Chemotherapy For Metastatic Disease Research Articles

The impact of androgen deprivation therapy on bone microarchitecture in men with prostate cancer: A longitudinal observational study (The ANTELOPE Study)

IntroductionAndrogen Deprivation Therapy (ADT) for prostate cancer (PC) has substantial negative impacts on the musculoskeletal system and body composition. Many studies have focused on the effects of ADT on areal bone mineral density (aBMD), but aBMD does not capture key determinants of bone strength and fracture risk, for example volumetric bone density (vBMD), geometry, cortical thickness and porosity, trabecular parameters and rate of remodelling. More specialist imaging techniques such as high-resolution peripheral quantitative computed tomography (HR-pQCT) have become available to evaluate these parameters. Although it has previously been demonstrated that bone microarchitectural deterioration occurs in men undergoing ADT, the aim of the ANTELOPE study was to examine longitudinal changes in bone microstructure alongside a range of musculoskeletal parameters and frailty, comparing men with PC receiving ADT alone or ADT plus chemotherapy for metastatic disease, with a healthy age-matched population. MethodsWe used HR-pQCT to investigate effects of 12 months of ADT on vBMD and microstructural parameters, complemented by assessment of changes in aBMD, serum bone turnover markers, sex hormones, body composition, grip strength, physical and muscle function, frailty and fracture risk. We studied three groups: Group A − men with localised/locally advanced PC due to commence ADT; Group B − men with newly diagnosed hormone-sensitive, metastatic PC, starting ADT alongside docetaxel chemotherapy and steroids; Group C − healthy, age-matched men. The primary endpoint was change in vBMD (Group A vs Group C) at the distal radius. ResultsNinety-nine participants underwent baseline study assessments (Group A: n = 38, Group B: n = 30 and Group C: n = 31). Seventy-five participants completed all study assessments (Group A (29), Group B (18), Group C (28). At baseline, there were no significant differences between Groups A and C in any of the BMD or bone microstructure outcomes of interest. After 12 months of ADT treatment, there was a significantly greater decrease in vBMD (p < 0.001) in Group A (mean 12-month change = -13.7 mg HA/cm3, −4.1 %) compared to Group C (mean 12-month change = -1.3 mg HA/cm3, −0.4 %), demonstrating achievement of primary outcome. Similar effects were observed when comparing the change in vBMD between Group B (mean 12-month change = -13.5 mg HA/cm3, −4.3 %) and Group C. These changes were mirrored in aBMD. ADT resulted in microstructural deterioration, a reduction in estimated bone strength and an increase in bone turnover. There was evidence of increase in total fat mass and trunkal fat mass in ADT-treated patients, with marked loss in upper limb mass, along with BMI gain. Frailty increased and physical performance and strength deteriorated in both ADT groups, relative to the healthy control group. ConclusionThe study showed that ADT has profound effects on vBMD, aBMD, bone microstructure and strength and body composition, and important impacts on frailty and physical performance. Whilst DXA remains a valuable tool (changes in aBMD are of the same magnitude as those observed for vBMD), HR-pQCT should be considered for assessing the effects of anti-androgens and other newer PC therapies on bone, as well as potential mitigation by bone-targeted agents.

Pyrotinib plus docetaxel as first-line treatment for HER2-positive metastatic breast cancer: the PANDORA phase II trial

The role of pyrotinib in the treatment of HER2-positive metastatic breast cancer (MBC) has been well-established. This multicenter, single-arm phase II trial (NCT03876587) aimed to assess the benefit of pyrotinib plus docetaxel as a first-line treatment for HER2-positive MBC. Women with HER2-positive MBC who had not undergone HER2 blockade or chemotherapy for metastatic disease were enrolled in the study and received daily oral pyrotinib 400 mg plus intravenous docetaxel 75 mg/m2 every 3 weeks. The primary endpoint was the objective response rate (ORR), secondary endpoints included progression-free survival (PFS), duration of response (DoR), clinical benefit rate (CBR), overall survival (OS) and safety. From June 2019 to June 2021, 79 patients were enrolled. The confirmed ORR was 79.7% (95% confidence interval [CI], 70.8-88.6), and the CBR was 87.3% (95%CI, 80.0-94.6) in the intention-to-treat population. The pre-specified primary endpoint was met. The median DoR was 15.9 months (interquartile range, 8.3-19.5); the median PFS was 16.0 months (95% CI, 11.2-20.8), and the median OS was not reached. The most common grade ≥3 treatment-related adverse events observed were leukopenia (29.1%), neutropenia (27.8%), and diarrhea (21.5%). This study demonstrates that pyrotinib plus docetaxel show an acceptable safety profile and promising antitumor activity as a first-line treatment option for patients with HER2-positive MBC.

Disparities in guideline-compliant care for patients with pancreatic ductal adenocarcinoma at minority-versus non-minority-serving hospitals

BackgroundWe examined disparities in guideline-compliant care at minority-serving hospitals (MSH) versus non-MSH among patients with localized or metastatic pancreatic adenocarcinoma (PDAC). MethodsPatients with PDAC were identified within the National Cancer Database (2004–2018). Guideline-compliant care was defined as surgery + chemotherapy ± radiation therapy for localized and chemotherapy for metastatic disease. Facilities in the top decile of minority patients treated were considered MSH. ResultsA total of 190,950 patients were identified and most (59.6%) had metastatic disease. Overall, 6.4% of patients with localized and 8.2% of patients with metastatic disease were treated at MSH.Patients treated at MSH were less likely to receive guideline-compliant care (localized: OR = 0.78, 95% CI: 0.67–0.91; metastatic: OR = 0.77, 95% CI: 0.67–0.88). Minority patients were less likely to receive guideline-compliant care at non-MSH (localized: OR = 0.71, 95% CI: 0.67–0.75; metastatic: OR = 0.85, 95% CI: 0.82–0.89) or MSH (localized: OR = 0.85, 95% CI: 0.74–0.98; metastatic: OR = 0.91, 95% CI: 0.82–0.99).Patients treated at non-MSH or MSH who received guideline-compliant care were more likely to have higher OS regardless of stage or race. ConclusionsMSH patients were less likely to receive guideline-compliant care and minority patients were less likely to receive guideline-compliant care regardless of MSH status. Guideline-compliant care was associated with improved OS.

Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease.

Overexpression of the HER2 protein occurs in 25% to 30% of human breast cancers and leads to a particularly aggressive form of the disease. Efficacy and safety of recombinant humanized anti-HER2 monoclonal antibody as a single agent was evaluated in women with HER2-overexpressing metastatic breast cancer that had progressed after chemotherapy for metastatic disease. Two hundred twenty-two women, with HER2-overexpressing metastatic breast cancer that had progressed after one or two chemotherapy regimens, were enrolled. Patients received a loading dose of 4 mg/kg intravenously, followed by a 2-mg/kg maintenance dose at weekly intervals. Study patients had advanced metastatic disease and had received extensive prior therapy. A blinded, independent response evaluation committee identified eight complete and 26 partial responses, for an objective response rate of 15% in the intent-to-treat population (95% confidence interval, 11% to 21%). The median duration of response was 9.1 months; the median duration of survival was 13 months. The most common adverse events, which occurred in approximately 40% of patients, were infusion-associated fever and/or chills that usually occurred only during the first infusion, and were of mild to moderate severity. These symptoms were treated successfully with acetaminophen and/or diphenhydramine. The most clinically significant adverse event was cardiac dysfunction, which occurred in 4.7% of patients. Only 1% of patients discontinued the study because of treatment-related adverse events. Recombinant humanized anti-HER2 monoclonal antibody, administered as a single agent, produces durable objective responses and is well tolerated by women with HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. Side effects that are commonly observed with chemotherapy, such as alopecia, mucositis, and neutropenia, are rarely seen.

Flashback Foreword: Anti-HER2 Monoclonal Antibody as a Single Agent

Article Tools FLASHBACK FOREWORD Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease. February 28, 2023 ARTICLE CITATION DOI: 10.1200/JCO.22.02679 Journal of Clinical Oncology - published online before print March 7, 2023 PMID: 36881997 Flashback Foreword: Anti-HER2 Monoclonal Antibody as a Single Agent Pamela J. Goodwin , MD, MSc1,2xPamela J. GoodwinSearch for articles by this author Show More 1Department of Medicine, Sinai Health System, University of Toronto, Toronto, Ontario, Canada2Former Associate Editor, Journal of Clinical Oncology, Alexandria, VA https://doi.org/10.1200/JCO.22.02679 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologyTHE TAKEAWAYIn 1999, Cobleigh et al1 demonstrated important activity of a single-agent recombinant humanized monoclonal antibody (now known as trastuzumab) targeting the human epidermal growth factor receptor (HER2) in women with pretreated metastatic HER2-positive breast cancer. This, along with subsequent studies of trastuzumab and other agents targeting HER2 in the metastatic and (neo)adjuvant settings, has revolutionized the management of HER2-positive breast cancer, leading to dramatic improvements in outcomes in both the early and metastatic settings.AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTFlashback Foreword: Anti-HER2 Monoclonal Antibody as a Single AgentThe following represents disclosure information provided by the author of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Pamela J. GoodwinResearch Funding: Epic Sciences (Inst)No other potential conflicts of interest were reported. Companion Multinational Study of the Efficacy and Safety of Humanized Anti-HER2 Monoclonal Antibody in Women Who Have HER2-Overexpressing Metastatic Breast Cancer That Has Progressed After Chemotherapy for Metastatic Disease

A novel immune monitoring platform for patients with gastrointestinal cancer.

424 Background: Understanding the impact of anticancer therapies on immune system is critical to successful design and incorporation of immunotherapies. We developed a novel immune monitoring platform that measures the relative amount of circulating effector T cells and antitumor cytotoxicity of circulating immune cells. We previously showed that this assay can differentiate patients’ clinical response to anti-PD-1 therapy. Here, we applied this assay to patients with gastric or gastroesophageal junction adenocarcinoma (GGEA) who received chemoradiation or chemotherapy-based therapies. Methods: Patients underwent peripheral blood collection at baseline and during follow-up. Levels of circulating effector T cells (CX3CR1+NKG7+/CD3+CD8+) were quantified by flow cytometry using peripheral blood mononuclear cells (PBMCs). Antitumor cytotoxicity of circulating immune cells was evaluated by co-culturing CD3/CD28 activated PBMCs with calcein-AM labeled GGEA tumor cells (FLO-1). Antitumor cytotoxicity of individual patients’ PBMCs was calculated based on the amount of calcein released by dead tumor cells. Results: In a pilot study of 8 patients with mismatch repair-proficient (pMMR) GGEA, the changes in the frequency of effector T cells appeared to be associated with radiographic response to treatment based on RECIST (3 partial response [PR], 3 stable disease [SD], and 2 progressive disease [PD]). The median interval between sequential blood collections was 64 days and an increase in effector T cells was observed in patients with PD. Antitumor cytotoxicity was evaluated in 4 patients who did not receive targeted therapies or immune checkpoint inhibitors. Two of these patients (a, b) had blood collected at the time of diagnosis (treatment naïve) and after neoadjuvant therapy. One developed pulmonary metastases after chemoradiation while the other had significant tumor shrinkage after chemotherapy. The decrease in antitumor cytotoxicity of PBMCs was less in the patient with PD (-19.4%) than the one with PR (-48.5%). Two patients (c, d) had blood collected twice while receiving the same chemotherapy for metastatic disease (not treatment naïve). The decrease in antitumor cytotoxicity of PBMCs was less in the patient with SD (-0.3%) than the one with PR (-14.5%). Conclusions: We demonstrated the feasibility of using PBMCs to monitor immune response to anticancer therapies. Our data raise the possibility that the amount of circulating effector T cells and antitumor cytotoxicity of PBMCs may be associated with tumor burden in patients with pMMR solid tumors. [Table: see text]

