TP Arm Research Articles

Phase 3 RCT comparing docetaxel-platinum with docetaxel-platinum-5FU as neoadjuvant chemotherapy in borderline resectable oral cancer

BackgroundNeoadjuvant chemotherapy (NACT) with TPF (docetaxel, cisplatin, and 5FU) is one of the treatment options in very locally advanced oral cancer with a survival advantage over PF (cisplatin and 5FU). TP (docetaxel and cisplatin) has shown promising results with a lower rate of adverse events but has never been compared to TPF. MethodsIn this phase 3 randomized superiority study, adult patients with borderline resectable locally advanced oral cancers were randomized in a 1:1 fashion to either TP or TPF. After the administration of 2 cycles, patients were evaluated in a multidisciplinary clinic and further treatment was planned. The primary endpoint was overall survival (OS) and secondary endpoints were progression-free survival (PFS) and adverse events. Results495 patients were randomized in this study, 248 patients in TP arm and 247 in TPF arm. The 5-year OS was 18.5% (95% CI 13.8–23.7) and 23.9% (95% CI 18.1-30.1) in TP and TPF arms, respectively (Hazard ratio 0.778; 95% CI 0.637–0.952; P = 0.015). Following NACT, 43.8% were deemed resectable, but 34.5% underwent surgery. The 5-year OS was 50.7% (95% CI 41.5–59.1) and 5% (95%CI 2.9–8.1), respectively, in the surgically resected versus unresected cohort post NACT (P < 0.0001). Grade 3 or above adverse events were seen in 97 (39.1%) and 179 (72.5%) patients in the TP and TPF arms, respectively (P < 0.0001). ConclusionNACT with TPF has a survival benefit over TP in borderline resectable oral cancers, with an increase in toxicity which is manageable. Patients who undergo surgery achieve a relatively good, sustained survival.

UNRAVELING THE EFFECTS OF TRANSFER PRICING DOCUMENTATION REGULATION: INDONESIA’ EVIDENCE

To counter tax avoidance using transfer mispricing practices, Indonesia introduced a transfer pricing documentation policy. This policy requires taxpayers to be transparent with their transfer pricing decisions. Treating the implementation of this policy as a shock to the taxpayers, this paper examines how the transfer pricing documentation policy affects a firm's tax avoidance behaviour by employing regression discontinuity design and difference-in-difference. Immediately after introducing the policy, a regression discontinuity analysis results indicate a 0.9 percentage point increase in tax/sales among taxpayers obligated to prepare transfer pricing documentation. A 0.3 to 0.7 percentage point increase in the tax/sales of the treatment group is observed when difference-in-difference is established. These findings show that such policy implementation can discourage taxpayers' tax avoidance behaviour. In light of these results, the Indonesian tax authority may consider taking several actions to improve the implementation of TP docs, such as amending summary of TP docs so that it contains more valuable information regarding taxpayer’s arm’s length principle application, requiring simple TP docs for taxpayers below the threshold, providing continuously providing assistance and capacity building to the taxpayers regarding appropriate TP docs preparation and arm’s length principle application.

Nab-paclitaxel plus cisplatin versus docetaxel plus cisplatin and 5-FU induction chemotherapy followed by concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: A multicenter parallel controlled phase III trial.

6071 Background: Although several large phase III clinical trials and meta-analysis have demonstrated significant clinical benefit of docetaxel combined with cisplatin and 5-FU (TPF) chemotherapy in head and neck cancer, serious adverse reactions are unsatisfactory. Therefore, this study was designed to evaluate the efficacy and safety of nab-paclitaxel plus cisplatin (TP) versus TPF induction chemotherapy (ICT) followed by concurrent chemoradiotherapy (CCRT) for locally advanced nasopharyngeal carcinoma (LA-NPC). Methods: In this open-label, phase 3 trial, patients were randomized 1:1 to received TP (260 mg/m2 nab-paclitaxel and 80 mg/m2 cisplatin on days 1 and 22) or TPF (60 mg/m2 docetaxel and 60 mg/m2 cisplatin on days 1 and 22; 3 g/m2 5-Fu on days 1-5 and 22-26) every 3 weeks for 2 cycles, both groups of patients received CCRT (100mg/m2 cisplatin and IMRT on days 43 and 64) every 21 days for 2 cycles. The primary endpoint was failure-free survival. Secondary endpoints included overall survival, objective response rate (ORR), quality of life and safety. Results: From January 2019 to July 2021, 281 patients were randomized to TP (n = 142, TP arm) or TPF (n = 139, TPF arm). The median age was 44 years (range, 20-63) in the TP arm and 45 years (range, 18-69) in the TPF arm. The pathological stages were 40.85% stage III and 59.15% stage IVA in the TP arm, while those of the TPF arm were 43.17% stage III and 56.83% stage IVA. There were 99.30% and 97.12% undifferentiated nonkeratinizing carcinoma in the two groups, respectively. All patients had Karnofsky performance status of 90. ICT was completed in 98.93% (100% in the TP arm and 97.84% in the TPF arm). The median relative dose intensity of nab-paclitaxel and cisplatin were 99.96% and 99.81% in the TP arm, 99.83%, 100% and 100% for docetaxel, cisplatin and 5-FU in the TPF arm, respectively. The ORR were 80.28% in the TP arm and 78.26% in the TPF arm after two cycles of ICT. 85.77% (83.10% in the TP arm and 88.49% in the TPF arm) completed the CCRT. After two cycles of CCRT, the ORR were 99.25% and 99.24%, respectively. 3 months after completion of all treatment, the ORR were 99.25% and 99.25%, respectively. During ICT, all treatment-related adverse events occurred in 40.14% of patients in the TP arm and 57.55% in the TPF arm. The most frequent grade 3 adverse events were neutropenia (0.70% vs 2.16%), leucopenia (0 vs 2.88%), diarrhea (0 vs 0.72%) in the TP arm and in the TPF arm. Over the entire course of treatment, the most common was 1 grade adverse events, and no patient developed grade 4 adverse events in the two groups. Conclusions: In this study, TP regimen showed similar trends in the ORR but excellent safety profile in patients with LA-NPC compared with TPF regimen, suggesting a potential therapeutic option for this population. Clinical trial information: ChiCTR1800019922 .

