Objective Tumor Response Rate Research Articles

330P - Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours

330P - Pharmacokinetics (PK), safety, and efficacy of [fam-] trastuzumab deruxtecan with OATP1B/CYP3A inhibitors in subjects with HER2-expressing advanced solid tumours

Impact of bladder volume on treatment planning and clinical outcomes of radiotherapy for patients with cervical cancer.

ObjectiveThis study aimed to investigate the impact of bladder volume on treatment planning and clinical outcomes of radiotherapy for patients with cervical cancer.Materials and methodsOne hundred and sixty-six patients with locally advanced cervical cancer were selected in this retrospective study. The patients were divided into four groups according to their average bladder volume during radiotherapy (external beam radiation therapy and intracavitary brachytherapy): group A: V<100 mL, group B: 100 mL≤V≤150 mL, group C: 150 mL<V≤200 mL, group D: V>200 mL. The bladder volume and the cumulative dose to planning target (D90), bladder (D2cc), rectum (D2cc), and sigmoid (D2cc) were calculated using the treatment planning system. Treatment outcomes including late adverse events (the maximum grade of radiation-induced proctitis and cystitis), the objective response rate of tumor and lymph node, overall survival (OS), and progression-free survival (PFS) were collected. Additionally, the correlation between bladder volume and the irradiated dose of organs at risk and treatment outcomes was analyzed.ResultsThe median follow-up time was 28 months. The D90 and D2cc of the rectum in group A were the highest (P<0.05). The D2cc of the bladder in group D was the highest (P<0.05). There was no significant difference in the tumor and lymph node regression rate, OS, and PFS among the groups. The difference in the late radiation-induced proctitis and cystitis maximum grade among the four groups was statistically significant (P<0.001, P=0.022, respectively), with group A the most serious and group B the mildest.ConclusionFor patients with cervical cancer, the bladder volume significantly affected the delivered dose to target, rectum, and bladder. When the bladder volume range was 100–150 mL, the rate of late radiation-induced proctitis and cystitis was low and the degree of reaction was mild. This is thought to be the optimum bladder volume for patients with cervical cancer during radiotherapy.

Long-term follow-up of patients (pts) with relapsed or refractory (r/r) follicular lymphoma (FL) treated with copanlisib.

7553 Background: The pan-class I phosphatidylinositol 3-kinase inhibitor copanlisib was approved by the FDA in September 2017 for treatment of relapsed FL based on results from the CHRONOS-1 study in pts with indolent non-Hodgkin lymphoma. We report efficacy and safety results of a 2-year (yr) follow-up of FL pts. Methods: Pts with indolent FL (grade [G] 1-3a) r/r to ≥2 prior lines of treatment received copanlisib (60 mg i.v. infusion) on days 1, 8, and 15 of a 28-day cycle. The primary endpoint was objective tumor response rate (ORR) per independent radiologic review (Cheson et al. 2007). Adverse events were reported using MedDRA (v20.1). Data cut-off: February 20, 2018. Results: 104 FL pts were enrolled. Median age was 62 yr (39% &gt;65 yr), the median number of prior lines of anti-cancer therapy was 3 (range 2-8), and 27 pts (26%) were classified as having G3a disease. The ORR was 59%, with complete responses (CR) in 20% ( n=21); 14 pts had a CR at the primary analysis in June 2016. The median duration of response (mDoR) was 12.2 months (mo) (range 0.03-43 mo). Stable disease (SD) was observed in 33% of pts; median duration of SD was 7.8 mo (range 1.3-23 mo). Median progression-free survival (mPFS) was 11.2 mo (range 0.03-44 mo) with 33% alive and progression-free at 2 yrs. Median overall survival (mOS) was 3.2 yr (range 0.06-4.2 yr) with 67% alive at 2 yrs. Median duration of treatment was 26 weeks (wk) (range 1-192 wk); median duration of safety follow-up was 29 wk. In the G3a subset, the ORR was 67% (26% CR), mDoR was 10.9 mo, mPFS was 12.5 mo, and mOS was 2.5 yr. The most common treatment-emergent adverse events occurring in &gt;25% of pts included (all grade/G3+): diarrhea (37%/9%), neutropenia (26%/23%), and pyrexia (28%/5%). Hyperglycemia (49%/40%) and hypertension (29%/23%) were transient. Incidences of pneumonitis (6.7%/1.9%) and colitis (1.0% G4) were low. Conclusions: Long-term follow-up of r/r FL pts treated with copanlisib revealed robust and durable responses with CRs exceeding 20%, including in pts with higher grade disease. The safety profile continues to be both manageable and favorable, with no evidence of late-onset severe toxicities. Clinical trial information: NCT01660451.

