Carboplatin-paclitaxel Arm Research Articles

Trimodality therapy with carboplatin/paclitaxel (CP) or FOLFOX (FFX) for esophageal/esogastric junctional cancer (EC/EGJ): Expanded safety and efficacy data from PROTECT.

370 Background: When combined to preoperative radiation therapy (RT), CP and FFX regimen provide both high complete resection (R0) rate for EC/EGJ cancer (Adenis, ASCO 2022). However, it appeared that neoadjuvant chemoradiation (nCRT) with CP is associated with a severe postoperative morbidity rate higher than expected. We present here the expanded safety and efficacy analyses from the PROTECT trial. Methods: PROTECT is a randomized, phase 2 trial which included stage II/III and ECOG PS ≤2 EC or Siewert I-II EGJ cancers. Patients (pts) received FFX or CP with concurrent RT (41.4Gy, 1.8Gy, 23 fractions), followed by surgery 4-8 weeks after completion of nCRT (Messager, BMC Cancer 2016). Co-primary endpoints were proportion of R0 rate and proportion of Clavien-Dindo severe postoperative morbidity. Main secondary endpoints were nCRT and postoperative safety (NCI CTCAE v.4), DFS and OS. Results: 41/50 (82%) and 39/50 (78 %) pts received the planned chemo cycles and concurrent RT in FFX and CP arms, respectively. Grade (gr.) 3–4 AEs related to nCRT (FFX 14/50, 28%; CP 14/50, 28%) occurring in ≥5% of pts included lymphopenia (n=3, 6%; n=4, 8%), neutropenia (n=1, 2%; n=3, 6%), fatigue (n=2, 4%; n=0) and esophagitis-related to RT (n=1, 2%; n=1, 2%). No death was reported during nCRT. Surgery (FFX and CP; mini invasive: 15 and 15, hybrid: 22 and 21, open: 7 and 12) was performed in 44 and 48 pts, in FFX and CP groups, respectively. The main gr. III-V surgical complications (Clavien-Dindo scale) occurring in ≥5% of pts included esophageal fistula (n=2/43 evaluable pts, 6%; 8/48, 17%), conduit necrosis (n=2, 5%; n=1, 2%), ARDS (n=3, 7%; n=3, 6%), pleural effusion (n=3, 7%; n=4, 8%), and haemorrhage (n=0; n=3, 6%). There were no postoperative deaths. With a median follow-up of 54m, median DFS were 12.3m and 20m (HR=0.84; 95%CI: 0.52-1.35; p=0.48) and median OS were 31.7m and 45.8m (HR=0.79; 95%CI: 0.47-1.32; p=0.36) in FFX and CP arms, respectively. Prognostic factors significantly associated to DFS in univariate analysis were: R0 resection, TRG1-2 and ypT0N0 status. Conclusions: A higher than expected number of severe esophageal fistula was observed in the CP arm. We could not demonstrate a significant benefit of CP compared to FFX in terms of survival outcomes, but the study was not primarily designed to specifically address this issue. Clinical trial information: NCT02359968 .

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

PFS by blinded independent central review (BICR) in the VELIA trial of veliparib (V) plus carboplatin/paclitaxel (CP) and as monotherapy in newly diagnosed patients (pts) with high-grade serous ovarian cancer (HGSC).

6077 Background: The phase III VELIA trial (NCT02470585) demonstrated statistically significant improvement in PFS per investigator (INV) for V added to CP and continued as maintenance (CPV-V) vs. CP alone in pts with newly diagnosed HGSC in the BRCA mutated ( BRCAm), homologous recombination deficient (HRD), and whole populations. Here we present pre-specified analyses of PFS per BICR. Methods: Pts with Stage III-IV HGSC received V or Placebo (PL) with CP (6 cycles) and as maintenance (30 additional cycles). Primary analysis of PFS by INV compared CPV-V to CP alone in the BRCAm, HRD, and whole populations. Exploratory analyses of PFS in BRCA wildtype (wt) and non-HRD HGSC were performed. Radiologic tumor assessments were also prospectively submitted to an independent central reviewer for blinded assessment per RECIST v 1.1. PFS per BICR and rates of concordance between INV and BICR for determination of disease progression were analyzed. Safety data from the primary analysis were previously reported. Results: 1140 total pts were enrolled (CPV-V 382; CP 375). In the whole population, 26% of HGSCs were BRCAm and 55% were HRD. Concordance rates between INV and BICR were 68-85% by arm for each population. Analyses of PFS per BICR and per INV were consistent (Table). PFS was prolonged in the CPV-V vs. CP arm in all primary and exploratory populations assessed. Conclusions: Analyses of PFS per BICR supported the primary analysis of PFS per INV in the BRCAm, HRD, and whole populations, as well as exploratory BRCAwt and non-HRD populations. Median PFS per BICR was longer compared to PFS per INV assessments in all populations and in both arms. These findings support the reliability of PFS by INV in ovarian cancer trials. Alternate strategies like audits may be appropriate to support PFS by INV with less time and expense than full BICR. Clinical trial information: NCT02470585. [Table: see text]

Veliparib (V) monotherapy after progression on placebo (PL) + carboplatin/paclitaxel (CP) in patients with advanced HER2-negative gBRCA-associated breast cancer: Crossover outcomes and exploratory biomarker analyses in BROCADE3.