Biweekly mXELIRI versus FOLFIRI in combination with bevacizumab as the first-line treatment for metastatic colorectal cancer (EXIST): A multicenter, randomized, open-label, phase 2 study.

3594 Background: Irinotecan and fluorouracil are the most effective drugs in the treatment of metastatic colorectal cancer (mCRC). But XELIRI (irinotecan plus capecitabine) has not been recommended in the 1st-L setting due to the toxicity in the Western countries. While, modified 3-weekly XELIRI has been proved to be effective and safe in the 2nd-L therapy in Asian mCRC patients. Therefore, this study aimed to assess the efficacy and safety of biweekly mXELIRI with reduced dose of irinotecan in the 1st-L treatment of mCRC. Methods: This was a randomized, open-label, non-inferiority study undertaken at 11 hospitals in China. Eligible patients were aged ≥18 years with unresectable metastatic histologically diagnosed colorectal adenocarcinoma; had an ECOG of 0 or 1 and at least one measurable disease according to the RECIST v 1.1 without any systemic chemotherapy for metastatic disease. Patients were randomly assigned (1:1) stratified by the location of primary tumor (left or right site) to receive 9 cycles of mXELIRI + bevacizumab (Bev) (irinotecan 150mg/m2 D1, capecitabine 1000mg/m2 bid D1-10, Bev 5mg/kg D1, Q2W) or FOLFIRI + Bev (irinotecan 180mg/m2 D1, CF 400mg/m2 D1, 5-Fu 400mg/m2 bolus D1, 5-Fu 2400mg/m2 civ 46h D1, Bev 5mg/kg D1, Q2W) followed by maintenance treatments with capecitabine + Bev or 5-FU + CF + Bev. The primary endpoint was 12-month progression-free survival (PFS) rate. The secondary endpoints included objective response rate (ORR), PFS, overall survival (OS) and safety. Results: From May, 2018 to Apr, 2021, 264 pts were randomized (mXELIRI + Bev 132; FOLFIRI + Bev 132). The median age was 61 (29-80) years old. 62.5% of the patients were men. With a median follow-up of 17.1 months, the 12-month PFS rates were 43.9% vs. 28.8% in the mXELIRI + Bev and FOLFIRI + Bev groups, respectively. The HR was 0.72 (95%CI 0.51 -1.02) which didn’t cross the predefined non-inferiority margin of 1.18 (upper bound &lt; 1.18). The median PFS were 10.5 months vs. 9.6 months (p = 0.056, HR 0.74, 95%CI 0.55-1.01). The median OS was still not mature. The ORR were 51.5% vs. 47.0% (p = 0.460), respectively. The incidence of treatment related adverse events (TRAEs) between these two groups were similar. The most common TRAEs were neutropenia (mXELIRI + Bev vs. FOLFIRI + Bev: 51.8% vs. 57.0%), leukopenia (43.9% vs. 55.3%), anemia (54.4% vs. 45.6%), nausea (31.6% vs. 40.4%), ALT/AST increased (22.8% vs. 23.7%), diarrhea (21.1% vs. 16.7%), fatigue (20.2% vs. 23.7%), vomiting (17.5% vs. 20.2%) and hyperbilirubinemia (14.9% vs. 17.5%). No treatment- related deaths were reported. Conclusions: Biweekly mXELIRI with reduced dose of irinotecan plus bevacizumab was noninferior to the standard dose of FOLFIRI + Bev in PFS, with similar safety profile in the patients with untreated mCRC. Clinical trial number: NCT04247984. Research Sponsor: No Clinical trial information: NCT04247984.

Results from plasmaMATCH trial cohort E: A phase II trial of olaparib and ceralasertib in patients with triple-negative advanced breast cancer (CRUK/15/010).