Comparing a PD-L1 inhibitor plus chemotherapy to chemotherapy alone in neoadjuvant therapy for locally advanced ESCC: a randomized Phase II clinical trial

BackgroundA Phase II study was undertaken to evaluate the safety and efficacy of the neoadjuvant socazolimab, a novel PD-L1 inhibitor, in combination with nab-paclitaxel and cisplatin for locally advanced esophageal squamous cell carcinoma (ESCC).MethodsSixty-four patients were randomly divided between the Socazolimab + nab-paclitaxel + cisplatin (TP) arm (n = 32) and the control arm (n = 32), receiving either socazolimab (5 mg/kg intravenously (IV), day 1) or a placebo with nab-paclitaxel (125 mg/m2 IV, day 1/8) and cisplatin (75 mg/m2 IV, day 1) repeated every 21 days for four cycles before surgery. The primary endpoint was major pathological response (MPR), and the secondary endpoints were pathological complete response (pCR), R0 resection rate, event-free survival (EFS), overall survival (OS), and safety.ResultsA total of 29 (90.6%) patients in each arm underwent surgery, and 29 (100%) and 28 (98.6%) patients underwent R0 resection in the Socazolimab + TP and Placebo + TP arms, respectively. The MPR rates were 69.0 and 62.1% (95% Confidence Interval (CI): 49.1–84.0% vs. 42.4–78.7%, P = 0.509), and the pCR rates were 41.4 and 27.6% (95% CI: 24.1–60.9% vs. 13.5–47.5%, P = 0.311) in the Socazolimab + TP and Placebo + TP arms, respectively. Significantly higher incidence rates of ypT0 (37.9% vs. 3.5%; P = 0.001) and T downstaging were observed in the Socazolimab + TP arm than in the Placebo + TP arm. The EFS and OS outcomes were not mature.ConclusionsThe neoadjuvant socazolimab combined with chemotherapy demonstrated promising MPR and pCR rates and significant T downstaging in locally advanced ESCC without increasing surgical complication rates.Trial registrationRegistration name (on clinicaltrials.gov): A Study of Anti-PD-L1 Antibody in Neoadjuvant Chemotherapy of Esophageal Squamous Cell Carcinoma. Registration number: NCT04460066.

Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2-positive metastatic breast cancer, followed by T-DM1 after progression

IntroductionOlder patients are at higher risk of chemotherapy-induced toxicity, raising interest in less toxic anti-HER2 regimens for older persons with HER2-positive (HER2+) metastatic breast cancer (MBC). Patients and methodsThis phase II study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide (M) + Trastuzumab (T) and Pertuzumab (P) or TP alone. T-DM1 was offered in case of progression. ResultsIn total, 39 and 41 patients were randomized to TP and TPM arm respectively. Median follow-up is 54.0 months. 24-month PFS was 18.7% (95% CI 8.2–32.4) and 28.7% (95% CI 15.8–43.0), respectively. A total of 49 (61.3%) patients died of whom 37 (75.5%) from disease progression; number of deaths per arm was 27 (69.2%) for TP and 22 (53.7%) for TPM. There was no significant difference in OS between the two arms (median OS TP vs TPM: 32.1 vs 37.5 months, p 0.25). Among the 40 patients who have started T-DM1 after disease progression on TP/TPM, PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7–58.5) and grade 3 or higher AE occurred in 18 pts (45%). ConclusionsMetronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and relatively well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years. Nevertheless, the majority of this older/frail population died from breast cancer, highlighting the need for well tolerated and efficacious treatments in these patients.

Abstract P1-18-06: Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer, followed by T-DM1 after progression