1097 Background: In BROCADE3 (NCT02163694), addition of the PARP inhibitor (PARPi) V to CP improved PFS in patients (pts) with g BRCA-associated advanced breast cancer (hazard ratio 0.71 [95% CI 0.57–0.88], p = 0.002). Reversion mutations may account for resistance to platinum-based CT and PARPi. Efficacy, safety, and exploratory biomarker analyses for pts randomized to PL + CP who received crossover (Cx) V monotherapy after progression are reported. Methods: 513 total pts were randomized 2:1 to V + CP or PL + CP. V/PL, C, and P could be discontinued independently prior to progression, leading to varying platinum-free intervals at the time of progression. After progression, pts in the PL + CP arm could receive open-label Cx V monotherapy (300–400 mg BID continuous), beginning within 60 d of progression and continuing to second progression. Adverse events (AEs) and activity during Cx V were assessed. Exploratory analysis of BRCA reversion mutations restoring BRCA1/2 protein function that emerged during PL + CP treatment was performed on plasma circulating tumor DNA using targeted-amplicon next generation sequencing. Results: At data cutoff, 75 pts initially randomized to PL + CP had ≥1 dose of Cx V. Mean (range) duration of Cx V was 154 d (2–966). Activity during Cx V is in the Table. Mean (range) platinum-free interval at time of first dose of Cx V was 3.1 mos (0.4–10.9) vs 8.1 mos (1.0–34.9) in pts who had progressed vs had not progressed by 24 wks after first dose of Cx V. BRCA reversion analysis was completed for 18 Cx pts. Reversion mutations were identified in 1/18 pts (5.6%). This patient had Cx V duration of 19 d and had progressed by 24 wks. BRCA reversion analysis on additional Cx pts will be presented. Most common AEs during Cx V were nausea (61%), vomiting (29%), fatigue (24%), and diarrhea (21%). Any grade anemia, neutropenia, and thrombocytopenia occurred in 7%, 15%, and 7% of pts. Three pts (4%) experienced a convulsion event. Conclusions: Platinum-free interval may influence efficacy of subsequent PARPi. Impact of BRCA reversion mutations warrants further evaluation. Cross-resistance may limit PARPi efficacy after platinum failure. Clinical trial information: NCT02163694 . [Table: see text]

Efficacy and safety of concurrent chemoradiotherapy in ECOG 2 patients with locally advanced non-small-cell lung cancer: a subgroup analysis of a randomized phase III trial

BackgroundThere is no consensus on the therapeutic approach to ECOG 2 patients with locally advanced non-small-cell lung cancer (LA-NSCLC), despite the sizable percentage of these patients in clinical practice. This study focused on the efficacy, toxicity and the optimal chemotherapy regimen of CCRT in ECOG 2 patients in a phase III trial.MethodsPatients capable of all self-care with bed rest for less than 50% of daytime were classified as ECOG 2 subgroup. A subgroup analysis was performed for ECOG 2 patients recruited in the phase III trial receiving concurrent EP (etoposide + cisplatin)/PC (paclitaxel + carboplatin) chemotherapy with intensity-modulated radiation therapy (IMRT) or three-dimensional conformal external beam radiation therapy (3D-CRT).ResultsA total of 71 ECOG 2 patients were enrolled into the study. Forty-six (64.8%) patients were treated with IMRT technique. The median overall survival (OS) and progression free survival (PFS) for ECOG 2 patients were 16.4 months and 9 months, respectively. No difference was observed in treatment compliance and toxicities between ECOG 2 patients and ECOG 0–1 patients. Within the ECOG 2 group (31 in the EP arm and 40 in the PC arm), median OS and 3-year OS were 15.7 months and 37.5% for the EP arm, and 16.8 months and 7.5% for the PC arm, respectively (p = 0.243). The incidence of grade ≥ 3 radiation pneumonitis was higher in the PC arm (17.5% vs. 0.0%, p = 0.014) with 5 radiation pneumonitis related deaths, while the incidence of grade 3 esophagitis was numerically higher in the EP arm (25.8% vs. 10.0%, p = 0.078).ConclusionsCCRT provided ECOG 2 patients promising outcome with acceptable toxicities. EP might be superior to PC in terms of safety profile in the setting of CCRT for ECOG 2 patients. Prospective randomized studies based on IMRT technique are warranted to validate our findings.Trial registrationClinicalTrials.gov registration number: NCT01494558. (Registered 19 December 2011).

Comparison of clinico-pathological characteristics and survival of recurrent ovarian cancer patients on seven different chemo-protocols.