1024 Background: The plasmaMATCH trial was an open label platform trial, consisting of circulating tumour DNA (ctDNA) testing in ̃1000 patients with advanced breast cancer (ABC) linked to parallel treatment cohorts with therapies matched to mutations identified in ctDNA. Cohorts A-D have already reported (Turner N et al, Lancet Oncol 2020). Cohort E recruited patients with triple negative breast cancer (TNBC) without a targetable mutation identified at ctDNA screening, treating with olaparib (PARP inhibitor) plus ceralasertib (ATR inhibitor). Methods: Patients with TNBC who had received 1 or 2 lines of chemotherapy for advanced disease or relapsed within 12 months of (neo)adjuvant chemotherapy were eligible. Treatment was olaparib 300mg b.i.d continuously and ceralasertib 160mg qd on days 1–7 on a 28 day cycle, until disease progression. The primary endpoint was confirmed objective response rate by RECIST v1.1. Secondary endpoints included clinical benefit rate, progression-free survival (PFS) and safety. Biomarker analysis included response according to BRCA and somatic DNA repair gene status and ATM loss. Using a two-stage design with a target response rate of 25%, unacceptable response rate of 10%, alpha=2% and power=90%, ≥13 responses out of 69 evaluable stage 2 patients were required to infer efficacy (5/37 stage 1). Results: Between 17/09/18 and 5/10/20 75 patients enrolled in Cohort E of whom 70 were evaluable for response. The median age was 55.6 years. 42 (56%) patients had 1 and 13 (17.3%) had 2 prior line(s) of chemotherapy for metastatic disease. Efficacy is shown in Table. The most common grade ≥3 adverse events were: hypertension 12 (17%) and anaemia 9 (13%). Dose reductions and interruptions occurred in 19 (26.4%) and 34 (47.2%) patients respectively. Conclusions: The response rate to olaparib and ceralasertib did not meet pre-specified criteria for efficacy in the overall evaluable population. Responses were observed in patients without germline or somatic BRCA1/2 mutations. Translational analyses are underway to identify potential biomarkers of response in this population and will be presented at the meeting. Clinical trial information: ISRCTN16945804. [Table: see text]

6: PALLIATIVE GASTRECTOMY FOR METASTATIC GASTRIC ADENOCARCINOMA: A NATIONAL POPULATION-BASED COHORT STUDY

Abstract Background and aim The impact of palliative gastrectomy for metastatic gastric adenocarcinoma, especially by site of metastasis remains unclear. This study aimed to evaluate the long-term outcomes of palliative gastrectomy for metastatic gastric adenocarcinoma. Methods The National Cancer Database (2010–2015) was used to identify patients with clinical metastatic (cM1) gastric adenocarcinoma (n = 19,411) at diagnosis. The main variable was index management for cM1 gastric adenocarcinoma (i.e. no treatment, palliative chemotherapy or palliative gastrectomy). Cox multivariable analyses were used to account for treatment selection bias. Results Of 19,411 patients, 10,893 (56%) received palliative chemotherapy, and only 1,101 (6%) received palliative gastrectomy only. The median survival was 6.1 months, and 5-year survival was 4% in the entire cohort. Patients receiving palliative gastrectomy had a significantly longer survival than patients without any treatment or palliative chemotherapy (median: 12.8 vs 1.8 vs 9.5 months, P &amp;lt; 0.001), which remained after multivariable adjustment (HR: 0.30, CI95%: 0.28–0.33, P &amp;lt; 0.001). Stratified analyses by clinical nodal stage (cN) demonstrated survival benefit with palliative gastrectomy: cN0 (HR: 0.28, CI 95%: 0.24–0.32), cN1 (HR: 0.27, CI 95%: 0.23–0.31), cN2 (HR: 0.29, CI 95%: 0.24–0.37), and cN3 (HR: 0.26, CI 95%: 0.20–0.32). Palliative gastrectomy remained superior compared to palliative chemotherapy for metastatic disease limited to liver, bone and peritoneum, but equivalent to lung metastasis and inferior to brain metastasis. Conclusion Palliative gastrectomy appears to have a modest survival benefit over palliative chemotherapy alone. Differences in outcomes by site of metastasis warrant further research to understand tumor biology and identify specific subgroups which may benefit from palliative gastrectomy.

Chemo- immunotherapy and radiation in locally advanced head and neck cancer: Where do we stand?

Immunotherapy represents an effective therapeutic option in the management of recurrent/metastatic head and neck squamous cell carcinoma, along with chemotherapy in metastatic disease or radiotherapy/re-irradiation for (locoregionally confined) recurrent disease.On the other hand, concomitant chemo-radiation remains the primary treatment modality in many patients with locally advanced disease. In spite of promising preclinical, it is difficult to clearly establish the role of immunotherapy in the upfront management of locally advanced head and neck squamous cell carcinoma and its integration with the standard of care. In this paper, we discuss/review the main results thus far available and outline some unanswered questions that might help design future clinical trials.

