Paclitaxel Bevacizumab Research Articles

MO19-3 PD-L1 expression in patients with HER2-negative advanced breast cancer: A multicenter retrospective study

Programmed death-ligand 1 (PD-L1) overexpression was seen in about 40% of triple-negative advanced breast cancer (TN-ABC) patients (pts). However, PD-L1 status in HER2-negative (HER2-ve) ABC pts is poorly understood, and no biomarker related to chemotherapy (CT) for HER2-ve ABC pts excluding PD-L1 in TN-ABC has been clarified. We evaluated PD-L1 status using SP142 and explored biomarkers for first-line (1L) paclitaxel + bevacizumab (PB) therapy using immune signatures in HER2-ve ABC pts.

A randomized phase II study of bevacizumab and weekly anetumab ravtansine or weekly paclitaxel in platinum-resistant or refractory ovarian cancer NCI trial#10150.

5514 Background: Mesothelin and its binder, antigen-CA125, are highly expressed in high grade serous and endometrioid ovarian cancers (HGOC) and, can inhibit paclitaxel-induced cell death. Anetumab ravtansine (AR) is a fully-human antibody directed at the mesothelin antigen, conjugated to a tubulin polymerization inhibitor. We assessed the safety and activity of the combination AR/bevacizumab (ARB) versus weekly paclitaxel/bevacizumab (PB) in patients (pts) with platinum resistant HGOC. Methods: An initial run-in phase I assessed the safety of ARB. After determination of the recommended phase 2 dose (RP2D), a multicenter 1:1 randomized phase 2 trial was designed to evaluate the progression free survival (PFS) in pts with platinum resistant/refractory HGOC. Pts were stratified by platinum resistant or refractory and prior bevacizumab (bev). Eligibility required measurable disease and mesothelin tested positive centrally on archival tissue by IHC. No limitation on the number of prior lines of therapy. A futility analysis was planned at 35 PFS events. The control arm was weekly intravenous paclitaxel 80mg/m2 with bev 10mg/kg every 2 weeks. A CT was performed every 8 weeks for RECIST1.1 assessment. The toxicities were reported according to CTCAE version 5.1. NCT03587311. Results: 7 pts were enrolled in the run-in phase 1 and the RP2D determined as bev (10mg/kg) biweekly with AR (2.2mg/kg) weekly on a 28 day-cycle. In the phase 2, 57 pts were enrolled, 28 pts in the ARB and 29 pts in the control group. The positivity rate for mesothelin screening was 88%. Pts were heavily pre-treated, median prior lines of 3 (range (1-9) with 24 pts received prior bev (42%) and 13 pts were platinum refractory (7 in ARB and 6 in PB). At the time of 35 PFS events, one CR and 4 PR were observed (ORR = 18%) in the ARB arm, versus no CR and 16 PR in the weekly PB (ORR = 55%). The estimated median PFS was 5.3 (95% CI: 3.7-7.4) months for ARB and 9.6 (95% CI: 7.4-17.4) months for PB (HR = 1.7(95% CI: 0.9-3.4)). The median number of cycles were 4 (1, 29) and 8 (1, 19) respectively. The most common treatment-related AEs in the ARB arm were mostly grade 1/2 increase AST (71%) and ALT (64%), thrombocytopenia (61%), fatigue (57%), and peripheral neuropathy (46%). In the PB arm, the most common treatment-related AE were anemia (66%), neutropenia (59%), epistaxis (48%), fatigue (45%) and peripheral neuropathy (45%). Conclusions: At the time of futility analysis, weekly PB had better outcome than weekly ARB leading to the study termination. Molecular and blood analyses are on-going to assess potential biomarkers of response. This study highlights the importance of randomization in assessment of novel therapies and potential for re-challenge with bevacizumab. These data show that weekly PB is an effective regimen and can be considered as the control arm in platinum resistant HGOC. Clinical trial information: NCT03587311.

Effect of prior immunotherapy on the efficacy of chemotherapy in advanced non-small cell lung cancer: A retrospective study.