Despite growing prevalence of ovarian cancer (OC) in Pakistan, no literature evidence exists regarding its clinic-pathological characteristics, survival and compliance of patients with recurrent ovarian cancer on various chemo-protocols. An observational study was conducted by enrolling 251 recurrent OC patients on 7 different chemo-protocols, from a specialized cancer care hospital, Lahore, Pakistan, using convenient judgmental sampling. The study was conducted for a period of 6 months. Most of the patients were between 18 and 70 years of age, with IIIC FIGO stage and papillary serous histological grade. As per RECIST, improved partial response (PR) (63.3 %) and complete response (CR) (52.1 %) was observed in the CP (carboplatin + paclitaxel) arm, substantiated by improved median progression free survival (PFS) and overall survival (OS) in CP and CD (carboplatin + docetaxel) arms, respectively, yet with no significant differences in survival curves, PFS (p = 0.12) and OS (p = 0.22). Interestingly, the highest and the lowest patient non-compliance were observed in CG (carboplatin + gemcitabine) (81.6 %) and paclitaxel (4.5 %) arms, resp. As per the hazard model for survival, topotecan showed significant association with the therapy related events/deaths compared to other protocols. These data suggest that CP regimen exhibited improved clinical efficacy and decreased toxicity related non-compliance in recurrent ovarian cancer patients of Lahore.

Abstract OT3-06-04: A randomized phase II study of neoadjuvant panitumumab /carboplatin/paclitaxel (PaCT) versus carboplatin/paclitaxel (CT) followed by adriamycin and cyclophosphamide (AC) for newly diagnosed primary triple-negative inflammatory breast cancer (TNIBC)

Abstract Primary Objective: To determine pathological complete response (pCR) rate in patients with primary TNIBC treated with PaCT in comparison with CT, followed by AC. To explore if the pCR rate correlates with reduced nodal expression status; and with arginine methylation status of epidermal growth factor receptor (EGFR). We will identify molecular biomarkers predictive of the pCR rate by analysis of multiplexed immunohistochemical (IHC) staining, identify molecular biomarkers predictive of the pCR rate by genomic and proteomic analysis, and determine whether the inhibition of the EGFR pathway down regulates the COX-2 pathway and mesenchymal marker. Background: EGFR is overexpressed in triple negative breast cancer (TNBC) and inflammatory breast cancer (IBC). Therefore, EGFR targeted therapy may have a promising role in TNBC and IBC. A study showed that EGFR-targeted therapy may enhance the initial chemosensitivity of TNBC cells. Panitumumab blocks epidermal growth factor ligands and transforming growth factor EGFá (TGFá) binding to EGFR, inhibits tumor growth, and elicits both tumor regression and eradication of established tumors in murine xenograft tumor models. Panitumumab, a fully humanized anti-EGFR antibody, has been shown to be active in a breast cancer preclinical model using human breast cancer cell line MDA-MB-468, which has been shown to overexpress EGFR by both IHC and fluorescence in situ hybridization (FISH). Furthermore, EGFR tyrosine kinase inhibitors such as erlotinib have antitumor activity against human IBC cell lines. Thus, EGFR targeted therapy may have a promising role in TNBC and IBC. Study Design: In this open label randomized phase II trial, up to 72 patients with primary IBC, have no HER2 overexpression, and have <10% expression of ER and PgR, who also meet other criteria will be randomized to PaCT arm - receiving panitumumab single agent in window study and 4 cycles PaCT, or CT arm - receiving 4 cycles of CT. All patients will receive 4 cycles of AC before surgery. Statistical Considerations: A sample size of 36 patients per arm will achieve 84% power to detect a difference of 0.24 in pCR rate between 0.2 in the CT arm and 0.44 in the PaCT arm with a type I error rate of 10% using one-sided Z test. Based on historical data, we expect that the pCR rate of a PaCT regimen to achieve 24% additional efficacy compared with the CT regimen. Status of the study: Activation date: Oct. 2016. So far 6 patients have been enrolled. Enrollment continues. Sponsor: Amgen. State of Texas appropriation for rare and aggressive breast cancer research. NIH grant 1R01CA205043-01A1 Citation Format: Willey JS, Parker CA, Lim B, Valero V, Le-Petross HT, Krishnamurthy S, Woodward WA, Lucci A, Wood AL, Sun H, Babiera GV, Song J, Shen Y, Valero V, Wang X, Ueno NT. A randomized phase II study of neoadjuvant panitumumab /carboplatin/paclitaxel (PaCT) versus carboplatin/paclitaxel (CT) followed by adriamycin and cyclophosphamide (AC) for newly diagnosed primary triple-negative inflammatory breast cancer (TNIBC) [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 OT3-06-04.

Retrospective analysis of neoadjuvant chemoradiotherapy with carboplatin/ paclitaxel versus FOLFOX in newly diagnosed esophageal or junctional cancers: A single instituition experience.