Abstract Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at high risk of chemotherapy-induced toxicity ,raising interest in less toxic anti-HER2 therapy regimens.Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed. T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6months, already reported (Lancet Oncol 2018, Wildiers et al). We now present data on long term outcome (including cause of death), and on response and tolerance of T-DM1 given after progression on TP(M).Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior (neo)adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 70% and/or to short physical performance battery (&amp;lt;10) 81%, Charlson comorbidity score &amp;gt; 0 in 41%. With 54.0 months of median follow-up, 6-month PFS was 43.1% (95% CI 27.1-58.1) versus 73.0% (95% CI 55.8-84.3) for TP and TPM, respectively. 12-month PFS was 33.7% and 51.9%, and 24-month PFS 18.7% and 28.7%, respectively. A total of 49 (61.3%) patients died, 27 (69.2%) in the TP arm and 22 (53.7%) in the TPM arm. There was no significant difference in OS between the two arms (TPM vs TP: HR=0.72, 95% CI 0.41-1.26) with median OS 32.1 months for TP, and 37.5 months for TPM. The causes of death were progressive disease (N=37, 75.5%), toxicity (cardiac failure, N=1, 2.0%), and other causes not due to PD/toxicity (N=9, 22.5%). Among the 40 patients who have started T-DM1 (22 in TPM arm and 18 in TP arm), median follow-up was 33.7 months from T-DM1 start. PFS rate at 6 months after start of T-DM1 was 43.6% (95% CI: 27.7-58.5). Grade 3 or higher AE occurred in 18 pts (45%). Most relevant reported grade III or higher toxicities on T-DM1 were fatigue (N=3), anorexia (N=2), anemia (N=1), febrile neutropenia (N=1), diarrhoea (N=1), hepatic failure (N=1), lung infection (N=1), increased GGT (N=1), thrombocytopenia (N=1), weight loss (N=1), hypophosphatemia (N=1), dyspnoea (N=1), epistaxis (N=1), hematoma (N=1). Two patients (5%) experienced grade 5 toxicity: one death was considered as related to cachexia and tumor progression; the other death was considered to be related to acute pneumonia and renal failure. The prognostic impact of geriatric assessment on PFS and OS, and frailty evolution during therapy will be presented at the meeting.Conclusions: Metronomic chemotherapy-based dual blockade (TPM), followed by T-DM1 after progression, provides an active and well tolerated treatment option in an older/frail HER2+ MBC population, with a median survival of over 3 years despite the associated frailty in the majority of the study population. T-DM1 provides a PFS rate at 6 months of 43.6% (95% CI: 27.7-58.5) with a wide range of possibly related toxicities in this generally frail population. Citation Format: Hans Wildiers, Sandrine Marreaud, Lissandra Dal Lago, Peter Vuylsteke, Giuseppe Curigliano, Simon Waters, Barbara Brouwers, Bart Meulemans, Berta Sousa, Coralie Poncet, Etienne Brain. Long term outcome data from the EORTC 75111-10114 ETF/BCG randomized phase II study: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer, followed by T-DM1 after progression [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 P1-18-06.

Sintilimab with chemotherapy as first-line treatment for locally advanced or metastatic squamous non-small-cell lung cancer: a real-world data study.

The ORIENT-12 study demonstrated the promising results of sintilimab combined with gemcitabine and platinum (GP) therapy in squamous non-small-cell lung cancer (sqNSCLC) patients. However, the efficacy of sintilimab plus paclitaxel/nab-paclitaxel and platinum (TP) in sqNSCLC is not yet known. Real-life data were retrospectively collected from patients with untreated locally advanced or metastatic sqNSCLC who were treated with sintilimab plus TP (arm A) or sintilimab plus GP (arm B) between January 2019 and January 2021. Baseline characteristics, the efficacy of sintilimab, and adverse events were analyzed. A total of 52 patients were included (arm A, n = 32 and arm B, n = 20). The overall response rate was 59.4% in arm A and 40.0% in arm B. The median progression-free survival was 13.9months (95% confidence interval [CI], 6.9-21.0) in arm A and 8.5months (95% CI, 6.9-10.2) in arm B (hazard ratio [HR], 0.61; 95% CI, 0.30 to 1.25; p = 0.18). The median overall survival was 21.3months (95% CI, 13.4-29.3) in arm A and 13.3months (95% CI, 9.1-17.5) in arm B (HR, 0.62; 95% CI, 0.28-1.36; p = 0.23). Adverse events of grade 3 or higher occurred in 37.5% of the patients in arm A and 55.0% of the patients in arm B. Sintilimab-TP may have similar clinical benefits compared with sintilimab-GP in patients with untreated advanced or metastatic sqNSCLC. These results require further validation by prospective randomized controlled studies.

Efficacy of epirubicin plus cyclophosphamide followed by taxanes versus carboplatin plus taxanes as adjuvant chemotherapy in triple-negative breast cancer: 8.1 years median follow-up on a randomized clinical trial.

529 Background: Four cycles of adjuvant taxanes (paclitaxel or docetaxel) after four cycles of adjuvant doxorubicin plus cyclophosphamide (ECT) are considered a standard adjuvant treatment and improves survival outcomes of triple negative breast cancer (TNBC). The purpose of this analysis was to further assess whether adjuvant carboplatin plus taxanes (TP) was non-inferior to or superior to standard ECT chemotherapy in prolonging the survival time. Methods: This randomized, open-label, multicenter clinical trial conducted at three hospital in China from June, 2009 and October, 2015. Eligible early triple-negative breast cancer (TNBC) patients were randomized (1:1) to receive ECT (four cycles of epirubicin 90 mg/m2 + cyclophosphamide 600 mg/m2 followed by four cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 every 3 weeks, ECT arm, n = 154) or receive TP (six cycles of docetaxel 75 mg/m2 or paclitaxel 175 mg/m2 + carboplatin AUC 5 every 3 weeks; TP arm, n = 154), which was then followed by surgery. Results: Three hundred and eight patients were recruited in this trial and final date of follow-up was January 20, 2021. Baseline characteristics were balanced between ECT arm and TP arm. Median follow-up was 97.6 months. Median disease free survival (DFS) was not reached; 8-year DFS rate was 78.35% with ECT arm and 81.73% with TP arm (hazard ratio [HR] = 0.84; 95% confidence interval [CI] = 0.50 - 1.40; P = 0.496). Median overall survival (OS) was also not reached; 8-year OS rate was 87.15% with ECT arm and 89.14% with TP arm (HR = 0.87; 95% CI = 0.44 - 1.70; P = 0.676). For TNBC patients with DFS &gt; 4 year, TP arm had a longer DFS than ECT ( P = 0.01), and had a tendency with better OS ( P = 0.4). In this subgroup analysis of SPARC &gt; 50%, TP arm had a longer DFS than ECT ( P &lt; 0.05), and also had a tendency with better OS ( P = 0.06). In subgroup analysis of PD-1 (-) and intravascular invasion (+), TP arm had a better DFS ( P = 0.02) and OS ( P = 0.03) than ECT arm. DFS or OS had no significant differences in ECT and TP arm with BRCA mutation or BRCA wild ( all P values &gt; 0.05). Conclusions: TP chemotherapy showed significant non-inferiority for PFS and OS versus ECT in the first-line adjuvant treatment of early TNBC. For some particular subgroup of TNBC, TP may be a more effective chemotherapy than ECT. TP may be considered an effective alternative to early TNBC. Clinical trial information: NCT01150513.