BackgroundThe effect of the sequential combination of chemotherapy and immune checkpoint inhibitors (ICIs) remains unclear. Here, we evaluated the efficacy of different chemotherapy regimens administered after ICIs in advanced non‐small cell lung cancer (NSCLC), compared to the same regimens administered without previous ICIs.MethodsWe retrospectively included all patients treated between 2015 and 2019 for an advanced NSCLC, receiving a salvage chemotherapy just after ICI (CAI group) comparing them to ICI naive patients (CWPI group) undergoing the same chemotherapy at Bordeaux University Hospital. The primary outcome was the time to treatment discontinuation (TTD), and secondary endpoints were overall survival (OS) and overall response rate (ORR).ResultsA total of 152 patients were included, with 34/23 (CAI/CWPI) receiving paclitaxel/bevacizumab (PB), 24/11 paclitaxel (P), 27/12 gemcitabine (G) and 6/15 pemetrexed (PE). Characteristics were comparable, except for CAI treated with PB (more patients with an ECOG PS ≤1 [p <0.001]). Median number of lines received was higher in CAI for all groups. There was no difference between CAI and CWPI for TTD, OS and ORR. However, PB was associated with a nonsignificant increase in OS in the CAI group (HR = 0.65; 95% CI: 0.38–1.2, p = 0.17].ConclusionOur data showed no difference in TTD, OS and ORR regardless of chemotherapy, but a trend towards an increased OS with PB when given after an ICI, while patients received chemotherapy later in the CAI group. This suggests that a sequential combination of ICI followed by chemotherapy could be an interesting strategy in advanced NSCLC for selected patients.

Abstract P1-10-25: The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab

Abstract Purpose: Many reports have provided real-world evidence that inflammatory response biomarker (IRB) scores may be useful for predicting the therapeutic effect of chemotherapy and the prognosis for various neoplasms. The aim of this retrospective study was to evaluate the clinical roles of the neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR) as predictive factors of Paclitaxel + Bevacizumab (PB) therapy for patients with HER2-negative metastatic breast cancer (HER2-MBC). Methods: We reviewed the medical records of 123 HER2-MBC patients who underwent PB therapy in our institute. The NLR, PLR, and LMR were calculated from blood cell counts prior to the initiation of PB therapy. The optimal cut-off point of each ratio was determined according to receiver operating characteristic (ROC) curves. The Kaplan-Meier test and Wilcoxon test were used to analyze the progression- free survival (PFS) and overall survival (OS). The differences were considered significant for p &amp;lt; 0.05. Results: The median age at the start of treatment was 53 years old. Of the 123 patients, 98 (80%) were hormone- receptor- positive, and 82 (67%) had multiple (&amp;gt;2) metastatic sites. The median PFS was 7.0 months (95% confidence interval, 5.8-8.4), and the median treatment line before PB therapy was 0 (range: 0-10). The cut-off points of the NLR, PLR, and LMR for the PFS and OS were 2.7, 178, and 3.0, respectively. We found that a high NLR and low LMR were associated with a poor PFS (NLR, median 6.5 vs. 8.4 months, p=0.04: LMR, median 5.6 vs. 8.1 months, p=0.02), and a high LMR was associated with a superior OS (median, not reached vs. 187 months, p=0.02) and 10- year survival rate (76.4% vs. 52.9%, p=0.02). The PLR showed no relationship with the PFS or OS. Conclusion: The NLR and LMR might be independent biomarkers, i.e. predictive factors, for patients with HER2-MBC receiving PB therapy in the real world. A prospective study to confirm the utility of those biomarkers is warranted. Citation Format: Tomomi Hayashi, Junichiro Watanabe, Shyogo Nakamoto. The prognostic and predictive roles of the neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and lymphocyte-to-monocyte ratio in HER2-negative metastatic breast cancer patients treated with paclitaxel-bevacizumab [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 P1-10-25.

Phase 1b study of safety, tolerability and efficacy of R1507, a monoclonal antibody to IGF-1R in combination with multiple standard oncology regimens in patients with advanced solid malignancies