Effect of High-Dose vs Standard-Dose Vitamin D3 Supplementation on Progression-Free Survival Among Patients With Advanced or Metastatic Colorectal Cancer

In observational studies, higher plasma 25-hydroxyvitamin D (25[OH]D) levels have been associated with improved survival in metastatic colorectal cancer (CRC). To determine if high-dose vitamin D3 added to standard chemotherapy improves outcomes in patients with metastatic CRC. Double-blind phase 2 randomized clinical trial of 139 patients with advanced or metastatic CRC conducted at 11 US academic and community cancer centers from March 2012 through November 2016 (database lock: September 2018). mFOLFOX6 plus bevacizumab chemotherapy every 2 weeks and either high-dose vitamin D3 (n = 69) or standard-dose vitamin D3 (n = 70) daily until disease progression, intolerable toxicity, or withdrawal of consent. The primary end point was progression-free survival (PFS) assessed by the log-rank test and a supportive Cox proportional hazards model. Testing was 1-sided. Secondary end points included tumor objective response rate (ORR), overall survival (OS), and change in plasma 25(OH)D level. Among 139 patients (mean age, 56 years; 60 [43%] women) who completed or discontinued chemotherapy and vitamin D3 (median follow-up, 22.9 months), the median PFS for high-dose vitamin D3 was 13.0 months (95% CI, 10.1 to 14.7; 49 PFS events) vs 11.0 months (95% CI, 9.5 to 14.0; 62 PFS events) for standard-dose vitamin D3 (log-rank P = .07); multivariable hazard ratio for PFS or death was 0.64 (1-sided 95% CI, 0 to 0.90; P = .02). There were no significant differences between high-dose and standard-dose vitamin D3 for tumor ORR (58% vs 63%, respectively; difference, -5% [95% CI, -20% to 100%], P = .27) or OS (median, 24.3 months vs 24.3 months; log-rank P = .43). The median 25(OH)D level at baseline for high-dose vitamin D3 was 16.1 ng/mL vs 18.7 ng/mL for standard-dose vitamin D3 (difference, -2.6 ng/mL [95% CI, -6.6 to 1.4], P = .30); at first restaging, 32.0 ng/mL vs 18.7 ng/mL (difference, 12.8 ng/mL [95% CI, 9.0 to 16.6], P < .001); at second restaging, 35.2 ng/mL vs 18.5 ng/mL (difference, 16.7 ng/mL [95% CI, 10.9 to 22.5], P < .001); and at treatment discontinuation, 34.8 ng/mL vs 18.7 ng/mL (difference, 16.2 ng/mL [95% CI, 9.9 to 22.4], P < .001). The most common grade 3 and higher adverse events for chemotherapy plus high-dose vs standard-dose vitamin D3 were neutropenia (n = 24 [35%] vs n = 21 [31%], respectively) and hypertension (n = 9 [13%] vs n = 11 [16%]). Among patients with metastatic CRC, addition of high-dose vitamin D3, vs standard-dose vitamin D3, to standard chemotherapy resulted in a difference in median PFS that was not statistically significant, but with a significantly improved supportive hazard ratio. These findings warrant further evaluation in a larger multicenter randomized clinical trial. ClinicalTrials.gov Identifier: NCT01516216.

Abstract P1-06-07: Characterization of chromosomal instability in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012)

Abstract Background A distinctive trait of triple negative breast cancer (TNBC) is the acquisition of genome wide highly aberrant copy number states, which is more evident in metastatic settings. The level of copy number alterations can be characterized by quantitative estimates of chromosomal instability, such as allelic imbalanced copy number aberrations, telomeric allelic imbalance (NtAI), homologous recombination deficiency (HRD) score, referred here as genomic scars. Several of these scars are reported as being indicative of BRCAness and potential predictive and/or prognostic biomarkers of chemotherapy response, currently mostly demonstrated in neoadjuvant settings in TNBC. Aims Using several genomic scar measures, we aim to capture chromosomal instability and test their predictive and prognostic value in metastatic or recurrent locally advanced triple negative or BRCA1/2 mutated breast cancer in the TNT trial. Methods Patients recruited to TNT (n=376) had ER-/PR-/Her2- breast cancer or were germline BRCA mutation carriers. Genome-wide copy numbers (CN) were derived from FFPE samples including primary tumours and positive lymph nodes (n=183, docetaxel=93, carboplatin=90; BRCA1 mut=25). Genomic scars were generated using ASCAT (Van loo et al., PNAS 2010) CN profiles. HRD scores were established by Myriad Genetics, Inc. assay (n=272). BRCA1-like classifier was applied as described in Schouten et al., Mol Onc 2015. Shannon diversity index was calculated using ASCAT raw CN profiles. Association of genomic scars with PAM50 subtypes and BRCA1 deficiency status were evaluated using Kruskal-Wallis test; p-values were adjusted for multiple comparisons (Dunn's test). Statistical significance was defined as p&amp;lt;0.05. Association of genomic scars with objective tumour response rate (ORR) and Progression Free Survival (PFS) was assessed using logistic regression and restricted mean survival analysis, respectively. Results HRD and NtAI scores were higher in basal like samples compared to non-basal like (median diff. HRD=11.5, p=0.005; NtAI=3, p=0.04). HRD (p=2e-14) and NtAI (p=0.003) scores were also higher in BRCA1 deficient (BRCA1 germline/somatic mutant or BRCA1 methylated) samples compared to non-deficient. Using the BRCA1-like classifier, 42 out of 50 BRCA1 deficient samples and 93 out of 133 BRCA1 non-deficient/undetermined samples were identified as BRCA1-like. The Shannon diversity index, measuring CN heterogeneity, clustered samples into 3 groups. Analysis of ORR showed non-significant trends to preferential response rates with docetaxel in cluster 1 and 3. Membership of cluster 2 predicted higher ORR to carboplatin over docetaxel (interaction p=0.017). PFS indicated a treatment effect in cluster 2, but not in cluster 1 or 3; there was no evidence of interaction between subgroups and treatment (p=0.15). Conclusions Our results suggest that the overall heterogeneity of the copy number landscape is a promising area for seeking predictive/prognostic biomarkers in metastatic TNBC, and combined with other modalities of high-dimensional omics data could provide essential treatment response information. Citation Format: Sipos O, Tovey H, Quist J, Haider S, Nowinski S, Gazinska P, Kernaghan S, Toms C, Timms KM, Lanchbury JS, Linn SC, Pinder SE, Bliss JM, Tutt A, Cheang MC, Grigoriadis A, On behalf of the TNT Trial Management Group and Investigators. Characterization of chromosomal instability in the TNT trial: A randomized phase III trial of carboplatin compared with docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012) [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 P1-06-07.