Abstract GS3-02: Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer

Abstract Background: Pyrotinib (an irreversible tyrosine kinase inhibitor targeting EGFR, HER2 and HER4) plus capecitabine significantly improved progression-free survival (PFS) compared with that for lapatinib plus capecitabine in women with HER2-positive metastatic breast cancer after treatment with trastuzumab and taxanes in the interim analysis of the PHOEBE trial (NCT03080805; Xu et al. Lancet Oncology, 2021). In this report, we present an updated analysis of the overall survival data from this trial. Methods: This PHOEBE trial enrolled patients with HER2-positive metastatic breast cancer who had received prior trastuzumab and taxanes and up to two prior lines of chemotherapy for metastatic disease. Patients were randomly assigned (1:1) to receive either oral pyrotinib 400 mg or lapatinib 1250 mg once daily, combined with oral capecitabine 1000 mg/m² twice daily on days 1-14 of each 21-day cycle. Stratification factors were hormone receptor status (estrogen receptor [ER]- and/or progesterone receptor [PR]-positive vs. ER- and PR-negative) and previous lines of chemotherapy for metastatic disease (≤1 vs 2). The primary endpoint was PFS assessed by masked independent central review. Data cutoff for the updated overall survival analysis was March 31, 2021. Results: Between July 31, 2017 and October 30, 2018, 267 eligible patients were enrolled and randomized to either pyrotinib plus capecitabine (pyrotinib group) or lapatinib plus capecitabine (lapatinib group). 134 patients in pyrotinib group and 132 in lapatinib group started the assigned treatment. At data cutoff, the median follow-up duration was 33.2 months (95% CI 31.4-34.2) in the pyrotinib group and 31.8 months (95% CI 31.2-34.1) in the lapatinib group. 78 (58.2%) patients in the pyrotinib group and 98 (74.2%) patients in the lapatinib group received post-discontinuation therapy, with trastuzumab (60 [44.8%] in the pyrotinib group and 65 [49.2%] in the lapatinib group) being the most common. As of data cutoff date, 54 (40.3%) of 134 patients randomly assigned to the pyrotinib group and 69 (52.3%) of the 132 patients randomly assigned to lapatinib group had died. Median OS was not reached (95% CI 34.0-not reached) in the pyrotinib group and 26.9 months (22.4-not reached) in the lapatinib group (HR 0.69 [95% CI 0.48-0.98]; P=0.019). Kaplan-Meier estimated OS at 24 months was 66.6% (95% CI 57.7-74.0) and 58.8% (95% CI 49.7-66.7), respectively. 99 (73.9%) patients in the pyrotinib group and 121 (91.7%) in the lapatinib group had disease progression or had died. Pyrotinib plus capecitabine significantly improved PFS assessed by investigator compared with that for lapatinib plus capecitabine (12.5 months [95% CI 9.8-13.8] vs 5.6 months [95% CI 5.5-7.0]; HR 0.48 [95% CI 0.37-0.63]; P&amp;lt;0.0001). The benefits of pyrotinib plus capecitabine were observed in most clinically relevant subgroups for the updated analysis of both OS and PFS (Table 1). Conclusion: With extended follow-up, pyrotinib plus capecitabine demonstrated statistically significant OS improvement compared with lapatinib plus capecitabine in patients with HER2-positive metastatic breast cancer after trastuzumab and chemotherapy. This updated analysis of overall survival in the PHOEBE trial reaffirmed pyrotinib plus capecitabine as an established treatment option in this patient population. Table 1.Subgroup analysis of OS and PFS per investigator.HR for OSHR for PFSAll Patients0.69 (0.48-0.98)0.48 (0.37-0.63)Trastuzumab therapy for metastatic disease&amp;lt;3 months0.67 (0.33-1.35)0.34 (0.17-0.69)3-6 months0.78 (0.34-1.76)0.66 (0.32-1.34)≥3 months0.79 (0.37-1.66)0.44 (0.26-0.75)Trastuzumab resistanceNo0.60 (0.39-0.91)0.44 (0.32-0.61)Yes0.94 (0.48-1.85)0.58 (0.35-0.98)HER2 amplification by FISH0.76 (0.39-1.51)0.57 (0.35-0.92)Pathological gradingII0.65 (0.33-1.28)0.51 (0.31-0.85)III0.82 (0.41-1.65)0.51 (0.31-0.83)Unknown0.70 (0.41-1.21)0.45 (0.29-0.70)Visceral lesionsVisceral0.59 (0.40-0.88)0.45 (0.33-0.62)Non-visceral1.28 (0.55-2.95)0.57 (0.31-1.04)ECOG performance status00.72 (0.40-1.29)0.42 (0.26-0.66)10.67 (0.43-1.04)0.50 (0.36-0.71)Estrogen and progesterone receptor statusPositive0.74 (0.44-1.25)0.58 (0.39-0.86)Negative0.64 (0.39-1.04)0.41 (0.28-0.60)Previous lines of chemotherapy for metastatic disease00.72 (0.38-1.35)0.47 (0.30-0.74)10.73 (0.44-1.22)0.49 (0.32-0.73)20.56 (0.24-1.32)0.56 (0.28-1.08)Data are median (95% CI). HRs are from unstratified analyses. Citation Format: Binghe Xu, Min Yan, Fei Ma, Xichun Hu, Jifeng Feng, Quchang Ouyang, Zhongsheng Tong, Huiping Li, Qingyuan Zhang, Tao Sun, Xian Wang, Yongmei Yin, Ying Cheng, Wei Li, Xiaoyu Zhu, Chunxia Chen, Jianjun Zou. Updated overall survival (OS) results from the phase 3 PHOEBE trial of pyrotinib versus lapatinib in combination with capecitabine in patients with HER2-positive metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS3-02.

Metastatic colo-rectal cancer: real life experience from an Indian tertiary care center

BackgroundNo data exist for the long-term outcome of metastatic colorectal cancer (mCRC) from the Southern part of Asia. The primary objective of the study is to evaluate the survival outcome of mCRC from an Indian tertiary care center. The study also aims to highlight the treatment pattern practiced and the unique clinico-pathologic characteristics.MethodsThis is a single-center retrospective observational study done at a large referral tertiary care center in North India. All patients with synchronous or metachronous mCRC who received at least one dose of chemotherapy for metastatic disease, registered between 2003 to 2017 were included. Primary outcome measures were overall survival and progression-free survival and prognostic factors of overall survival. Descriptive analysis was done for the clinicopathological characteristics and treatment patterns. Kaplan Meier method for overall survival and progression-free survival. Cox regression analysis was performed for the determination of the prognostic factors for overall survival.ResultOut of 377 eligible patients, 256 patients (68%) had de novo metastatic disease and the remaining 121 (32%) progressed to metastatic disease after initial treatment. The cohort was young (median age, 46 years) with the most common primary site being the rectum. A higher proportion of signet (9%) and mucinous histology (24%). The three common sites of metastasis were the liver, peritoneum, and lung. In the first line, most patients received oxaliplatin-based chemotherapy (70%). Only 12.5% of patients received biologicals in the first-line setting. The median follow-up and median overall survival of study cohort were 17 months and 18.5 months. The factors associated with poor outcome for overall survival on multivariate analysis were ECOG performance status of > 1, high CEA, low albumin, and the number of lines of chemotherapy received (< 2).ConclusionThe outcome of mCRC is inferior to the published literature. We found a relatively higher proportion of patients with the following characteristics; younger, rectum as primary tumor location, the signet, and mucinous histology, higher incidence of peritoneum involvement. The routine use of targeted therapies is limited. Government schemes (inclusion of targeted therapies in the Ayushman scheme), NGO assistance, and availability of generic low-cost targeted drugs may increase the availability.

