 wks on, and 1 wk off (n=3). PAM50 intrinsic subtyping was applied to the PDX gene expression data and subtype assessed as well as a genomic-based proliferation score. ANOVA p-values were calculated by comparing median values across all gene signature or correlation scores. Results: We found 10 pairs of 40601 samples that kept their tumor purity values, however, their subtype changed to Luminal A after treatment (i.e., in the residual disease), and in these cases no minor tumor subclone became a dominant clone in the post treatment sample. Pretreatment subtypes were 6 Luminal B, 3 Luminal A, and 1 HER2-enriched. The tumor purity values did not change after the treatments, but correlation to Luminal A was significantly higher (p=0.01), while correlation to HER2-enriched (p=0.004) and proliferation signature scores (p=0.003) were significantly lower in the post-treatment samples. Among the WHIM35 PDX tumors, one sample changed its subtype from HER2-enriched to Luminal A after the lapatinib treatment and the rest remained HER2-enriched, suggesting environmental differences between patient samples and the PDX model. However, correlation to Luminal A was significantly higher in all lapatinib treated WHIM35 samples (p=8.3e-12), and notably went back to the initial low levels just one week after removing lapatinib. Likewise, correlation to HER2-enriched (p=1.2e-10) and proliferation signature scores (p=6.2e-12) also got lower while treated with lapatinib, but went back to the initial levels after cessation of treatment. Conclusions: Our findings suggest that the apparent subtype change during HER2-targeting therapy is not permanent, but is more likely a transient state change from a HER2-enriched subtype into a more Luminal A-like state. When we plan additional treatment strategies using residual disease phenotypes, it may not be clear what is the true subtype of the sample due to this inherent plasticity. Citation Format: Tanioka M, Parker JS, Henry LN, Tolaney S, Dang C, Krop IE, Harris L, Polley M, Berry DA, Winer EP, Carey LA, Perou CM. Transient state change, but not permanent subtype change, after HER2-targeted therapy for HER2-positive breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P3-08-04.

Abstract Background: Neratinib (N) is a potent irreversible inhibitor of HER1, HER2, and HER4 and has been shown to have antitumor activity in patients (pts) with human epidermal growth factor receptor 2 (HER2) - positive breast cancer. A previous study of combination of neratinib with capecitabine (X) was associated with > G 3 diarrhea in > 20% of patients. Currently, the NALA study is evaluating this combination of N with X at standard schedule against control. X at 7 day on and 7 day off schedule (7/7) has been shown to be well-tolerated with less ≥G3 toxicities. We are conducting a phase Ib/II study of N with X (7/7) in pts with pretreated HER2+ MBC (NCT03377387). Methods: Eligible pts had HER2+ MBC, normal left ventricular ejection fraction (LVEF ≥ 50%); pts can have any and up to 4 prior chemotherapy-based treatments in phase Ib and II portions, respectively. Primary endpoints are to define maximum tolerated dose and efficacy in phase I and phase II portions, respectively. Secondary endpoints include safety and tolerability; exploratory endpoint is to quantify cell-free DNA to correlate with response for phase II portion. There were 4 cohorts for phase Ib with dose level 1 with starting dose of X at 1500 mg BID at 7/7 schedule with N at 240 mg daily. Results: As of July 1, 2018 8 pts have been enrolled in 2 cohorts. The median age is 63y (range: 57-79), and median ECOG is 0 (range: 0-1). 4 patients were treated at dose level 1 and 2 of 4 patients experienced dose-limiting toxicity with G3 diarrhea during cycle 1. Other significant toxicities included G3 hand foot syndrome (n=1), G3 fatigue (n=1) and G3 nausea (n=1). Three pts have now been treated at dose level -1 (X at 1000 mg twice daily 7/7 and N at 240 mg daily) and no ≥ G3 toxicities has been noted. Once MTD is reached, the phase II portion will occur to assess the efficacy and to further establish the safety and tolerability of capecitabine and neratinib at the MTD. Conclusions: The phase Ib/II study combining neratinib and capecitabine 7/7 is ongoing and updated result will be presented. Citation Format: Wang R, Singh J, Sterlin V, Goldstein M, Lake D, Wong S, Baselga J, Norton L, Dang C. Phase Ib/II study of capecitabine 7/7 schedule with neratinib in patients with HER2-positive metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-30.