Patient and Oncologist Preferences for the Treatment of Adults with Advanced Soft Tissue Sarcoma: A Discrete Choice Experiment.

There has been no single standard-of-care treatment of patients with advanced/metastatic soft tissue sarcoma (STS). This study was designed to understand patient and oncologist preferences in the advanced/metastatic setting. Adult patients diagnosed with STS and oncologists treating patients with STS completed discrete choice experiment surveys. Study participants chose between pairs of hypothetical treatment profiles for advanced STS characterized by varying levels of overall survival (14, 20, or 26months), progression-free survival (3, 5, or 7months), objective tumor response rate (12, 18, or 26%), risk of hospitalization due to side effects (12, 30, or 46%), and days/month to administer treatment (1, 2, or 4days). A hierarchical Bayes model was used to estimate preferences and relative importance of attributes. Seventy-six patients (23.7% male, mean age 52.8years) and 160 oncologists (73.8% male, mean 16.9years in practice) completed the surveys. Among patients, overall survival had the highest relative importance (39.5%, standard deviation [SD] 18.2%), followed by response rate (21.2%, SD 10.4%), and hospitalization (19.8%, SD 12.5%). Among oncologists, overall survival had the highest relative importance (44.6%, SD 16.0%), followed by hospitalization (18.4%, SD 8.3%). Both patients with STS and oncologists preferred a treatment that maximizes the life of patients while avoiding hospitalizations.

Outcomes of concurrent chemoradiotherapy versus chemotherapy alone for stage IV esophageal squamous cell carcinoma: a retrospective controlled study

BackgroundThe purpose of this study is to compare the efficacy and safety of concurrent chemoradiotherapy (CCRT) versus chemotherapy alone for patients with stage IV esophageal squamous cell carcinoma (ESCC).MethodsEligible patients were retrospectively enrolled at the authors’s institution from January 2010 to October 2015. Of the 141 patients enrolled, 55 (39.0%) received CCRT and 86 (61.0%) received chemotherapy alone. The outcomes and adverse events (AEs) were compared between the two groups.ResultsThe baseline clinical characteristics of the two groups were similar. However, the CCRT group showed a significantly better primary tumor objective response rate (ORR) than that of the chemotherapy group (74.5% versus 45.3%, p = 0.001). The 1-year, 2-year, 3-year overall survival (OS) rates and median OS were 58.0% versus 43.0%, 25.5% versus 14.0%, 10.7% versus 4.7%, and 14 months versus 11 months for patients treated with CCRT or chemotherapy, respectively (p = 0.007). The 1-year and median progression-free survival (PFS) were 29.8% versus 14.9% and 8 months versus 6 months (p = 0.005). Multivariate analysis identified CCRT (p = 0.013) and solitary metastasis (p = 0.037) as independent factors for greater OS. The frequency of leucocytopenia (grade 3 or higher) was significantly higher in the CCRT group than in the chemotherapy-alone group (p = 0.040), whereas the rates of other AEs did not differ.ConclusionsIn this study, it is suggested that CCRT is more effective than chemotherapy alone for stage IV ESCC, yielding better primary responses and survival outcomes with tolerable side effects.

A Phase 1 Clinical Trial of Ipilimumab, Nivolumab and Radiation Therapy for Patients with Metastatic Melanoma