R1507 is a human IgG1 Mab that binds to the insulin-like growth factor-1 receptor (IGF-1R) and inhibits IGF-1- or IGF-2-mediated anchorage-independent growth of malignant cells. A phase 1b study evaluated the safety, tolerability and efficacy of R1507 in combination with multiple standard oncology regimens. R1507 (3, 5, 9, 10 and 16 mg/kg IV, Q2 W or Q3 W) was added to six treatment regimens: gemcitabine + erlotinib (GE); paclitaxel + bevacizumab (PB); carboplatin + etoposide (CE); mFOLFOX6 + bevacizumab (FB); capecitabine + trastuzumab (CT); and sorafenib (S). If tolerable, R1507 dose was escalated utilizing a 3 + 3 + 6 and a 3 + 9 design. A total of 104 patients enrolled into regimens 1-6: 93 % were non-recent diagnoses. Eighteen withdrew for safety [one death, 17 adverse events (AEs)]. A total of 1,337 AEs any grade, across regimens and doses were nausea, vomiting and diarrhea. A total of 123 had grade ≥3 AEs (n = 28 dose level 1; n = 95 dose level 1) and in 60 patients were myelosuppression, fatigue and mucosal inflammation. ORR (PR plus SD) of evaluable patients across six regimens was 36 % with five PRs: regimens PB (non-small cell lung cancer, nasopharyngeal cancer), CE (melanoma), FB (colon cancer) and S (GIST). The GIST pt (>4 prior therapies) had a PR for 3 years. Three patients (breast cancer, melanoma and adenoid cystic carcinoma) were on study for >1 year; 76 % of patients had SD or better for 4 months. R1507 added to six standard oncology regimens was well tolerated with an ORR of 36 %.

Phase Ib study of safety, tolerability, and efficacy of R1507 a monoclonal antibody to IGF-1R in combination with multiple standard chemotherapy regimens in patients with advanced solid malignancies.

e13574 Background: R1507 is a human IgG1 Mab that binds to the insulin-like growth factor-1 receptor (IGF-1R), implicated in the pathogenesis of several solid tumor types. IGF-1 or IGF-2 activate the IGF-1R and promote anchorage independent growth of malignant cells. A phase 1b study was conducted to establish the safety, tolerability and efficacy of R1507 in combination with multiple standard oncology regimens. Methods: This was an open-label, multi-center study in advanced stage cancer patients (pts). R1507 (3, 5, 9, 10 and 16 mg/kg IV, Q2W or Q3W) was added to 6 treatment regimens: gemcitabine + erlotinib (GE); paclitaxel + bevacizumab (PB); carboplatin + etoposide (CE); mFOLFOX6 + bevacizumab (FB); capecitabine + trastuzumab (CT); sorafenib (S). All arms started with R1507 dose lower than the recommended single agent dose (level -1). If tolerable, R1507 dose was escalated in subsequent cohorts of pts. Accrual to each regimen was dependent on the number of pts developing a DLT at dose level -1. The study used a 3 + 3 + 6 and a 3 + 9 design. Results: N=104 pts enrolled into regimens 1 to 6: 6% new diagnosis, 93% non-recent diagnosis, and 1% not classified. N=18 withdrew for safety [1 death, 17 AEs]. N=80 withdrew for non-safety reasons [n=61 PD, n=17 refused further treatment, n=1 insufficient response, n=1 ‘other’]. A total of 1337 AEs were reported: any grade, across regimens and doses were nausea, diarrhea, and vomiting. N=123 had grade ≥3 AEs (n=28 dose level -1; n=95 dose level 1) in 60 pts that were myelosuppression, fatigue and mucosal inflammation. ORR (partial response [PR] plus stable disease) of evaluable pts across 6 regimens was 36% with 5 PRs: regimens PB (non-small cell lung cancer, nasopharyngeal cancer), CE (melanoma), FB (colon cancer) and S (gastrointestinal stromal tumor: GIST). The GIST pt (&gt;4 prior therapies) had a PR for 3 years. Three pts (breast cancer, melanoma, adenoid cystic carcinoma) were on study for &gt;1 year. 71% pts had SD ≥ 4 months. Conclusions: R1507 added to 6 standard chemotherapy regimens was well tolerated with no significant safety issues. Trial was terminated early due to discontinued development of R1507. Clinical trial information: NCT00811993.