168 Background: The retrospective study aimed to evaluate carboplatin / paclitaxel (CP) versus FOLFOX in the neoadjuvant combined modality setting for newly diagnosed esophageal or junctional cancers. Methods: Patients with esophageal or junctional cancers treated in combined modality setting were included. During the study period, there were seventy three patients who had T2-4N0-1M0 esophageal and junctional carcinomas. Results: 49 (67%) patients received CP and 24 (33%) patients received FOLFOX. Concurrent radiation was delivered 5400-cGy in CP arm and 5040-cGy in FOLFOX arm. 38 (78%) patients in CP arm and 19 ( 79 %) in FOLFOX arm underwent curative resection. In CP arm, 11(12%) did not undergo curative resection due to disease progression (5/11), death secondary to infection (2/11) and poor functional status post chemotherapy (4/11). In FOLFOX arm, 5(21%) patients did not have surgery due to progressive disease (3/ 5), sepsis ( 1/ 5) and Tracheo–esophageal fistula ( 1 / 5). In patients who underwent curative resection, overall response rate (RR) was 92% in the CP arm with *CR–10(26%), PR–25 (66%), NR–3 (8%); in FOLFOX arm, RR was 100 % with *CR–6(32 %), PR–13(68 %), NR- 0 (p = 0.06). Median follow-up in all patients was 22 months, with median overall survival (OS) for the CP group 20-months and the FOLFOX group 30.5-months.With curative resection the median OS was 23-months in CP arm and 41-months in FOLFOX arm. Median relapse free survival (RFS) was 9.5-months in CP arm and 11 months in FOLFOX arm. 45% relapsed in the CP arm and 42% relapsed in the FOLFOX arm after curative resection. Conclusions: With CROSS trial in esophageal and juntional cancers, there has been a paradigm shift away from infusional 5-FU based regimens (5FU/cisplatin and FOLFOX). With this study, we demonstrated the activity of FOLFOX in comparison to CP in the neoadjuvant setting with concurrent radiotherapy in the treatment of localized esophageal cancers. There was a trend in clinical efficacy and response rate towards FOLFOX when combined with curative resection. To definitively assess this and compare the efficacy, long term prospective studies are needed.

Combining two different chemotherapy agents with platinum analogs as induction and consolidation regimes in nonsmall cell lung carcinoma

Background: There are limited data pertaining to the combined use of induction and consolidation chemotherapy with concurrent chemo-radiotherapy (RT) for treating nonsmall cell lung carcinoma (NSCLC). To find out an optimum/effective regime for treating NSCLC utilizing both induction and consolidation approach with concurrent chemo-RT is the primary aim of this study. Materials and Methods: We retrospectively analyzed 132 patients with NSCLC. Fifty-four patients treated with paclitaxel-carboplatin and 78 with gemcitabine-cisplatin combinations in induction and consolidation phases. Concurrent chemo-RT included 60-66 Gray (Gy) of RT with weekly cisplatin and was similar in both the arms. Results: After completion of the consolidation phase, we observed on overall response rate (ORR) of 42.7% in the paclitaxel-carboplatin arm and 42.3% in gemcitabine-cisplatin arm with 2 and 3 years’ survival rates of 32% and 19% with paclitaxel-carboplatin and 38% and 24% with gemcitabine-cisplatin regimes. We also observed higher ORR for squamous cell histology treated with the gemcitabine-cisplatin combination. Conclusion: Although both paclitaxel-carboplatin and gemcitabine-cisplatin combinations are equally effective in treating NSCLC, gemcitabine-cisplatin provided slightly better response rates but with clinically more frequent and relevant toxicities. © 2017 Journal of Medical Sciences.

Abstract C122: A randomized, multicenter, open-label, phase 2 study of paclitaxel-carboplatin (PC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus PC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC)

Abstract Background: Necitumumab (N) is a 2nd-generation human IgG1 anti-EGFR monoclonal antibody. In a phase 3 trial (SQUIRE) conducted in the first-line setting, N combined with gemcitabine plus cisplatin improved overall survival (OS) in pts with sq-NSCLC compared with chemotherapy alone. PC, another standard of care was selected for this exploratory phase 2 study. Materials and Methods: Pts with stage IV sq-NSCLC, stratified by ECOG PS (0 vs. 1) and sex (females vs. males) were randomized 2:1and received either PC (P = 200 mg/m2 iv, day 1; C = AUC 6 iv, day 1) plus N (800 mg iv, days 1 and 8) (PC+N arm), or PC alone (PC arm) every 21 days for up to 6 cycles. PC+N pts with a response of stable disease or better continued on N alone until progressive disease or intolerable toxicity. Rash prophylaxis was permitted from the beginning of the trial. The primary endpoint was objective response rate (ORR) based on RECIST 1.1. Secondary endpoints included progression-free survival (PFS), OS, and safety. Sample size and randomization allowed for a 95% confidence interval estimate of ORR for Arm PC+N with a width ≤ 20 percentage points. Final analysis was performed after a minimum of 98 OS events had been observed. No formal hypothesis testing was planned; the study was not powered to show a statistically significant effect for PFS or OS. Results: 167 pts were randomized (n = 110, PC+N; n = 57, PC). Baseline characteristics were balanced between PC+N and PC, respectively, including males (79% and 77%), ECOG PS 0 (16% and 19%), and PS 1 (85% and 81%). Exposure to chemotherapy was similar in both arms; median dose intensity (DI) for P was 98% vs 95% (PC+N vs PC), and DI for C was 100% vs 95%, respectively, and DI for N was 96%. 53% of PC+N pts continued N alone for a median of 4 additional cycles (range 2.0-7.5). The addition of N to PC resulted in an ORR of 48.9% vs 40.0%. Disease control rate was 87.2% vs 84.0% in PC. PFS HR was 1.0 (mPFS 5.4 vs 5.6 months). Median OS was 13.2 vs 11.2 months (HR = 0.83, p = 0.379). There was a higher rate of events for the PC+N arm during the first 4 months, with a later trend toward improved survival after 4 months. Most frequently reported SAEs were pneumonia (12.3% vs. 5.5%) and febrile neutropenia (5.7% vs. 3.6%). Grade ≥3 AEs typically associated with EGFR mAbs that showed a >2% increase were hypomagnesemia (5.7% vs 0) and rash (2.8% vs 0). Any grade venous thromboembolic events occurred in 3.8% of patients in the PC+N group vs 3.6% of patients in the PC group. Infusion related reactions of any grade occurred in 3.8% of patients in the PC+N group vs 9.1% in the PC group. Conclusions: The addition of N to PC resulted in an increased ORR compared to PC alone, indicating an add-on effect. The lower incidence of grade 3 rash observed here (2.8%) versus SQUIRE (7%) may be due to the permission of first cycle rash prophylaxis (SQUIRE no rash prophylaxis permitted prior to cycle 2). The safety profile in this study is consistent with the expected safety profile of an EGFR mAb administered in this combination in the sq-NSCLC population. Clinical trial information: NCT01769391. Citation Format: David Spigel, Alexander Luft, Rodryg Ramlau, Mazen Khalil, Joo-Hang Kim, Carlos Mayo, Henrik Depenbrock, Grace Chao, Coleman Obasaju, Ronald Natale. A randomized, multicenter, open-label, phase 2 study of paclitaxel-carboplatin (PC) chemotherapy plus necitumumab (IMC-11F8/LY3012211) versus PC alone in the first-line treatment of patients (pts) with stage IV squamous non-small cell lung cancer (sq-NSCLC). [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C122.