Combined blockade of immune checkpoints CTLA-4 and PD-1 with ipilimumab and nivolumab (ipi/nivo) represents the most effective strategy for the systemic treatment of metastatic melanoma. Preclinical studies suggest that tumor radiation therapy (RT) may modulate immune response in conjunction with ipi/nivo, and that the dose-fractionation of RT is relevant to this effect. This study was designed to assess the safety of combining ipi/nivo with 2 different RT dose-fractionation regimens: lower dose, conventionally-fractionated RT (Cohort A) and higher dose, hypofractionated RT (Cohort B). The hypothesis for this study is that the combination of ipi/nivo and RT is safe in metastatic melanoma. After IRB approval, a prospective, single-arm, two-cohort, Phase 1 clinical trial (NCT02659540) was initiated at 2 cancer centers. Eligible patients had ≥2 sites of metastatic melanoma: ≥1 site was amenable to RT and ≥1 site was observed for response by RECIST v1.1. Patients (n=9 per cohort) were enrolled in 2 consecutive cohorts (Cohort A, RT 30 Gy/10 fractions; Cohort B, RT 27 Gy/3 fractions) and started RT between the first and second doses of ipi/nivo given at the FDA-approved dose and schedule. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events that occurred within 24 weeks of the first dose of ipi/nivo were characterized according to CTCAE v4.03. Exploratory analyses of irradiated tumor and overall objective response rate (ORR, exclusive of the irradiated tumor) were performed in patients who received at least one dose of ipi/nivo and RT. In Cohort A, 10 patients (median age: 65 [range: 28-86] years; 6 female) were enrolled because 1 patient withdrew consent after ipi/nivo/RT, but before disease assessment. Grade 3-4 TEAEs were observed in 7/10 patients, while Grade 3-4 TRAEs were observed in 4/10 patients and included pruritus, anemia, thrombocytopenia, and lipase elevation. Irradiated tumor ORR was 44% (95% confidence interval [CI]: 14-79%), and ORR outside of the irradiated tumor was 44% (95% CI: 14-79%), with 2 patients dying of disease progression. Cohort B has enrolled 5 of 9 patients; safety and efficacy analyses are anticipated to be complete at the time of presentation. This is the first prospective clinical trial to report on the combination of ipi/nivo and RT. Despite the small number of planned accruals in this Phase 1 trial, the TRAE rate after ipi/nivo/lower dose, conventionally-fractionated RT was similar to what has been observed after ipi/nivo without RT, suggesting this regimen is safe. Further analyses will be required to better characterize the safety and efficacy of this regimen in Cohort B, as well as potential immunologic differences between the two RT cohorts in this study.

Dual-Port versus Mono-Port Implantation for Intra-Arterial Chemoinfusion Therapy for Treatment of Hepatocellular Carcinoma in Patients with Anatomic Hepatic Artery Variation

PurposeTo compare the feasibility and safety of mono-port catheter system and dual-port catheter system for advanced hepatocellular carcinoma (HCC) in patients with anatomic hepatic artery variation and portal vein tumor thrombosis. Materials and MethodsThis retrospective study consisted of 22 patients with infiltrative or multiple HCC with unilateral or bilateral portal vein thrombosis who had hepatic artery variation. A mono-port or dual-port catheter system was determined according to the degree of blood supply to the entire tumor through the common hepatic and variant hepatic arteries. Intrahepatic perfusion pattern, hepatic toxicity, and tumor response were investigated on computed tomography, medical records, and follow-up imaging study. ResultsThe most common hepatic arterial variation was replaced right hepatic artery arising from the superior mesenteric artery (n = 16), followed by replaced left hepatic artery (n = 5) and replaced right posterior segmental artery (n = 1). Twelve patients were treated with mono-port catheter system, and 10 patients were treated with dual-port catheter system. All 10 patients in the dual-port group showed homogeneous distribution of contrast material in the entire liver after port implantation, and 6 patients (50%, n = 6/12) in the mono-port group showed heterogeneous distribution (P = .018). The objective tumor response rates (P = .361) were 18.2% and 40%, and the disease control rates (P = .395) were 36.4% and 60% in the mono-port and dual-port groups, respectively. ConclusionsThe dual-port catheter system is a safe and effective technique that allows the even distribution of hepatic arterial infusion chemotherapy without hemodynamic modification of anatomic variation in the hepatic arteries.

Application of cyberknife in treatment of retroperitoneal lymph node metastatic tumors in 81 cases

Objective To evaluate the clinical efficacy and side effects of cyberknife therapy in the treatment of retroperitoneal lymph node metastatic tumor. Methods Among the 81 patients presenting with postoperative retroperitoneal lymph node metastases, 33 cases suffered from abdominal pain or low back pain, 7 had unilateral hydronephrosis and ureteral dilatation, and 8 developed unilateral or bilateral lower limb swelling. Using stereotactic radiotherapy with a cyberknife, DT was delivered at 33-45 Gy/3-6 F. The improvement of symptoms, objective tumor response rate, and irradiation-induced side effects were observed. Results At 4 weeks after treatment, pain and swelling of the lower extremities were completely mitigated, and hydronephrosis was fully healed in all patients. Enhanced CT or MRI was performed every 2 to 3 months. After 6-month follow-up, the complete response (CR) rate was calculated as 77%(62/81), 21%(17/81) for the partial response (PR) rate, 3%(2/81) for the stable disease (SD) rate and the effective rate (CR+ PR) was 98%.No case progressed. The main side effect was intestinal injury, including grade 1 in 16%(13/81), grade 2 in 9%(7/81). Multivariate analysis demonstrated the CR rate was not correlated with the type of the primary tumor or the size of the tumor (P>0.05), but was significantly associated with the distance of>0.5 cm between the tumor and intestine and the BED (α/β=10)>70 Gy of the tumor irradiation (P 5 cm and the distance of<0.5 cm between the tumor and intestine (P<0.01). Conclusion Cyberknife is an efficacious and safe approach in the treatment of retroperitoneal lymph node metastatic tumors. Key words: Retroperitoneal lymph node metastatic neoplasms/stereotactic radiotherapy; Radiotherapy, cyber knife

Pressurized intraperitoneal aerosol chemotherapy (PIPAC) for peritoneal carcinomatosis: systematic review of clinical and experimental evidence with special emphasis on ovarian cancer.