Insulin-Like Growth Factor Receptor

The insulin-like growth factor (IGF) signaling axis plays an essential role in the balance between cellular proliferation and apoptosis. Higher levels of IGF receptor are seen in lung tumor cells than normal tissue. IGF-1 receptor (IGFR-1R) and its ligand IGF-2 is overexpressed in non-small cell lung cancer (NSCLC). Elevated levels of IGF-1 in plasma are associated with an increased risk of developing lung cancer, and IGF-1R has been shown to promote the proliferation of lung cancer cells in vitro. 1 IGF-1R can hybridize with other membrane receptors leading to the activation of different tyrosine kinase domains. 2 The central role that the IGFR pathway plays in various signaling pathways in tumor cells makes the IGF axis an attractive target for therapeutic intervention. Dr. Pollak presented an overview of the science of the IGFR to establish the rationale for the development of this class of drugs for the treatment of NSCLC. There are a number of possible avenues through which the effects of IGF can be inhibited. These strategies include antibodies directed against IGF ligand, IGF-1R tyrosine kinase inhibitors, and antibodies targeting the IGF-1R. The approach of blocking the IGF-1 receptor tyrosine kinase pathway and the insulin receptor (IR) via signal transduction inhibitors is also undergoing clinical evaluation. IMC-A12 IMC-A12 is a fully humanized IgG1 monoclonal antibody with a half-life of 15 to 21 days that targets the IGF-1 receptor. 3 Both weekly and q21-day schedules are being explored. There are three ongoing randomized phase II trials with differentfirst-line platinum-based regimens including a trial that is comparing gemcitabine, carbopatin with the addition of IMC-A12, cetuximab, or both, and another evaluating carboplatin, paclitaxel bevacizumab with or without IMC-A12 in nonsquamous NSCLC. There is one randomized first-line trial of etoposide, cisplatin with or without either IMC-A12 or the hedgehog inhibitor GDC-0449 in extensive disease small cell lung cancer (EDSCLC). The combination of erlotinib plus A12 was closed due to toxicity of the combination. Currently, no additional toxicity or efficacy data are available. AMG-479 Phase I studies established thrombocytopenia as the dose-limiting toxicity of AMG-479, a fully human monoclonal antibody to IGF-1R. 4 AMG-479 is being evaluated in the front-line setting in combination with etoposide and carboplatin or cisplatin in a randomized phase I/II trial in patients with EDSCLC. Patients will receive up to six cycles of the combination then single-agent AMG 479 as maintenance therapy until disease progression. Preliminary results indicate that AMG-479 can be safely combined with etoposide and cisplatin (or carboplatin) in this patient population without impact on the delivery of AMG-479 or the chemotherapy. Activity in the phase I portion was similar to reported with chemotherapy alone. 5 The phase II portion of the trial has completed accrual and results are pending. MK-0646 MK-0646 is a fully humanized monoclonal IgG1 antibody that selectively binds to the IGF-1 receptor and not to the insulin receptor. 6 The recommended phase II dose is 10 mg/kg weekly. An overview of the compound and the design of several clinical trials were presented. In the randomized phase II IMPACT study, MK-0646 is being evaluated in combination with pemetrexed (500 mg/m 2 ) and cisplatin (75 mg/m 2 ) as first-line therapy in patients with stage IIIB or IV nonsquamous NSCLC. The phase I/II design of MK-0646 plus cisplatin and etoposide in patients with treatment-naive EDSCLC was also presented. Both studies are ongoing but not actively recruiting participants.

A Randomized Phase II Study of Paclitaxel and Bevacizumab With and Without Gemcitabine as First-Line Treatment for Metastatic Breast Cancer

Background The addition of bevacizumab to paclitaxel improved progression-free survival (PFS) of patients with metastatic breast cancer (MBC). We examined the efficacy and safety of adding gemcitabine to paclitaxel/bevacizumab (PB). Patients and Methods In this multicenter, open-label, randomized phase II trial, women with locally advanced or MBC were randomly assigned to receive paclitaxel 90 mg/m 2 (days 1, 8, 15) and bevacizumab 10 mg/kg (days 1, 15) with or without gemcitabine 1500 mg/m 2 (days 1, 15) in 28-day cycles. Patients with prior cytotoxic therapy for MBC were ineligible. The primary endpoint was investigator-assessed overall response rate (ORR); secondary endpoints were PFS, overall survival (OS), safety, and quality of life. Results Ninety-four patients received PB, and 93 received paclitaxel/bevacizumab/gemcitabine (PB+G). The ORRs were 48.9% (95% confidence interval [CI], 38.5%-59.5%) and 58.7% (95% CI, 47.9%-68.9%; P = .117) with PB and PB+G, respectively. The median PFS was 8.8 months (95% CI, 8.1-10.4 months) and 11.3 months (95% CI, 9.7-12.7 months; P = .247; hazard ratio, 0.82); the median OS was 25.0 months (95% CI, 18.8-not assessable [N/A] months) and 24.3 months (95% CI, 20.3-N/A months; P = .475; hazard ratio, 0.84), with PB and PB+G, respectively. There was significantly more grade 3-4 neutropenia ( P = .001) and dyspnea ( P = .014) with PB+G. Patients treated with PB experienced more improvement in total FACT-B (Functional Assessment of Cancer Therapy-Breast) ( P = .021), FACT-B Social/Family Well-being ( P = .041), and Breast Cancer-Additional Concerns ( P = .008) scores than patients treated with PB+G. Conclusion The addition of gemcitabine to PB was not associated with a statistically significant improvement in ORR. Treatment with PB+G increased the incidence of severe neutropenia and dyspnea, although the regimen generally was well tolerated.