Optimal induction chemotherapeutic regimen followed by concurrent chemotherapy plus intensity-modulated radiotherapy as first-line therapy for locoregionally advanced nasopharyngeal carcinoma

For patients with locoregionally advanced nasopharyngeal carcinoma (NPC), induction chemotherapy (IC) regimens based on TPF (docetaxel, cisplatin, and 5-fluorouracil), TP (docetaxel and cisplatin), and GP (gemcitabine and cisplatin) have shown excellent survival outcomes as the first-line therapy; however, no trials comparing the efficacy and safety of TPF, TP, and GP have been reported. We report 2 phase II trials comparing the treatment outcomes and side effects of 3 different IC regimens followed by concurrent chemoradiotherapy in locoregionally advanced patients with NPC.A total of 206 locoregionally advanced patients with NPC treated with a combination treatment from January 2012 to January 2014 were enrolled in the 2 studies. The patients received TPF-, TP-, and GP-based IC regimens every 3 weeks, followed by intensity-modulated radiotherapy and concurrent therapy with cisplatin every 3 weeks.After a median follow-up duration of 47 months (10–60 months), the 3-year local recurrence-free survival, regional recurrence-free survival, distant metastases-free survival, progression-free survival, and overall survival rates were 96.4%, 100%, 87.7%, 86%, and 94.7% in the TPF arm; 91.7%, 95.9%, 91.9%, 85.2%, and 92% in the TP arm; 98.6%, 100%, 89.0%, 87.6%, and 89.2% in the GP arm. The survival differences among the 3 arms were not statistically significant (P > .05). The multivariate analysis demonstrated that the IC regimen was not an independent prognostic factor for any survival outcomes. The patients in the TP arm experienced significantly lower grade 3/4 toxicities than the patients in the other 2 arms.TP-based IC regimen has similar efficacy compared with TPF- and GP-based IC regimens; however, TP-based IC regimen has a lower toxicity profile.

Abstract PD1-04: Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC)

Abstract Background: IDO1 is a mediator of tumor immune suppression through alteration of tryptophan metabolism. Indoximod (1-methyl-tryptophan) is an IDO1 pathway inhibitor. There is preclinical evidence that indoximod acts synergistically with chemotherapy such as taxanes (Uyttenhove, 2003) in an immune dependent fashion. Previous studies demonstrated the safety and activity of indoximod combined with docetaxel in patients with advanced solid tumors, including breast cancer (Soliman, 2014). A phase 2 clinical trial was designed to study the efficacy of indoximod plus taxanes in metastatic breast cancer (MBC) patients (pts). Method: This is a phase II randomized, 1:1 placebo controlled clinical trial, that enrolled MBC pts in multiple centers in the US and Poland. Eligibility criteria included ER+ or ER- HER2- MBC, ability to receive taxane therapy, PS 0-1, normal organ function and absence of autoimmune disease. Pts were randomized to taxane (either weekly paclitaxel 80mg/m2 3 on 1 off or q3wk docetaxel at 75mg/m2 per treating physician’s discretion) + placebo (TP) or taxane + indoximod 1200mg PO BID (TI) as first line treatment for MBC. Primary endpoint was PFS. The sample size of 154 patients was designed to detect a HR of .64 with one sided α=.1 and β=.2 after 95 events. Archival tumor tissue was stained with IHC for IDO1 expression when available. Aperio digital pathology positive pixel algorithm was used for scoring, with manual verification. Median value was used as cut-off for IDO positivity. Results: 164 pts were randomized and treated (85 TI, 79 TP). Demographics and tumor features are shown in table 1. Treatment discontinuation was due to disease progression (60%), adverse events (10%), other (30%). Objective response rate was 40% in TI and 37% in TP arm (p=.74). The median PFS was 6.0 (95% CI, 4.5, 8.1) months in the TI arm and 8.4 (95% CI, 5.6, 9.8) in the TP arm, HR of 1.14 (0.81, 1.60). The median OS was 21.6 months (CI 95%, 16, 39.1) in the TI arm and 21.2 (CI 95%, 19.1, 32.1) in the TP arm. The median follow up was 17.4 (range 0.1, 39.4) months. Grade ≥3 treatment emergent adverse events were observed in 60% of patients in both arms with neutropenia, fatigue, anemia, diarrhea being most common but not significantly different between arms. An exploratory analysis of IDO staining with outcomes in 42 samples (22 in TI and 20 TP) suggested a difference in median PFS in pts with high IDO expression assigned to TI vs. TP (10.3 vs 4 months, p=.047). No other prognostic or predictive associations were observed based on IDO status in the analysis. Conclusions: The combination of indoximod with a taxane in 1st line HER2- MBC was safe and did not result in added toxicity. In an unselected population, no improvement in clinical outcomes was observed for the combination over taxane alone. However, higher tumor IDO expression may select for MBC pts who benefit more from indoximod and should be investigated as a predictive biomarker in future studies. Demographics and tumor featuresIndoximodPlaceboOverallParameterStatistic(N=85)(N=79)(N=164)Age (years)n8579164median (min, max)58 (29,76)57 (29,85)58 (29,85)GenderMalen (%)1 (1.2)2 (2.5)3 (1.8)Femalen (%)84 (98.8)77 (97.5)161 (98.2)RaceWhiten (%)71 (83.5)66 (83.5)137 (83.5)African Americann (%)12 (14.1)10 (12.7)22 (13.4)Asiann (%)1 (1.2)01 (0.6)Othern (%)1 (1.2)3 (3.8)4 (2.4)ECOG status0n (%)41 (48.8)43 (54.4)84 (51.5)1n (%)44 (52.2)36 (44.3)80 (46.6)Hormone Receptor StatusNegativen (%)23 (27.1)23 (29.1)46 (28.0)Positiven (%)62 (72.9)56 (70.9)118 (72.0)Choice of TaxaneDocetaxeln (%)62 (72.9)59 (74.7)121 (73.8)Paclitaxeln (%)23 (27.1)20 (25.3)43 (26.2) Citation Format: Veronica Mariotti, Shou-Ching Tang, Patrick Dillon, Alberto Montero, Andrew Poklepovic, Susan Melin, Ibrahim Nuhad, Petros Nikolinakos, Eugene Kennedy, Hyo Han, Roohi Ismail-Khan, Daniel Bruetman, Oana Danciu, Paul Gilman, Boguslawa Karaszewska, Krzysztof Lesniewski-Kmak, Timothy Panella, Dhimant Patel, Malgorzata Suszko-Kazarnowicz, Fabio Volterra, Hatem Soliman. Results of a phase II double-blinded, randomized, placebo-controlled clinical trial of Indoximod, an Indoleamine-2,3-dioxygenase 1 (IDO1) inhibitor, in combination with Taxane chemotherapy in metastatic breast cancer (MBC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr PD1-04.