Systemic chemotherapy is not effective in patients with peritoneal carcinomatosis (PC) and only a minority of affected patients is eligible for cytoreductive surgery. Intraperitoneal chemotherapy may provide a therapy alternative for these patients. We performed a systematic review of clinical and experimental evidence on the safety and efficacy of pressurized intraperitoneal aerosol chemotherapy (PIPAC) in patients with PC and provide clinical recommendations based on the available evidence. Fifty-eight reports were identified, categorized as experimental (18 reports), clinical (28 reports), and other articles (14 reports). Experimental studies demonstrated improved tissue penetration and peritoneal coverage. The 28 clinical studies reported on 3515 procedures in 1547 patients with PC of various primary tumors with 16 of these studies reporting on patients with ovarian cancer. Toxicity was manageable. Based on 1197 patients in 22 studies, adverse events CTCAE grades 1, 2, 3, 4, and 5 were observed in 537 (45%), 167 (14%), 83 (7%), 10 (0.8%), and 19 (1.6%) cases, respectively. In a pooled analysis, the objective tumor response rate was 69% and the mean overall survival duration was 13.7months. No significant hepatic, renal, or hematologic toxicity was described. PIPAC maintained and/or improved quality of life, as reported in 10 studies with 396 patients. Available evidence from controlled trials (phase I and phase II) and retrospective cohort studies in > 1500 patients unequivocally demonstrates that PIPAC is feasible, safe, and effective. PIPAC maintains quality of life in patients with recurrent cancer and PC. PIPAC is as evidence-based as any other treatment in women with ovarian cancer and PC beyond the third line of systemic chemotherapy and can be recommended in this indication.

Renal cell carcinoma (RCC) primary tumor shrinkage on vascular endothelial growth factor (VEGF)-targeted therapy (TT): A pooled analysis.

629 Background: Cytoreductive nephrectomy (CRN) is an important treatment modality in patients (pts) with advanced RCC, however the role and timing in the context of VEGF-TT remains under investigation. The aim of this study is to determine the efficacy of VEGF-TT to induce primary tumor shrinkage in advanced RCC. Methods: We conducted a pooled analysis of 12 Pfizer-sponsored trials in pts with metastatic RCC treated with sunitinib, sorafenib, axitinib, bevacizumab, termsirolimus or interferon-α. Primary endpoint was the primary tumor objective response rate (ORR) by RECIST in pts who have not undergone prior nephrectomy. Kaplan-Meier method was used to estimate median overall survival (OS) of responders (PR or CR) v. non-responders. Cox regression adjusting for demographics, histology type, prior therapy, metastasis sites, IMDC risk factors and neutrophil-to-lymphocyte ratio was used to compare OS between pts with and without primary tumor ORR. Results: 565 (12%) out of 4736 pts included had their primary tumors intact, of which 360 (8%) received VEGF-TT. In pts with primary tumor intact, 87% had clear-cell RCC and IMDC risk group were 4% favourable, 33% intermediate, 39% poor, 24% unknown. 35% had bone metastasis and 32% had liver metastases. 65% had ECOG performance status ≥1. Compared to pts with prior nephrectomy, primary tumor intact pts were more likely to have bone or liver metastases or to be IMDC poor risk. Primary tumor ORR was 17% (95% exact CI, 14, 20) in all pts, 19% (95% exact CI, 16, 23) in first line treated pts and 23% (95% Exact CI, 19, 28) in pts treated with VEGF-TT (any line). Primary tumor ORR was 20% (95% exact CI, 15, 26) in IMDC intermediate risk pts and 9% (95% exact CI, 5 – 13) in the poor risk. No pts had PD as best response in their primary tumor at the time they stopped systemic therapy. Median OS was 33.98 months in pts with primary tumor ORR and 9.8 months in pts without ORR, adjusted HR 0.42 [95%CI, 0.28, 0.6; p &lt; 0.0001]. Conclusions: VEGF-TT resulted in primary tumor shrinkage in 23% of pts with IMDC intermediate and poor risk advanced RCC who have not undergone CRN. VEGF-TT may potentially facilitate future CRN in select pts. Trials assessing the utility of CRN are underway.