SABRE-B: an evaluation of paclitaxel and bevacizumab with or without sunitinib as first-line treatment of metastatic breast cancer

BackgroundThe vascular endothelial growth factor (VEGF) pathway can be targeted through VEGF neutralization or VEGF receptor (VEGFR) blockade using tyrosine kinase inhibition. Because laboratory models suggest that combining these approaches might be synergistic, we sought to evaluate the feasibility and efficacy of combining sunitinib with paclitaxel + bevacizumab (PB). MethodsPatients with human epidermal growth factor receptor 2 (HER2)-negative, metastatic breast cancer receiving first-line chemotherapy were randomized to PB or PB with sunitinib (PBS), with planned escalation of the sunitinib dose. ResultsForty-six patients were randomized to PB or PBS with sunitinib dosed at 25 mg p.o. daily. Patients receiving PBS encountered substantial toxicity that precluded adequate treatment. The percentage of patients with grade ≥3 adverse events was greater in the PBS arm than the PB arm (83% versus 57%), and sunitinib dosing was modified in 78% of patients, most often due to neutropenia, febrile neutropenia, and fatigue. In addition, 44% of patients had sunitinib dose reduction to 12.5 mg, and 39% required discontinuation. Patients receiving PBS had more bevacizumab treatment interruptions and discontinuations because of toxicity. Median treatment duration was longer in the PB arm compared with the PBS arm (14.1 versus 11.1 weeks), reflecting early treatment discontinuation of PBS. Because of poor tolerability of the addition of sunitinib to PB, the planned sunitinib dose escalation was halted and the study accrual was terminated. ConclusionAdding sunitinib to standard doses of bevacizumab plus paclitaxel for metastatic breast cancer is not feasible. Different strategies will be required to evaluate whether there is additional clinical benefit to combining VEGF/VEGFR-targeted agents.

Examining the cost and cost-effectiveness of adding bevacizumab to carboplatin and paclitaxel in advanced non-small cell lung cancer

6057 Background: Two-drug platinum-containing regimens are considered the standard of care in advanced non-small cell lung cancer. A recent randomized trial (ECOG 4599) compared carboplatin + paclitaxel (PC) with PC + bevacizumab (PCB). PCB was found to result in a modest improvement in survival (12.5 months vs 10.2 months with PC, p = .007). This finding was exceptional in showing a survival benefit with the addition of a molecularly targeted agent to chemotherapy in a largely unselected population, and doing so in this most common cause of malignant death in the US. Additionally, new therapies can have a major impact on health care costs. Using the known survival data and costs, we analyzed the cost-effectiveness of the addition of bevacizumab to this chemotherapy regimen. Methods: Medicare reimbursement (cost) of the two regimens was developed using the CMS Drug Payment Table and Physician Fee Schedule for January, 2005. Incremental cost effectiveness was calculated. Results: Carboplatin and paclitaxel regimen costs $14,073 for 6 cycles (the number of cycles planned in the clinical trial.) The addition of bevacizumab increases cost by $66,270 to $80,343. Given an increase of 2.3 months in median overall survival over chemotherapy alone, the addition of bevacizumab to chemotherapy costs $345,762 per year of life gained. Conclusions: Adding bevacizumab to chemotherapy is not cost effective even at the $100,000 per Year of Life Gained (YLG) threshold. To be cost effective at the $100,000/YLG level, bevacizumab reimbursement would have to be reduced to $14.70/10 mg. ($1,764/cycle) or 26% of 2005 Medicare reimbursement of $57.08/10 mg. ($6,849/cycle). Prior analyses have examined the impact of chemotherapy on survival and cost-effectiveness. Several factors beneficially influence survival in NSCLC, as shown in meta-analyses, including: chemotherapy vs supportive care, two-agents vs one, and the choice of which platinum agent to use. While all of these may increase costs, some are cost-effective, while others are not. The addition of bevacizumab is the most costly and least cost-effective of any of these interventions. [Table: see text]