P3.01-116 Randomized Clinical Trial on Three Different Platinum Based Chemotherapy in Advanced NSCLC in Bangladeshi Population

Lung cancer constitutes the major mortality in the world and incidence of the disease varies considerably among different ethnic population throughout the world. Palliative chemotherapy has been a choice in advance Non-Small Cell Lung Cancer (NSCLC) due to better result. The primary objective of the study was to evaluate the response and toxicity of three different platinum based regimens in Bangladeshi people. This Randomized Clinical Trial (RCT) was carried out in the Department of Medical Oncology at National Institute of Cancer Research and Hospital (NICRH), Mohakhali, Dhaka. Patients were enrolled from January 2012 for one year. Total 90 patients with above 18 years of age, both sexes presented with histologically confirmed stage IIIA, IIIB and IV NSCLC were enrolled and randomized (1:1:1) in to three arms. Cumulatively 26 patients were lost to follow up. Chemotherapy was given in 21 days interval (4-6 cycles). Toxicities were measured on Day 1, 7, 21, 28, 42, 3 months and on 6 months. Median follow up period was 6 months. Survival data was estimated by Kaplan-Meier method. Significant G-1/2 Hb% was found in Day7 in TP (16.67%) and EP (10.52%) arm and in 6 months EP (31.58%) and TP (29.17%). WBC G-1/2 toxicity was found in EP (31.58%) and TP (20.83%) arm at 6 months. Similarly, in case of neutropenia and thrombocytopenia, GP arm was found to be significantly less toxic than TP and EP arm at 6 months. Response rate and survival data are provided in table 1. In locally advanced or metastatic NSCLC response rate of platinum based combination therapy was satisfactory with increased survival than other reference trials along with lower G1/2 toxicity in GP arm followed by TP and EP in Bangladeshi Ethnic population.

Positive Effects of Tomato Paste on Vascular Function After a Fat Meal in Male Healthy Subjects.

Tomato consumption has been recently associated with a reduced incidence of cardiovascular disease (CVD). The aim of this study was to test whether a seven-day period of tomato paste purèe (tomato paste, TP) supplementation could improve some haemodynamic parameters in healthy volunteers before and after a standardized fat meal (FM). Methods and results: Nineteen healthy male volunteers participated in a randomized, single-blind (operator) crossover study. Participants maintained low fiber diets (LFD) during the study periods. They were randomized either to a LFD and TP arm (80 g of TP/day) for seven-days, or to a control arm (LFD-only) with a two-week washout period. Flow Mediated Dilatation and other morpho-functional vascular indices were measured by ultrasound. Stiffness Index and Reflection Index were estimated by digital photo-plethysmography. All these parameters were measured one h before and two and 3.5 h after the FM. The difference in Stiffness Index was increased in the LFD and TP + FM-arm, as compared to the LFD-only + FM arm at both two and 3.5 h points. After the FM, in both arms, at two h, we observed a reduction in the Reflection Index and an increase in heart rate. Interestingly, only in the LFD and TP + FM-arm, some haemodynamic changes were detectable at two h; notably, there was an increase in brachial artery diameter and a reduction in diastolic blood pressure (BP). Conclusions: TP has no effect on Flow Mediated Dilatation but acutely modifies some haemodynamic parameters triggered by FM, suggesting possible haemodynamic beneficial effects in people consuming tomatoes.