A phase Ib study of xentuzumab plus abemaciclib and fulvestrant in patients (pts) with advanced hormone receptor-positive (HR+), HER2-negative breast cancer (BC) with visceral or non-visceral disease.

1057 Background: Cyclin-dependent kinase (CDK) 4 &amp; 6 inhibitors plus endocrine therapy (ET) are standard of care for advanced HR+ BC. Combining xentuzumab, an insulin-like growth factor (IGF) ligand-neutralizing antibody, with ET and everolimus, suggested progression-free survival (PFS) benefit in pts with advanced HR+ BC and non-visceral disease. Activation of the IGF pathway leads to an increase in cyclin D1, providing a rationale for combining IGF and CDK4 &amp; 6 inhibition. This prospective, open-label study is investigating xentuzumab plus abemaciclib, a CDK4 &amp; 6 inhibitor, with fulvestrant. In dose-finding cohorts, the recommended phase II dose (RP2D) was determined as xentuzumab 1000 mg weekly intravenously plus abemaciclib 150 mg every 12h orally (Q12h). Here, we report preliminary data on disease control rate (DCR) from two expansion cohorts in pts with advanced HR+ BC with visceral (D1) or non-visceral disease (D2). Methods: Postmenopausal women with advanced/metastatic HR+ BC that had progressed on or after ET (including adjuvant ET) were enrolled. Pts could not have received &gt;1 line of ET or any chemotherapy for metastatic disease. No prior CDK4 &amp; 6 inhibitor therapy was permitted. Pts had to have ≥1 documented visceral metastasis in D1 and no visceral metastases in D2. Pts received xentuzumab weekly plus abemaciclib Q12h (at RP2D) plus fulvestrant 500 mg per label. Protocol primary endpoint was PFS rate at 18 months (mos). Secondary endpoints included DCR (complete response [CR], partial response [PR] and non-CR/non-progressive disease [PD] or stable disease [SD] lasting ≥24 weeks [wks]). Results: In D1/D2, 33/31 pts were treated: median age 60/53 years. 19 pts in D2 had bone-only, non-measurable disease. At data cut-off (Jan 2021), median treatment duration was 7.5/9.2 mos in D1/D2; 40 pts remain on treatment. In D1, DCR was 64%: 17 (52%) pts had PR and 4 (12%) had SD lasting ≥24 wks. In D2, DCR was 55%: 5 (16%) pts had PR, 10 (32%) had non-CR/non-PD lasting ≥24 wks and 2 (7%) had SD lasting ≥24 wks. Median duration of disease control was 10.9 mos in each cohort. Some pts had not reached 24 wks; full DCR data will be presented. Most common AEs are shown in the table (≥33% all-grade in either cohort). No hypo/hyperglycemia was reported. Conclusions: Xentuzumab plus abemaciclib and fulvestrant demonstrated encouraging disease control in pts with advanced HR+ BC with visceral and non-visceral disease. The safety profile was manageable, and consistent with the known profiles of the three agents. Clinical trial information: NCT03099174 .[Table: see text]