Carboplatin and pegylated liposomal doxorubicin versus carboplatin and paclitaxel in very platinum-sensitive ovarian cancer patients: Results from a subset analysis of the CALYPSO phase III trial

AimTo perform a subset analysis of patients with very platinum-sensitive recurrent ovarian cancer (ROC) enrolled in the phase III CALYPSO trial. Patients and methodsThe international non-inferiority trial enrolled women with ROC that relapsed >6months following first- or second-line platinum- and paclitaxel-based therapies. Patients were randomised to CD [carboplatin–pegylated liposomal doxorubicin (PLD)] or CP (carboplatin–paclitaxel) and stratified by treatment-free interval (TFI). In this analysis, patients with a TFI>24months were analysed separately for progression free survival (PFS), the primary endpoint of CALYPSO, overall survival (OS) and safety. ResultsA total of 259 very platinum-sensitive patients were included (n=131, CD; n=128, CP). Median PFS was 12.0months for the CD arm and 12.3months for CP [HR=1.05 (95% CI, 0.79–1.40); P=0.73 for superiority] and median OS was 40.2months for CD and 43.9 for CP [HR=1.18 (95% CI 0.85–1.63); P=0.33 for superiority]. Overall response rates were 42% and 38%, respectively (P=0.46). Toxicities were more common with CP versus CD, including grade 3/4 neutropenia (40.8% versus 27.5%; P=0.025), nausea (4.8% versus 3.1%; P=0.47), allergic reaction (8% versus 3.1%; P=0.082) sensory neuropathy (4.8% versus 2.3%; P=0.27) and grade 2 alopecia (88% versus 9.2%; P<0.001). Grade 3/4 thrombocytopenia (12.2% versus 3.2%; P=0.007) and mucositis (2.3% versus 0%; P=0.089) were more common with CD. Grade 3/4 hand-foot syndrome occurred rarely with CD (3 patients versus 0 in CP arm; P=0.089). ConclusionCP and CD were equally effective treatment regimens for patients with very platinum-sensitive ROC. The favourable risk–benefit profile suggests carboplatin–PLD as treatment of choice for these patients.

A province-wide retrospective comparison of pathologic response and progression-free survival in locally advanced esophagus cancer patients treated with either cisplatin-5FU (CF) or carboplatin-paclitaxel (CP) concurrent with radiation (XRT) with or without surgery.

107 Background: The 2012 CROSS trial demonstrated an overall survival (OS) benefit for neoadjuvant, concurrent Carboplatin-Paclitaxel (CP) and radiation versus surgery alone. Based on this trial, the standard chemotherapy treatment for locally advanced esophageal (LAE) cancer in British Columbia (BC) became CP instead of Cisplatin-5FU (CF). This study evaluates the pCR rates and progression free survival (PFS) of those patients treated immediately prior and immediately after the change in provincial standard. Methods: All BC patients with LAE cancer diagnosed between February 2010 and February 2013 who completed at least 40 Gy of neoadjuvant radiation were analyzed. Standard demographics, chemotherapy delivered, radiation dose, surgical pathology and follow-up data were collected. Pathologic response was compared by chi-squared analysis. Patients were followed until death or last follow-up. Survival was compared by log-rank test. Results: Seventy-three patients received CF and 39 received CP. The tumor characteristics of the subgroups were similar: squamous histology was 57% (CF) vs. 49% (CP), node positivity rate on pre-treatment PET scan was 66 vs. 67%, and median tumor length was 5.7 vs. 5.8 cm. Median radiation dose was 50 Gy in both arms. The CP arm was slightly older (Median 66 vs. 61 yo) and had a greater percentage of males (80% vs. 57%). Forty eight and 49% percent of patients were able to undergo resection. The pCR rates were 49% (CF) vs. 16% (CP) (p&lt;0.01) in the surgical subgroups. Median FU was 14.5 (CF) vs. 9.3 (CP) months. Median PFS for all patients was 16.5 (CF) and 14.6 (CP) (p=0.44). Median PFS in surgical patients was 23.4 months (CF) and 14.6 months (CP) (p=0.16. Conclusions: In patients with similar tumor characteristics, XRT with CF resulted in greater pCR rates than with CP. The pCR rate in the CP subgroup is lower than the 29% seen in the trial. With relatively short follow-up, no difference in PFS has yet been identified. [Table: see text]