Abstract PD3-09: Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study

Abstract Introduction: Pertuzumab (P) is approved as first line therapy for HER2-positive (HER2+) metastatic breast cancer (MBC) combined with trastuzumab (T) and docetaxel. However older patients are at higher risk of chemotherapy-induced toxicity raising high interest in a less toxic backbone such as metronomic chemotherapy and in chemo-free dual HER2 blockade (TP). Patients and Methods: This phase II selection study randomized (1:1) patients with HER2+ MBC, aged 70+ or frail 60+, to first line chemotherapy with metronomic oral cyclophosphamide 50 mg/day + TP (TPM) or TP alone. Prior endocrine therapy and up to 1 line of anti-HER2 therapy (without chemotherapy) for MBC were allowed.T-DM1 was offered in case of progression. Randomization was stratified according to hormonal receptors, previous anti-HER2 treatment and geriatric assessment. Primary endpoint was progression-free survival (PFS) rate at 6 months seeking a difference of ≥ 10% between the two arms. Results: Between July 2013 and May 2016, 39 and 41 patients were randomized to TP and TPM arm respectively: median age 76.7 years, hormone receptor positivity 69%, prior adjuvant T 11%, prior metastatic T (with endocrine therapy) 3%, visceral involvement 93.7%, potential frailty profile according to geriatric screening G8 (≤14) 71% and/or to short physical performance battery (&amp;lt;10) 81%, Charlson comorbidity score &amp;gt; 0 in 40%. With 20.7 months of median follow-up, 6-month and median PFS were 46.2% (95% CI 30.2-60.7) and 5.6 months (95% CI 3.6-16.8) versus 73.4% (95% CI 56.6-84.6) and 12.7 months (95% CI 6.7-24.8) for TP and TPM, respectively. Four patients in TPM and 2 in TP developed brain metastases only as progression event. OS and breast cancer specific survival were comparable between the two arms; 9/29 deaths were not breast cancer-related. Response rate was 44% in TP arm and 53% in TPM arm. In 29 patients who received T-DM1 second line, 6-month PFS, median PFS and response rate were 49.5% (95% CI 29.2-66.9), 5 months (95% CI 2.5-12.5) and 13.5%. In patients who discontinued TP(M), 37, 9 and 14 stopped because of progression, toxicity or other reasons, respectively. During TPM treatment, 1 patient died of heart failure and 1 developed grade 3 heart failure; 1 patient in each arm developed a ≥ 10% asymptomatic left ventricular ejection fraction decrease below 50%. Diarrhea any grade and grade ≥ 3 were observed in 56% and 8% versus 71% and 12% patients in TP and TPM arms, respectively. No grade 3 or febrile neutropenia was reported. There was no relevant difference in functional evolution between both groups. In the whole population, several geriatric items were of prognostic value by multivariate analysis: e.g. for OS, G8 &amp;gt;14 vs ≤ 14 HR=0.12 (95% CI 0.03-0.55, p 0.006). In 29 patients receiving T-DM1, grade 3 toxicity was rare: fatigue (2 patients), thrombocytopenia and epistaxis (1 patient). Conclusions: Metronomic chemotherapy-based dual blockade (TPM) seems to be superior to dual blockade alone (TP) in an elderly/frail HER2+ MBC population, with an attractive safety profile. TPM, followed by T-DM1 after progression, may delay or supersede taxane chemotherapy in this population. Citation Format: Wildiers H, Tryfonidis K, dal Lago L, Vuylsteke P, Curigliano G, Waters S, Brouwers B, Aalders K, Meulemans B, Litiere S, Touati N, Cardoso F, Brain E. Pertuzumab and trastuzumab with or without metronomic chemotherapy for older patients with HER2- positive metastatic breast cancer: Results from the EORTC 75111- 10114 ETF/BCG randomized phase II study [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr PD3-09.

Role of induction chemotherapy in downstaging of locally advanced head-and-neck squamous cell cancer

Aims and Objectives: To study the effect of induction chemotherapy (CT) in locally advanced head-and-neck squamous cell carcinoma (LAHNSCC) and to compare the two commonly used regimens of CT, including paclitaxel and cisplatin (CDDP) in one arm and CDDP, methotrexate (MTX), and bleomycin in the other arm as induction CT. Materials and Methods: It is a retrospective study, including 100 histopathologically proven cases of LAHNSCC who received treatment at a government medical college and hospital in Central India between November 2015 and June 2016. All the patients were randomly divided into two arms: arm A received paclitaxel + cisplatin (TP) and arm B received cisplatin + MTX + bleomycin as induction CT had adequate hematologic, hepatic, and renal functions, and their response to treatment was evaluated clinically after each cycle up to three cycles before external beam radiotherapy. Results: The present study showed beneficial effects of induction CT in HNSCC as 82% of the patients showed response or T-downstaging. Among the patients responding to induction CT, 34% showed complete and 48% showed partial response at the primary tumor site according to Response Evaluation Criteria in Solid Tumors. The difference in response between the two arms was statistically significant (P = 0.037). Conclusion: The current study shows the beneficial effects of induction CT in LAHNSCC. No statistically significant difference was seen in the response of both regimens of induction CT in terms of overall survival, but significant disease-free survival and progression-free survival were obtained in the TP arm.

Induction chemotherapy in locoregionally advanced nasopharyngeal carcinoma in adults: Results from a nonendemic region

Recently published prospective clinical trials and two meta-analyses have shown that addition of induction chemotherapy (IC) to concurrent chemoradiation (CRT) could potentially improve outcomes in comparison to CRT alone, in locoregionally advanced nasopharyngeal carcinoma (LANPC). Although it remains unclear which is the best IC regimen to be offered and for how many cycles. Unfortunately, till date, there are no published data from India regarding the outcomes of various commonly used IC regimens before CRT, in LANPC. Patients diagnosed with LANPC from January 2012 to December 2017, who received three cycles of IC before definitive CRT were reviewed retrospectively. Patients' profile, toxicity of IC, response rates, failure-free survival, and overall survival (OS) were evaluated. A total 34 patients with LANPC who received IC were reviewed. The median age at diagnosis was 36 years, and the majority were males (67.6%, n = 23). Nineteen patients received IC with paclitaxel plus cisplatin regimen (TP) and the remaining 15 patients received IC with docetaxel/paclitaxel plus cisplatin plus 5-FU regimen (TPF). The overall response rates after three cycles of TP and TPF IC were 68.4% and 80%, respectively, and the corresponding rates were 84.2%and 93.3%, respectively, 2 months after completion of CRT. At a median follow-up of 24 months, 2-year failure-free survival and OS for TP arm were 78.9% and 89.5%, and the corresponding rates for TPF arm were 86.7% and 93.3%, respectively. All Grade III-IV toxicities were numerically higher with triplet IC regimen in comparison to doublet regimen. In this retrospective analysis, there was no significant difference between taxane-based doublet and triplet IC regimens, in terms of survival outcomes, although Grade III-IV toxicities were numerically higher with triplet IC regimen. Clearly, these hypothesis-generating findings should be tested in a prospective randomized setting.