Combined effects of neoadjuvant letrozole and zoledronic acid on γδT cells in postmenopausal women with early-stage breast cancer

IntroductionAdjuvant bisphosphonates lead to better prognosis in postmenopausal breast cancer. However, the association between clinical outcomes and immune modulation by them is still unclear. MethodsIn this prospective, open-label phase II study, postmenopausal women with estrogen receptor-positive and human epidermal growth factor receptor 2-negative early-stage breast cancer received neoadjuvant letrozole (LET) for one month, followed by treatment with a single dose of zoledronic acid. The patients underwent an additional 5 months of treatment with LET prior to surgery. The primary endpoint was the tumor objective response rate (ORR) determined by diameter via MRI. The association between the ORR and γδT cell frequencies was assessed as a secondary endpoint. ResultsOut of sixty patients, 55 patients were evaluable for response by MRI. The ORR for LET with zoledronic acid was 38.2% (21/55), which was comparable to that of historical controls (45%). A decrease in the frequency of the Vδ2 T cell subset was observed throughout treatment, and Vδ2 T cells were activated for 6 months. In planned subgroup analyses, patients with low frequencies of Vδ2 T cells prior to zoledronic acid infusion experienced a favorable tumor response compared to those with high frequencies (59.3% [16/27] vs 17.9% [5/28], p = .002). There were no serious adverse events with this treatment regimen. ConclusionThese results showed that neoadjuvant LET with zoledronic acid could not achieve overall effect for local tumor response. However, patients with a low frequency of γδ T cells would benefit from the treatment including zoledronic acid. (UMIN 000008701).

Safety and efficacy of low-dose transarterial chemoembolization in the hepatocellular carcinoma patients with portal vein tumor thrombosis

Aim: The aim of the study is to analyze the safety and efficacy of low-dose transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) patients with portal vein tumor thrombosis (PVTT). Materials and Methods: Seventy-five HCC patients with PVTT, who were admitted to our hospital between 2011 and 2015 and underwent TACE, were analyzed. The safety and efficacy of low-dose TACE were evaluated. Results: The objective tumor response rate was 25.3%. The median overall survival time was 10.7 months (95% confidence interval [CI]: 8.2–13.2). The cumulative survival rates at 6, 12, 18, and 24 months were 65.3%, 44%, 17.3%, and 2.6%, respectively. Univariate analysis revealed that alpha-fetoprotein (heart rate [HR] = 1.307, 95% CI: 1.019–1.427, P P P P P P P P P = 0.03) were independent predictive factors for survival rates. The incidence of complications due to procedures was 85.3%. Conclusion: The low-dose TACE may be considered selectively to HCC patients with PVTT. Child–Pugh classification, type of PVTT, number of tumor, and size of tumor were checked accurately before operation.

Ki-67 labeling index is a predictive marker for a pathological complete response to neoadjuvant chemotherapy in breast cancer: A meta-analysis.

A pathological complete response (pCR) after neoadjuvant chemotherapy (NCT) is a strong indicator of the benefit of therapy and presents an early surrogate for a favorable long-term outcome. It remains unclear whether Ki-67, a marker for tumor proliferation, can function as a predictor of the response to NCT in breast cancer. The objective of this meta-analysis was to compare the pCR rate and clinical outcomes in breast cancer patients with different Ki-67 labeling indexes (Ki-67 LI) who received NCT. Clinical studies were retrieved from the electronic databases of PubMed, Embase, Clinical Trials, Wanfang, and the Chinese National Knowledge Infrastructure, from their inception to July 31, 2017. Meta-analysis was performed on pool eligible studies to determine whether Ki-67 LI was associated with the pCR rate and clinical outcomes of breast cancer patients who were treated with NCT. Pooled analyses were performed using fixed effects models. Two reviewers screened all titles and abstracts and independently assessed all articles. A total of 36 studies involving 6793 patients were included in the meta-analysis. Pooled analysis results revealed that patients with high Ki-67 LI exhibited significantly higher pCR rates (odds ratio [OR] = 3.94, 95% confidence interval [CI]: 3.33-4.67, P <.001) but poorer relapse-free survival (OR = 1.99, 95% CI: 1.39-2.85, P <.001) than those with low Ki-67 LI, but there was no significant difference in objective tumor response rate. The meta-analysis reported here demonstrates that pretherapeutic Ki-67 LI is associated with pCR in breast cancer patients undergoing NCT. More phase III randomized clinical trials will be required to confirm our findings.

P2.03-044 OSCILLATE - Phase 2 Trial of Alternating Osimertinib with Gefitinib in Patients with EGFR-T790M Mutation Positive Advanced NSCLC

Activating mutations of the epidermal growth factor receptor (EGFR) are key drivers of non-small cell lung cancer (NSCLC) in approximately 10-15% of Western patients and 30-35% of Asian patients. Patients with common activating mutations (L858R and del19) typically have objective tumor response rates (OTRR) of 56-74% and median progression free survival (PFS) of 9-13 months with first-generation EGFR tyrosine kinase inhibitors (TKI) such as erlotinib or gefitinib. The most common mechanism of acquired resistance to first generation EGFR TKI is the T790M mutation (50-60% of cases).

Safety and Efficacy Outcomes of Embolization in Hepatic Sarcomas.