Abstract PS11-03: Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial

Abstract Background: Veliparib (Vel) is a potent PARP1/2 inhibitor with demonstrated antitumor activity when administered alone or combined with carboplatin and paclitaxel (C/P). The phase 3 randomized, double-blind, multicenter BROCADE3 study (NCT02163694) evaluated the efficacy and safety of Vel + C/P treatment compared with placebo (Pbo) + C/P treatment in patients (pts) with germline BRCA1/2 mutations and HER2-negative metastatic or locally advanced breast cancer (BC). Vel + C/P significantly prolonged progression-free survival (PFS) compared with Pbo + C/P treatment (14.5 months [mo] vs 12.6 mo, hazard ratio [HR]=0.71 [95% CI: 0.57, 0.88]; P=0.002). Previous studies have identified increased acute hematologic toxicity in response to chemotherapy in pts with BC carrying BRCA1 mutations compared with BRCA2 mutations or wildtype BRCA1/2. Herein we report a subgroup analysis of the efficacy and safety of Vel + C/P treatment in pts with BRCA1- or BRCA2-positive BC. Methods: Pts ≥18 years of age who received ≤2 prior lines of cytotoxic chemotherapy for metastatic disease were randomized 2:1 to receive Vel + C/P or Pbo + C/P: Vel (120 mg PO BID) or Pbo on days -2 to 5, C (AUC 6 IV) on day 1, and P (80 mg/m2 IV) on days 1, 8, and 15 in 21-day cycles. Pts who discontinued C/P in the absence of disease progression could continue receiving Vel or Pbo monotherapy (300-400 mg BID continuous). Subgroup analysis of PFS stratified by BRCA1/2 status was preplanned. The primary endpoint was investigator-assessed PFS. Adverse events (AEs) were graded according to NCI CTCAE version 4.0. Ten pts with both BRCA1 and BRCA2 mutations were excluded from the analyses presented here. Results: In the intent-to-treat population, 256 pts had BRCA1 mutations and 243 pts had BRCA2 mutations. The proportion of as-treated pts with BRCA1 or BRCA2 mutations was comparable between the Vel + C/P (51.4% BRCA1, 48.6% BRCA2) and Pbo + C/P (50.9% BRCA1, 49.1% BRCA2) study arms. Investigator-assessed PFS for the Vel + C/P and Pbo + C/P arms was 14.2 mo vs 12.6 mo, respectively, in the BRCA1 subgroup (HR=0.75 [95% CI: 0.55, 1.03]; P=0.073) and 14.6 mo vs 12.6 mo, respectively, in the BRCA2 subgroup (HR=0.69 [95% CI: 0.50, 0.95]; P=0.021). Safety data in the as-treated population are presented in the Table. Regarding any grade AEs, thrombocytopenia and anemia were slightly more frequent in pts in the BRCA1 subgroup compared with the BRCA2 subgroup, whereas pts in the BRCA2 subgroup experienced slightly more frequent nausea, fatigue, and neuropathy. Conclusions: Globally, there was no clinically relevant difference in toxicity between BRCA1 and BRCA2 subgroups. Comparisons between treatment arms were generally consistent with findings in the overall study population, with more frequent thrombocytopenia and anemia of any grade reported in the Vel + C/P arm within both the BRCA1 and BRCA2 subgroups. Vel + C/P treatment improved PFS similarly in both BRCA1 and BRCA2 subgroups over C/P alone. BRCA1-Positive Subgroup (n=253)BRCA2-Positive Subgroup (n=241)Vel + C/P (n=168)Pbo + C/P (n=85)Vel + C/P (n=159)Pbo + C/P (n=82)Any grade AE [≥50% of pts], n (%)Any event167 (99.4)85 (100)158 (99.4)82 (100)Neutropenia151 (89.9)78 (91.8)140 (88.1)74 (90.2)Thrombocytopenia140 (83.3)66 (77.6)124 (78.0)54 (65.9)Anemia139 (82.7)64 (75.3)122 (76.7)52 (63.4)Nausea118 (70.2)49 (57.6)119 (74.8)58 (70.7)Alopecia89 (53.0)43 (50.6)89 (56.0)41 (50.0)Fatigue79 (47.0)37 (43.5)87 (54.7)48 (58.5)Peripheral sensory neuropathy69 (41.1)37 (43.5)82 (51.6)49 (59.8)Any grade ≥3 AE [≥30% of pts], n (%)Any event164 (97.6)82 (96.5)152 (95.6)77 (93.9)Anemia73 (43.5)31 (36.5)67 (42.1)35 (42.7)Leukopenia54 (32.1)20 (23.5)44 (27.7)25 (30.5)Neutropenia136 (81.0)72 (84.7)131 (82.4)67 (81.7)Thrombocytopenia72 (42.9)30 (35.3)59 (37.1)18 (22.0)Serious AEs, n (%)58 (34.5)26 (30.6)56 (35.2)22 (26.8)AEs of special interest, n (%)Infections within 14 days of neutropenia64 (38.1)34 (40.0)59 (37.1)25 (30.5)Hemorrhages within 14 days of thrombocytopenia14 (8.3)5 (5.9)17 (10.7)7 (8.5)Any AE leading to study drug discontinuation not due to disease progression, n (%)16 (9.5)5 (5.9)15 (9.4)4 (4.9)Any AE leading to study drug interruption, n (%)153 (91.1)77 (90.6)139 (87.4)67 (81.7)Any AE leading to study drug reduction, n (%)28 (16.7)6 (7.1)27 (17.0)7 (8.5)Any AE leading to death with reasonable possibility related to study drug, n (%)0 (0)0 (0)0 (0)0 (0)AE, adverse event; BRCA, breast cancer susceptibility gene; C/P, carboplatin plus paclitaxel; Pbo, placebo; pts, patients; Vel, veliparib. Citation Format: Hans Wildiers, Jean-Pierre Ayoub, Michael Friedlander, Bella Kaufman, Banu K. Arun, Hyo S. Han, Shannon L. Puhalla, David Maag, Dai Feng, Christine K. Ratajczak, Bruce A. Bach, Véronique Diéras. Safety and efficacy of veliparib plus carboplatin/paclitaxel in patients with HER2-negative metastatic or locally advanced breast cancer: A subgroup analysis of germline BRCA1 or BRCA2 mutations from the phase 3 BROCADE3 trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-03.

Cetuximab and paclitaxel combination therapy for recurrent basaloid squamous cell carcinoma in the ethmoid sinus

Basaloid squamous cell carcinoma (BSCC), a histologically distinctive variant of squamous cell carcinoma comprising basal cell carcinoma and squamous cell carcinoma, is aggressive and shows a poor prognosis because of frequent lymph node invasion and distant metastases. To date few articles regarding chemotherapy for metastatic disease have been reported, thus feasible chemotherapy is not well established. Cetuximab is a monoclonal antibody for epithelial growth factor receptor (EGFR), which has great efficacy for head and neck squamous cell carcinoma due to EGFR signaling pathway blockage. Because BSCC also highly expresses EGFR, cetuximab may be effective for BSCC. We report here a first case of recurrent BSCC in the ethmoid sinus with intracranial extension treated with cetuximab-based chemotherapy, which revealed great response in a 40-year-old man. Positron emission tomography (PET) revealed no lymph node or distant metastasis. The patient underwent chemoradiotherapy 66 Gy in 33 fractions with triweekly 100 mg/m2 cisplatin. However, 12 weeks after treatment completion PET revealed a residual tumor at the primary cancer site. Combination therapy with weekly paclitaxel and cetuximab was started, and complete response was observed 2 months from treatment initiation. The patient has maintained complete response for 32 months, and no tumor regrowth has been observed.