Addition of 5-fluorouracil to docetaxel/cisplatin does not improve survival in locoregionally advanced nasopharyngeal carcinoma.

Addition of induction chemotherapy (IC) to concurrent chemoradiotherapy (CCRT) is a potentially effective approach for treating locoregionally advanced nasopharyngeal carcinoma (NPC). In this study, we compared the efficacy and toxicity of IC regimens consisting of docetaxel plus cisplatin with (TPF) or without (TP) 5-fluorouracil followed by CCRT in these patients. Clinical data from 245 propensity score-matched pairs of newly diagnosed non-metastatic NPC patients who received either TPF or TP IC before CCRT were retrospectively reviewed. After a median follow-up of 60 months, 5-year locoregional relapse-free, distant metastasis-free, progression-free, and overall survival rates were 95.6%, 94.7%, 90.4%, and 92.9% in TPF arm patients and 96.7%, 94.2%, 91.7%, and 91.0% in TP arm patients, respectively. There were thus no differences in survival between the two arms. Multivariate analysis revealed that IC regimen was not an independent prognostic factor for any of the survival outcomes. However, patients who received TP experienced lower incidences of grade 3/4 toxicities than those who received TPF. These results indicate that omission of 5-fluorouracil from TPF-based IC did not affect survival outcomes, but was associated with reduced toxicity, in patients with locoregionally advanced NPC.

Abstract P1-09-04: Proliferation and p21 refine risk of relapse in residual disease after HER2-directed therapies

Abstract Background: Patients (pts) with residual disease (RD) after neoadjuvant therapy are at higher risk of relapse. We investigated whether biomarkers assessed at surgery in patients pts with RD in the NeoSphere study were informative for risk of distant event free survival (DEFS) Methods: In NeoSphere 417 HER2+ pts were randomized to neoadjuvant TD, TPD, TP or PD (T=trastuzumab, P=pertuzumab, D=docetaxel), and received FAC/FEC and trastuzumab after surgery. 296 pts had RD. Affymetrix derived gene expression profiles (GEPs) were available at surgery for 201 pts (67.9%). 176 pts (60.1%) had paired samples before and after treatment with available GEPs. We investigated the prognostic value of proliferation evaluated by Mitosis Kinase Score (MKS) (Bianchini G Cancer Res 2010), and performed a gene discovery for association between gene expression at surgery and DEFS. Results: MKS as continuous marker was associated with significantly higher risk of relapse when assessed at surgery (HR 1.80 [1.23-2.65]; p=0.002), but not before treatment (HR 1.50 [0.80-2.78]; p=0.20). In paired samples, there was an average decrease (p=9.2E-11) of MKS after treatment, which was prominent in ER+ and chemotherapy-containing arms. In ER- and TP arm there were cases of increase and of decrease of MKS. In ER+ the 5 years DEFS was 94.3% in the Low/Int MKS tertiles group (pooled) vs 70.5% in the High MKS tertile group (HR 5.41 [1.87-15.6]; p=0.002). In ER-, the 5 years DEFS was 85.0% in the Low/Int vs 64.1% in the High group (HR 2.89 [1.08-7.76]; p=0.035). Notably, MKS at surgery after the two monoclonal alone was also prognostic. In the gene discovery approach only the expression of CDKN1A (p21)at surgery was associated with DEFS after correction for false discovery rate (FDR=0.01). Pre-treatment p21 was not associated with DEFS. Paired comparison showed significant upregulation of p21 in all patients, treatment arms and ER groups. The Int/High p21 tertiles group (pooled) had lower risk of recurrence than the low tertile in ER+ (HR 4.31 [1.60-11.6]; p=0.004) and in ER- (HR 5.81 [1.87-18.1]; p=0.002) groups. p21 in TP arm was also prognostic. MKS and p21 expression provided independent prognostic information and remained significant after correction for clinico-pathological variables (nodes and T stage) and tumor-infiltrating lymphocytes. Combining the two markers, there was a group at very low risk (Low/Int MKS and Int/High p21) and one at high risk (High MKS and Low p21). The other tertiles combinations had intermediate risk. In ER+, the 5 yrs DEFS was 94.9% in the low risk group and 52.9% in the high risk (p=1.9E-05). In ER-, the 5 yrs DEFS was 96.5% in the low and 45.5% in the high risk group (p=0.001).The markers' combination was also prognostic in the two monoclonal only arm. Conclusions: Proliferation (MKS) and p21 expression are modulated by trastuzumab and/or pertuzumab regimens. Tumors with high MKS and low p21 in RD after neoadjuvant therapy defined a group at very high risk of relapse. Tumors with low/int proliferation and int/high p21 had low risk of recurrence similar to that of patients achieving pCR. Whether the pharmacodynamic modulation of p21 could be used as surrogate marker of long term benefit in patients with RD deserves additional investigation. Citation Format: Bianchini G, Pienkowski T, Im Y-H, Bianchi GV, Tseng L-M, Liu M-C, Lluch A, de la Haba-Rodríguez J, Semiglazov V, Oh D-Y, Poirier B, Pedrini JL, Valagussa P, Gianni L. Proliferation and p21 refine risk of relapse in residual disease after HER2-directed therapies [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P1-09-04.