The outcome for patients with unresectable hepatic sarcoma is poor with a median survival period of 12-16 months. The purpose of this study was to evaluate liver-directed transcatheter therapies for the treatment of hepatic sarcomas. In a retrospective study, the cases of patients with primary and metastatic hepatic sarcoma treated by transcatheter embolization, chemoembolization, and 90Y radioembolization between 2004 and 2015 were identified. Response Evaluation Criteria in Solid Tumors version 1.1 response was assessed for the target tumor. Survival was assessed by means of Kaplan-Meier analysis. Twenty-eight patients (17 [61%] men, 11 [39%] women; median age, 47 years) were included. Eighteen patients were treated electively. Two of the electively treated patients underwent embolization; eight, chemoembolization; six, radioembolization; and two, a combination of transcatheter treatments. Treatment was well tolerated; only one patient had grade 3 hepatic toxicity. The objective response rate of the index tumor was 61%, and the median overall survival period was 26.7 months. Ten patients underwent emergency embolization to control acute hemorrhage from tumor rupture. The median overall survival periods were 611 days for the patients with ruptured gastrointestinal stromal tumors (GIST) (n = 3) and 19 days for the patients with ruptured angiosarcoma (n = 7). Liver-directed transcatheter therapies are safe and may have a role in the elective management of unresectable primary and metastatic liver sarcomas. Emergency embolization for ruptured GIST may be effective for stabilizing the patient's condition and allowing more definitive therapy in the future. However, emergency embolization has limited efficacy in treating patients with ruptured angiosarcoma, likely because of substantial venous bleeding at rupture and the aggressive behavior of this lesion.

Transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil versus transarterial chemoembolization using doxorubicin for unresectable hepatocellular carcinoma with portal vein tumor thrombosis: a retrospective analysis.

Background:More than one-third of hepatocellular carcinoma (HCC) patients are diagnosed at advanced stage with portal vein tumor thrombosis (PVTT) or extrahepatic metastasis. However, the outcomes of current therapeutic approaches are unsatisfactory. As a novel therapeutic strategy for unresectable HCC with PVTT, we analyzed the outcomes of transarterial infusion of epirubicin and cisplatin combined with systemic infusion of 5-fluorouracil (TAC-ECF) and compared its therapeutic effects and toxicity with transarterial chemoembolization (TACE) using doxorubicin (DOX).Methods:A total of 540 consecutive HCC patients who received TACE at the Catholic Medical Center between January 2007 and November 2013 were enrolled. Of these patients, we retrospectively analyzed 129 Barcelona clinic liver cancer stage C HCC patients with PVTT who received either TAC-ECF or TACE using DOX.Results:The objective tumor response rate was higher in the TAC-ECF group, with 31.3% objective response rate after TAC-ECF compared to 10% after DOX treatment (p = 0.004). Median follow-up period was 7 months (range, 1–57 months). The overall survival rate was also significantly higher in the TAC-ECF group compared to the DOX group (median 9.3 versus 4.6 months, p < 0.0001). Multivariate analysis revealed that TAC-ECF and extrahepatic metastasis were independent predictive factors for overall survival (p < 0.0001 and p = 0.002 respectively). No serious adverse effects developed in both groups.Conclusions:TAC-ECF therapy was tolerable and showed higher overall survival rate and tumor response compared to the conventional TACE DOX in advanced stage HCC patients with PVTT. Therefore, TAC-ECF may be considered as an effective treatment option for patients with unresectable HCC.

Abstract CT149: Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study

Abstract Introduction: There are limited treatment options for patients with indolent B-cell lymphoma who have relapsed or are refractory to standard therapies. Copanlisib is an intravenously administered pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. We report here the primary results from a pivotal phase II study (NCT01660451, part B). Methods: Patients with indolent B-cell non-Hodgkin lymphoma (4 subtypes: follicular [FL], marginal zone [MZL], small lymphocytic [SLL] and lymphoplasmacytoid/Waldenström macroglobulinemia [LPL-WM]) and relapsed after, or refractory to, ≥2 prior lines of treatment were eligible. Previous treatment had to include rituximab and an alkylating agent. Copanlisib (60 mg, I.V.) was intermittently administered on days 1, 8 and 15 of a 28-day cycle. The primary efficacy endpoint was objective tumor response rate (ORR) as assessed per independent radiologic review (Cheson et al., JCO 20:579, 2007). Results: The full analysis set comprised 142 patients, of which 141 patients had indolent lymphoma (FL/MZL/SLL/LPL-WM: 104/23/8/6). At the time of primary analysis, median duration of treatment was 22 weeks (range 1-105); 46 patients remained on treatment. The most common treatment-related AEs (all grade/grade 3+) were transient hyperglycemia (49%/40%) and hypertension (29%/23%). Other AEs of interest included neutropenia (25%/19%), diarrhea (18%/4%), lung infection (14%/11%), pneumonitis (7%/1.4%), and colitis (0.7%/0.7%). No colonic perforations occurred. There were two non-fatal opportunistic infections. Laboratory toxicities of interest were principally grade-1, including alanine aminotransferase (23% all-grade/19% grade-1) and aspartate aminotransferase (28%/25%). There were 6 deaths, 3 of which were attributed to copanlisib: lung infection, respiratory failure, and a thromboembolic event. The ORR was 59.2%, including 12.0% complete response (CR) and 47.2% partial response (PR), with stable disease in 29.6% of patients and progressive disease in 2.1% of patients. In the FL subset, the ORR was 58.7%, including 14.4% CR and 44.2% PR. In the MZL subset, the ORR was 69.6%, including 8.7% CR and 60.9% PR. The estimated Kaplan-Meier (KM) median duration of response in the full analysis set was 687 days (range 0-687) and 370 days (range 0-687) in the FL subset. The KM-estimate of median PFS was 340 days (range 0-736). Median overall survival had not yet been reached. Conclusions: Treatment of patients with relapsed or refractory indolent B-cell lymphoma with copanlisib resulted in durable tumor responses. Administration of copanlisib had a manageable safety profile, with low rates of severe hepatic enzymopathy, diarrhea or inflammatory events, as well as low rates of opportunistic infections, fatal infections or other fatal serious adverse events. Citation Format: Martin Dreyling, Armando Santoro, Luigina Mollica, Sirpa Leppä, George A. Follows, Georg Lenz, Won Seog Kim, Arnon Nagler, Panayiotis Panayiotidis, Judit Demeter, Muhit Özcan, Marina Kosinova, Krimo Bouabdallah, Franck Morschhauser, Don A. Stevens, David Trevarthen, Marius Giurescu, Lisa Kupit, Shuxin Yin, Florian Hiemeyer, Jose Garcia-Vargas, Barrett H. Childs, Pier Luigi Zinzani. Copanlisib in patients with relapsed or refractory indolent B-cell lymphoma: Primary results of the pivotal Chronos-1 study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT149. doi:10.1158/1538-7445.AM2017-CT149