A rare case of recurrent epidermoid anal cancer treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy\u2014case report

BackgroundAnal cancer is a rare cancer with chemoradiation being the mainstay of treatment for locoregional presentation. In North America, the most common subtype is anal squamous cell carcinoma (epidermoid). A surgical approach is considered for persistent or recurrent anal disease and systemic chemotherapy for metastatic disease. We are presenting a unique case of recurrent anal cancer with isolated peritoneal malignancy, an oligometastatic state which is rare in itself. It was treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. There are currently no clear guidelines for the aforementioned presentation. The discussion drew on the feasibility and safety of this approach.Case presentationA 68-year-old woman diagnosed with an epidermoid anal cancer (stage 3B) was initially treated with chemoradiation therapy (Standard Nigro Protocol) in 2014. At the 5-year mark post-treatment, she was diagnosed with a recurrent anal epidermoid cancer in the form of isolated peritoneal carcinomatosis proven by biopsy. After declining systemic chemotherapy, she underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy with Mitomycin-C©. Peritoneal carcinomatosis index was evaluated at 10, and intraoperative frozen sections were positive for carcinoma of epidermoid origin compatible with anal cancer. A completeness of cytoreduction score of 0 was achieved during the cytoreductive surgery, and her hospital course was unremarkable. She remains disease-free 12 months later.ConclusionsTo our knowledge, this is the first case reporting the disease presentation of anal cancer with oligometastatic dissemination to the peritoneum. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy were performed. Thus far, this approach seems to be a safe and feasible option for short-term control of the disease.

Final results of PEANUT: Pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).

5017 Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts received 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression (PD) or unacceptable toxicity. Inclusion criteria were: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response was evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers included PD-L1 combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint was the progression-free survival (PFS). The target was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 65 pts: 24% were female, median age was 69 yrs (IQR: 61-73); 25% had failed &gt; 1 prior systemic therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up (FUP) of 5.5 months, 34 pts have relapsed (52.3%). The median PFS was 5 months (95%CI: 3-not reached). The 3-month PFS was 60.7% (95%CI: 49.8-74.1). The confirmed objective response-rate (ORR) was 47.7% (95%CI: 35.2-60.4): 22 partial responses and 9 complete responses (13.8%). The median duration of response was not reached, and 4 pts (6.1%) are long-term responders ( &gt; 12 months). Grade 3 treatment-related adverse events (TRAE) were seen in 20 pts (30.7%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%) and asthenia (33%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. In matched tumor/blood samples, objective responses were seen in 8/10 pts with PI3KCA mutations (80%); 6/10 pts with RB1 alterations (60%); 5/12 pts with DNA damage repair gene alterations (41.7%). Conclusions: Pembro-nab-paclitaxel, the first salvage CT-immunotherapy combination in UC, demonstrated a good tolerability, promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. As more mature data on biomarker selection emerges, this combination warrants additional studies in either second-line or earlier disease settings. Clinical trial information: NCT03464734 .

MP67-19 DUCTAL ADENOCARCINOMA OF THE PROSTATE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF INCIDENCE, PRESENTATION AND MANAGEMENT

MP67-19 DUCTAL ADENOCARCINOMA OF THE PROSTATE: A SYSTEMATIC REVIEW AND META-ANALYSIS OF INCIDENCE, PRESENTATION AND MANAGEMENT

Olaparib for advanced breast cancer.

Olaparib, an oral PARP-inhibitor, has shown clinical benefit for HER2-negative advanced breast cancer patients carrying a germinal BRCA1/2 mutation. In a randomized Phase III trial, olaparib significantly prolonged progression-free survival as compared with chemotherapy of physician choice. Moreover, in the same trial, a prespecified subgroup analysis reported an overall survival benefit for patients not previously pretreated with chemotherapy for metastatic disease. This review focuses on available preclinical, pharmacokinetic and pharmacodynamic data regarding olaparib and clinical evidence of its antitumor efficacy (both as monotherapy and in combination) and tolerability in breast cancer patients. Open questions, such as use of appropriate biomarkers for patient selection and combination/sequencing with other anticancer drugs, are also addressed.

Interim results of PEANUT: pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).

494 Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel (nPtx) demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigate their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts receive 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nPtx on D1 and D8, every 3 weeks, until disease progression (PD) or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response is evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers include PD-L1 expression with the combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 08/2019, PEANUT enrolled 46 pts evaluable for the study endpoint: 26% female, median age 66 y (range 43-78); 70% had failed 1 prior systemic therapy vs 30% 2 prior therapies; 24% had ECOG-performance status 1; 28% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up of 5 months, 18 pts have relapsed (39%). The projected median PFS was 7 months (95%CI: 4-not achieved). The confirmed objective response-rate (ORR) was 47.8% (95%CI: 32.9-63.1): 18 partial responses and 4 complete responses (8.7%). Grade 3 treatment-related adverse events (TRAE) were seen in 6 pts (13%). Most common any-grade TRAE included alopecia (91%), asthenia (21.7%), and neutropenia (15%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. 7/8 pts with PI3KCA mutations in matched tumor/blood samples had an objective response (87.5%). Conclusions: Preliminary results from PEANUT study demonstrated a promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. Updated data, including mature PFS, duration of response and biomarkers will be presented. Clinical trial information: NCT03464734.