Abstract A77: Randomized phase II study comparing paclitaxel/carboplatin intercalated with gefitinib to paclitaxel/carboplatin alone for chemotherapy-naive non-small cell lung cancer patients either with history of smoking or with wild-type EGFR.

Abstract Background: There are preclinical and clinical reports of schedule-dependent synergism or antagonism when combining cytotoxic chemotherapy and EGFR inhibitor therapy in non-small cell lung cancer (NSCLC). While antagonism was associated with EGFR inhibitor-induced G1-phase blockade protecting tumor cells from chemotherapy cytotoxicity, appropriate scheduling of EGFR inhibitor with chemotherapy might produce additive or synergistic tumor growth inhibition. This randomized phase 2 study compared the efficacy of paclitaxel-carboplatin (PC) intercalated with gefitinib (G) versus PC alone, as a first-line treatment in a selected population of advanced NSCLC patients either with history of smoking or with wild-type EGFR. Methods: Eligible patients were chemotherapy-naive advanced NSCLC patients with good ECOG PS of 0 or 1. Non-smoking patients with adenocarcinoma or patients with activating EGFR mutation were excluded because they could benefit from gefitinib alone. Eligible patients were randomized to either one of the treatments; PCG arm, P 175 mg/m2 and C AUC 5 intravenously on day 1 intercalated with G 250 mg orally on days 2 through 15 every 3 weeks for four cycles followed by G 250 mg orally until progressive disease; or PC arm, P 175 mg/m2 and C AUC 5 on day 1 every 3 weeks for four cycles only without maintenance therapy. The primary endpoint was objective response rate (ORR), and the secondary endpoints included progression free survival (PFS), overall survival (OS) and toxicity profile. Results: A total of 90 patients (male 85.6%; median age, 59; adenocarcinoma 63%; smoker 90%; and wild-type EGFR 24%, unknown EGFR status 76%) participated into the study. The ORR was 40.9% (95% CI 27.3-56.8%) and 37.0% (95% CI 23.8-51.2%) for the two arms (p=0.701). There was also no difference in terms of PFS (the median PFS; PCG arm, 4.1 mo vs. PC arm 4.1 mo, HR=0.941 [95%CI: 0.61-1.45], p=0.781) and OS (the median OS; PCG arm 9.3 mo vs. PC arm10.5 mo, HR=0.95 [95% CI: 0.58-1.54], p=0.827). Safety analyses showed a similar incidence of drug-related grade 3/4 toxicity in PCG arm (20.9%) compared with in PC arm (23.3%). G1/2 rash and diarrhea was more frequent in PCG arm (58% vs.9% and 14% vs. 7%, respectively). Conclusion: Paclitaxel-carboplatin chemotherapy intercalated with gefitinib did not improved ORR, PFS, and OS compared to PC chemotherapy alone in this selected population of advanced NSCLC patients either with history of smoking or with wild-type EGFR. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):A77. Citation Format: Dae Ho Lee, Jeong Eun Kim, Yoon Ji Choi, Chang Min Choi, Jung-Shin Lee, Sang-We Kim. Randomized phase II study comparing paclitaxel/carboplatin intercalated with gefitinib to paclitaxel/carboplatin alone for chemotherapy-naive non-small cell lung cancer patients either with history of smoking or with wild-type EGFR. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr A77.

Efficacy and safety analysis according to histology for S-1 in combination with carboplatin as first-line chemotherapy in patients with advanced non-small-cell lung cancer: updated results of the West Japan Oncology Group LETS study

BackgroundA phase III study (Lung Cancer Evaluation of TS-1) previously demonstrated noninferiority in terms of overall survival (OS) at interim analysis for carboplatin–S-1 compared with carboplatin–paclitaxel for first-line treatment of advanced non-small-cell lung cancer (NSCLC). Patients and methodsA total of 564 patients were randomly assigned to receive either carboplatin on day 1 plus oral S-1 on days 1–14 or carboplatin–paclitaxel on day 1 every 21 days. Updated results and post hoc subgroup analysis according to tumor histology are presented. ResultsThe updated analysis revealed a median OS of 15.2 months in the carboplatin–S-1 arm and 13.1 months in the carboplatin–paclitaxel arm, with a hazard ratio (HR) of 0.956 [95% confidence interval (CI) 0.793–1.151], consistent with the previous primary analysis. Median OS was 14.0 months in the carboplatin–S-1 arm and 10.6 months in the carboplatin–paclitaxel arm (HR 0.713; 95% CI 0.476–1.068) for patients with squamous cell carcinoma (SCC), with corresponding values of 15.5 and 13.9 months (HR 1.060; 95% CI 0.859–1.308) for those with non-SCC. ConclusionsThese results establish the efficacy and safety of carboplatin–S-1 in patients with advanced NSCLC regardless of tumor histology.