O3-020 - A Randomized Phase III Trial of Paclitaxel Plus Carboplatin (TC) Versus Paclitaxel Plus Cisplatin (TP) in Stage IVB or Recurrent Cervical Cancer: Japan Clinical Oncology Group Study (JCOG0505)

ABSTRACT Background TC is a less toxic regimen in terms of milder nephropathy, neuropathy and no need of hospitalization. This phase III trial was designed to evaluate the clinical benefits of TC compared with TP which is the current standard chemotherapy for stage IVB or recurrent cervical cancer. Methods Patients with stage IVB or recurrent cervical cancer—not amenable to curative therapy; 0-1 prior platinum; no prior taxanes—were randomized with the minimization method to either TP (T 135 mg/m2 24h d1 + P 50 mg/m2 2h d2) or TC (T 175 mg/m2 3h d1 + C AUC5 1h d1), both for maximum six cycles every 21 days. Primary end point was overall survival (OS). Secondary end points were progression-free survival (PFS), toxic effects, and the proportion of non-hospitalization periods (NHP) as a surrogate for QoL. The planned sample size was 250 patients with one-sided a = 5% and at least 70% power to confirm the non-inferiority of TC to TP (threshold hazard ratio [HR] 1.29) in terms of OS. HR is estimated by a stratified Cox regression. Results From February 2006 to November 2009, 253 patients were enrolled. The median follow-up is 17.4 months. 71% of patients of the TP arm and TC arm each received six cycles. Results are as follows: as an alevel for an interim analysis was Conclusions This first randomized, controlled trial comparing carboplatin doublet with cisplatin doublet showed significant non-inferiority of TC in terms of OS. More feasible and less toxic TC can be recommended as the new standard treatment of stage IVB or recurrent cervical cancer. TP TCOS (median) 18.3 months, 17.5 months, HR 0.99 (multiplicity adjusted 90% CI: 0.79–1.25); non-inferiority P = 0.032 PFS (median) HR 1.04 (95% CI: 0.80–1.35) 6.90 months 6.21 months neutropenia G3–4 85.1% 76.4% thrombocytopenia G3–4 3.3% 23.6% febrile neutropenia G3–4 16.0% 7.3% creatinine G2–4 9.8% 4.1% neuropathy (motor) G3–4 0.8% 2.4% neuropathy (sensory) G3–4 0% 4.9% NHP (P

A randomized, phase III trial of paclitaxel plus carboplatin (TC) versus paclitaxel plus cisplatin (TP) in stage IVb, persistent or recurrent cervical cancer: Japan Clinical Oncology Group study (JCOG0505).

5006 Background: TC is a less toxic regimen in terms of milder nephropathy, neuropathy and no need of hospitalization. This multicenter phase III trial was designed to evaluate the clinical benefits of TC compared with TP which is current standard chemotherapy for stage IVB or recurrent cervical cancer. Methods: Patients (pts) with stage IVB or recurrent cervical cancer; not amenable to curative therapy; 0-1 prior platinum; no prior taxanes; were randomized with minimization method to either TP (T 135 mg/m2 24h d1 + P 50 mg/m2 2h d2) or TC (T 175 mg/m2 3h d1 + C AUC5 1h d1), both for maximum 6 cycles every 21 days. Primary endpoint was overall survival (OS). Secondary endpoints were progression-free survival (PFS), toxicities, and the proportion of non-hospitalization periods (NHP) as a surrogate for QoL. The trial was powered at least 70% to confirm the non-inferiority of TC to TP (threshold hazard ratio [HR] 1.29) in terms of OS, and the planned sample size was 250 pts with one-sided alpha 5%. HR is estimated by a stratified Cox regression. Results: From 2/06 to 11/09, 253 pts were enrolled. 71% pts of TP arm and TC arm each received 6 cycles. Median follow-up is 17.4 mo. Results are as below. As an alpha level for an interim analysis was less than 0.0001, significance level for the final analysis is approximately 5% even after the multiplicity adjustment. Conclusions: This first randomized controlled trial comparing carboplatin doublet with cisplatin doublet showed significant non-inferiority of TC in terms of OS. More feasible and less toxic TC can be recommended as the new standard treatment for stage IVB or recurrent cervical cancer. [Table: see text]

A randomized trial of liposomal paclitaxel plus cisplatin as first-line therapy for advanced non-small cell lung cancer

背景与目的紫杉醇联合顺铂方案（pacilitaxel plus cisplatin, TP）是目前一线治疗晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的标准方案之一。本研究旨在比较紫杉醇脂质体联合顺铂（liposome pacilitaxel plus cisplatin, LP）方案与TP方案一线治疗晚期NSCLC的近期疗效、远期生存及毒副反应。方法100例患者随机分为两组，分别静脉注射紫杉醇脂质体和紫杉醇注射液150 mg/m2，第1天，联合顺铂75mg/m2，第1天-2天，21天一个周期。结果100例患者均可评价疗效，其中LP组中位无进展生存期（progression free survival, PFS）为5.1个月，中位总生存期（overall survival, OS）为9.0个月，客观反应率（response rate, RR）为26%；TP组中位PFS为4.2个月，中位OS为9.3个月，RR为24%；两组比较均无统计学差异（P=0.110; P=0.342; P=0.890）。两组Ⅲ度+Ⅳ度毒性反应均无统计学差异（P > 0.05），LP组末梢神经炎发生率低于TP组（8% vs 28%, P=0.030）。结论LP方案一线治疗晚期NSCLC疗效与TP方案相当，末梢神经炎发生率低于TP方案。