Abstract CT155: Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC)

Abstract Introduction: Sacituzumab govitecan (IMMU-132) is an antibody-drug conjugate (ADC) delivering SN-38, a topoisomerase-1 inhibitor, to mSCLC cells expressing Trop-2. We are studying the safety/tolerability and efficacy of IMMU-132 in patients with relapsed/refractory mSCLC who had received a platinum-containing first-line regimen. Experimental Procedure: Patients received 8 or 10 mg/kg IV IMMU-132 on days 1 and 8 of repeated 21-day cycles. Objective tumor response (ORR) was determined by RECISTv1.1 in patients receiving at least one treatment cycle, and progression-free survival (PFS) and overall survival (OS) in all patients by Kaplan-Meier methods. (ClinicalTrials.gov, NCT01631552) Summary of New Unpublished Data: A total of 53 patients (23/30 M/F, median 63 years old) with 1-7 (median 2) prior lines of therapy were enrolled between November, 2013 and June, 2016. Immunohistochemistry of evaluable archival tumor specimens for Trop-2 expression (N=26) showed 92% positivity (61% moderately to strongly positive). They received up to 32 treatment cycles (median 5); the most frequent Grade &amp;gt;3 adverse events were neutropenia (34%), fatigue (13%) and diarrhea (9%). Four patients did not complete one cycle of treatment. In the other 49 patients (14 at 8 mg/kg, 35 at 10 mg/kg), there were 7 confirmed PRs and 21 SDs as best response. The resulting ORR rate was 14% (7/49), with a median duration and time-to-progression of a response of 4.0 and 7.6 mos, respectively, and the clinical benefit rate (PR+SD &amp;gt;4 mos) was 35% (17/49). The ORR rate was similar in pts who were sensitive (&amp;gt;3 mos response) or resistant (&amp;lt;3 mos) to 1st-line therapy [13% (3/23) vs 15% (4/26), respectively]. In 2nd-line setting, IMMU-132 had a confirmed ORR rate of 14% (3/21), and a clinical benefit rate of 38% (8/21). This compares well to recent results with topotecan having an ORR of 13-16% in 2nd-line. Comparing dose levels, ORR was 17% (6/35) with 10 mg/kg vs 7% (1/14) with 8 mg/kg, with little difference in toxicity. Median PFS and OS in all 53 patients was 3.7 mos (95% CI, 2.0 - 4.3) and 7.0 mos (95% CI, 5.5 - 8.3), respectively, and included 6 long-term survivors (12.7 - 25.4 months). No antibody response to the ADC or antibody was detected despite multiple therapy cycles. Conclusion: These interim results demonstrate encouraging activity in patients with late-stage mSCLC having a high expression of Trop-2. Even after failing 1st-line platinum chemotherapy or 2nd-line topotecan therapy, IMMU-132 showed promising activity, and has a manageable toxicity profile. IMMU-132 given at 10 mg/kg on day 1 and 8 of a 3-week cycle was selected for further clinical evaluation in this population. Citation Format: Jhanelle E. Gray, Rebecca S. Heist, Alexander N. Starodub, D. Ross Camidge, Ebenezer Kio, Gregory Masters, W. Thomas Purcell, Michael J. Guarino, Jamal Misleh, Charles J. Schneider, Bryan J. Schneider, Allyson J. Ocean, Tirrell Johnson, Leena Gandhi, Kevin Kalinsky, Serengulam V. Govindan, Pius Maliakal, Boyd Mudenda, William A. Wegener, Robert M. Sharkey, David M. Goldenberg. Phase 2 study of sacituzumab govitecan (IMMU-132), an anti-Trop-2/SN-38 antibody-drug conjugate (ADC), in patients with pretreated metastatic small-cell lung cancer (mSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT155. doi:10.1158/1538-7445.AM2017-CT155