Randomized phase II study of concurrent cisplatin/etoposide or paclitaxel/carboplatin and thoracic radiotherapy in patients with stage III non-small cell lung cancer

ObjectiveTo evaluate the activity and safety of concurrent thoracic radiotherapy (TRT) plus weekly paclitaxel/carboplatin (PC) regimen compared with widely used cisplatin/etoposide (PE) regimen in patients with unresectable stage III non-small cell lung cancer (NSCLC). Patients and methodsPatients were randomly assigned to receive the following treatments: PE arm, cisplatin (50mg/m2) on days 1, 8, 29, and 36 and etoposide (50mg/m2) on days 1–5 and 29–33 plus 60Gy of TRT; PC arm, weekly concurrent carboplatin (AUC=2) and paclitaxel (45mg/m2) plus 60Gy of TRT. ResultsA total of 65 patients were randomized (PE arm, n=33; PC arm, n=32). The 3-year overall survival (OS) was significantly better in the PE arm than in the PC arm (33.1% vs. 13%, P=.04). The incidence of Grade 3/4 neutropenia was 78.1% in the PE arm and 51.5% in the PC arm (P=.05). The rate of Grade 2 or greater radiation pneumonitis was 25% in the PE arm and 48.5% in the PC arm (P=.09). ConclusionsCompared to PE regimen, weekly PC regimen cannot be recommended since it failed to achieve an improvement in either OS or PFS.

BEAM Trial: Lighting the Way Ahead?

BEAM Trial: Lighting the Way Ahead?

Decreased hypersensitivity reactions with carboplatin-pegylated liposomal doxorubicin compared to carboplatin-paclitaxel combination: Analysis from the GCIG CALYPSO relapsing ovarian cancer trial

Objective To describe and analyze observed hypersensitivity reactions (HSR) from the randomized, multicenter phase III CALYPSO trial that evaluated the efficacy and safety of the combination of carboplatin and pegylated liposomal doxorubicin (CD) compared with standard carboplatin–paclitaxel (CP) in patients with platinum-sensitive relapsed ovarian cancer (ROC). Methods HSR documented within case report forms and SAE reports were specifically analyzed. Analyses were based on the population with allergy of any grade and for grade > 2 allergy. Results Overall 976 patients were recruited to this phase III trial, with toxicity data available for 466 and 502 on the CD and CP arms, respectively. There was a 15.5% HSR rate associated with CD (2.4% grade > 2) versus 33.1% with CP (8.8% grade > 2), p < 0.001. HSRs occurred more often during first cycle in the CD (46%) arm than in the CP arm (16%). Multivariate predictors of allergy were chemotherapy regimen and age; patients randomized to CD and patients ≥ 70 years old on CP had less allergy. Few patients (< 6%) stopped treatment due to allergy. Allergy rates were higher in patients who did not receive prior supportive treatment; however there was no relationship between allergy and the type of carboplatin product received, or response rate. Conclusions Use of PLD with carboplatin instead of paclitaxel and older age were the only 2 factors predicting a low rate of HSRs in patients with ROC. CD has previously demonstrated superior progression-free survival and therapeutic index than CP. Taken together these data support the use of CD as a safe and effective therapeutic option for platinum-sensitive ROC.

Second-line Paclitaxel/Carboplatin Versus Vinorelbine/Carboplatin in Patients Who Have Advanced Non–Small-Cell Lung Cancer Pretreated With Non–Platinum-Based Chemotherapy: A Multicenter Randomized Phase II Study

PurposeThis study evaluates the activity and toxicity of the paclitaxel/carboplatin (PC) doublet versus vinorelbine/carboplatin (VC) doublet as second-line treatment in patients who have advanced non–small-cell lung cancer (NSCLC). Patients and TreatmentPatients pretreated with front-line docetaxel and gemcitabine were randomized to receive either PC (n = 75), which consisted of paclitaxel at a dose of 140 mg/m2 and carboplatin area under the curve (AUC3), or VC (n = 78), which consisted of vinorelbine at a dose of 45 mg/m2 orally and carboplatin AUC3; both drugs were administered on days 1 and 15. ResultsThe overall response rate was 18.6% (95% confidence interval, 9.85%-27.49%; one complete and 13 partial responses) in the PC arm and 7.7% (95% confidence interval, 1.78%-13.61%; one complete and five partial responses) in the VC arm (P = .056). Median time to tumor progression was 3.5 months (range, 0.3 - 23.73 months) and 3.07 months (range, 0.37-18.5) in the PC and VC arm, respectively (P = .287). Median overall survival was 7.83 months (range, 0.3-45.03 months) and 7.60 months (range, 0.5-30.27 months) for PC and VC arms, respectively (P value = .633). Chemotherapy was well-tolerated and grade III/IV toxicities were relatively infrequent. No toxic deaths were observed. ConclusionsPlatinum-based doublets with either paclitaxel or vinorelbine in patients with advanced/metastatic NSCLC pretreated with front-line docetaxel/gemcitabine show comparable efficacy when used in the second-line setting.

Randomized, phase III study of mitomycin/vindesine/cisplatin (MVP) versus weekly irinotecan/carboplatin (IC) or weekly paclitaxel/carboplatin (PC) with concurrent thoracic radiotherapy (TRT) for unresectable stage III non-small cell lung cancer (NSCLC): WJTOG0105

7504 Background: Weekly chemotherapy with concurrent TRT displays acceptable toxicities and dependable efficacy. We conducted a randomized phase III trial to assess the efficacy and toxicity of weekly chemotherapy with concurrent TRT against MVP with concurrent TRT via a non-inferiority design. Methods: MVP: mitomycin (8 mg/m2 on days 1, 29), vindesine (3 mg/m2 on days 1, 8, 29, 36), and cisplatin (80 mg/m2 on days 1, 29) with concurrent TRT (60 Gy). Patients (pts) subsequently received 2 courses of consolidation chemotherapy with MVP; IC: weekly irinotecan (20 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of irinotecan (50 mg/m2)/carboplatin (AUC 5); PC: weekly paclitaxel (40 mg/m2)/carboplatin (AUC 2) for 6 weeks and TRT (60 Gy) followed by 2 courses of paclitaxel (200 mg/m2)/carboplatin (AUC 5). The primary endpoint was overall survival (OS), with secondary endpoints of progression free survival (PFS), response, and toxicity. Results: From Sep 2001 to Sep 2005, 456 pts were randomized. Pretreatment characteristics were well-balanced among 3 arms. Major toxicity incidences: The incidence of G3–4 neutropenia in the MVP, IC, and PC arms was 95.9, 72.1, and 46.9 % (p&lt;0.001). The G3–4 non-hematologic toxicity incidences in terms of fatigue, febrile neutropenia, and gastrointestinal disorder were 13.0, 6.1, and 4.8 % (p&lt;0.001), 37.0, 8.8, and 10.2 % (p&lt;0.001), and 24.0, 8.2, and 9.5% (p&lt;0.001) in the respective arms. The overall response rates were 66.4, 56.5, and 63.3 %, in the MVP, IC and PC arms, respectively. The median survival times were 20.5, 19.8 and 22.0 months and the median PFS (MPFS), 8.2, 8.0 and 9.5 months in MVP, IC and PC. Non-inferiority of the 2 experimental arms compared with MVP was not achieved, though no significant differences in OS and PFS were apparent among treatments. The PC arm displayed the most favorable MST, MPFS, and hematologic/non-hematologic toxicities. Conclusions: Weekly PC with TRT displays similar efficacy and more favorable toxicity profiles compared to MVP with TRT. Weekly PC with TRT warrants use as the reference regimen in forthcoming studies. [Table: see text]

Simulation of survival with first- and second-line non-small cell lung cancer (NSCLC) therapy using a public domain drug-disease modeling framework

8087 Background: Modeling and simulation approaches are advocated to support drug development decisions. In this study, we evaluated the ability of a drug-disease model recently developed by scientists at the FDA using data from pivotal studies in NSCLC (Wang et al. http://www.fda.gov/ohrms/dockets/ac/08/briefing/2008–4351b1–00-index.htm ) to simulate survival and tumor response for approved therapies in NSCLC. Methods: The modeling framework comprises a longitudinal tumor size model and a survival model relating change in tumor size at first visit (week 8) and patient characteristics (tumor size and ECOG performance status at baseline) to survival time. The tumor size and survival models were used to simulate change in tumor size at first visit and expected survival in the carboplatin/paclitaxel (CP) arm of the E4599 study (first-line NSCLC, N Eng J Med. 2006;355:2542–2550) and in the erlotinib arm in the BR.21 study (second-line NSCLC, N Eng J Med. 2005;353:123–132). The predictive distributions (95% prediction interval [PI]) of survival times were derived from multiple replicates (500) of 400 CP patients and 500 erlotinib patients with similar characteristics to patients in the original studies. Results: There was a high level of concordance between the results of the simulation and the observed results in the two arms, indicating that the modeling framework successfully predicted survival and tumor response. Expected median survival was 9.8 (95% PI, 8.2–11.8) months (vs 10.3 months observed) for the CP arm and 6.8 (95% PI, 5.3–8.9) months (vs 6.7 months observed) for the erlotinib arm. The median change in relative tumor size from baseline at week 8 predicted by the model was 12.1% for the CP arm and 9.5% for the erlotinib arm. Conclusions: The modeling framework can be used to perform simulations of survival of approved treatments. These results suggest that the model could be used to simulate survival for investigational treatments based on tumor shrinkage data observed in early clinical studies (e.g. phase II) to support end-of-phase II decisions and the design of phase III studies. [Table: see text]