2015年肿瘤治疗资料集中贴

Ibrutinib Response Rates Improve With Longer Follow-Up in CLL - See more at: http://www.onclive.com/web-exclu ... er-Follow-Up-in-CLL
Single-agent ibrutinib (Imbruvica) demonstrated an overall response rate (ORR) of 91%, including a complete response rate of 14%, in patients with chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL), according to follow-up data from 94 patients treated in the phase I/IIb study PCYC-1102 and the PCYC-1103 extension study.

After up to 45 months of follow-up for the 94 patients treated with ibrutinib, the ORR was 85% in 27 treatment-naive (TN) patients and 94% in 67 relapsed/refractory (R/R) patients. Complete response rates were 26% (n = 7) and 9% (n = 6) for the TN and R/R patients, respectively.

The median treatment duration was 25 months (range, 0-45 months) for all patients (30 months TN; 22 months R/R). The median duration of response (DOR) and progression-free survival (PFS) have not yet been reached. The 30-month PFS rate was 96% in TN and 76% in R/R patients with CLL. The median number of prior therapies for R/R patients was four (range, 1-12 therapies). One patient with previously untreated CLL experienced disease progression during the follow-up.

Steven Coutre, MD, presented the follow-up data at the 2015 AACR Annual Meeting. In an interview with OncLive, Coutre, professor of Medicine (Hematology) at Stanford University Medical Center, called the results promising, while noting that ibrutinib has significantly impacted the treatment of patients with CLL, since its approval in 2014.

“What this study really demonstrates is the continued benefit that patients receive from the drug,” said Coutre. “The efficacy and response rates have continued to improve.”

The most frequently reported grade 3 or greater adverse events in the trial were hypertension (23%), pneumonia (15%), neutropenia (13%), atrial fibrillation (7%) and diarrhea (7%). During follow-up, 12 patients discontinued treatment due to disease progression. Discontinuation due to AEs declined over time; in total, 12 patients discontinued due to an AE (seven patients in year 1, three patients in year 2, and two patients beyond year 3).

These minimal side effects are what make the ibrutinib groundbreaking for the treatment of CLL and SLL patients, said Coutre.

“The drug has had significant impact,” he explained. “It is a very well tolerated therapy for patients who may not be able to tolerate standard chemoimmunotherapy or patients that no longer respond to standard therapy. There is a lack of late side effects. The side effects related to the treatment have actually decreased over time.”

All patients received ibrutinib 420 mg daily, dosed until disease progression in the PCYC-1102 and the PCYC-1103 extension study. The best ORR, including partial response with lymphocytosis (PR-L), was assessed by investigators using IWCLL criteria. The majority of patients entered the study with baseline cytopenias. Early and sustained improvements in hemoglobin and platelet counts were observed.

Ibrutinib is a first-in-class, once-daily, oral, covalent inhibitor of Bruton’s tyrosine kinase. It was granted an accelerated approval for the treatment of patients with CLL who have received at least one previous therapy in February 2014. This approval was based on early data from the phase Ib/II PCYC-1102-CA study in which ibrutinib demonstrated an ORR of 58.3% in previously treated CLL across all subtypes, with duration of response up to 24.2 months.

The drug was granted a full approval in July 2014, based on the phase III RESONATE study, which demonstrated a durable improvement in ORR, PFS, and overall survival (OS) compared with ofatumumab. This study was unblinded 4 months after the enrollment of the last patient. At the first analysis, 57 patients in the ofatumumab group had crossed over to receive ibrutinib following progression.

For the primary endpoint of PFS, the median in the ibrutinib arm was not reached compared with an 8.1-month median with ofatumumab (HR = 0.22, 95% CI, 0.15–0.32, P < .0001). At 6 months, 88% of patients treated with ibrutinib were disease-free compared with 65% in the ofatumumab group. In patients with a 17p13.1 deletion, the HR was 0.25 (95% CI, 0.14-0.45), warranting a separate FDA approval for high-risk patients with these alterations.

For the secondary endpoint of OS, ibrutinib also demonstrated superior efficacy. At 12 months, the OS rate was 90% for patients treated with ibrutinib compared with 81% in the ofatumumab group. The median OS was not reached for patients treated with ibrutinib (HR = 0.43; 95% CI, 0.24-0.79; P = .005).

Recently the phase III HELIOS study, which examined ibrutinib in combination with bendamustine and rituximab (BR), was unblinded following the demonstration of a significant extension in PFS with the triplet compared with BR alone in patients with CLL or SLL. Full data from the trial were submitted for presentation at the 2015 ASCO Annual Meeting and are being prepared for regulatory submission.

In a preceding phase Ib study exploring ibrutinib plus BR, the estimated 12-month PFS was 90% in 30 patients with relapsed/refractory CLL/SLL. The ORR with the combination was 93%.

The FDA initially approved ibrutinib for patients with MCL who received at least one prior therapy in November 2013. In late January 2015, the FDA expanded this indication to include the treatment of patients with Waldenstr&#246;m’s macroglobulinemia.

好好学习下，谢谢老马

感谢老马的好贴，学习了

妈妈长寿 发表于 2015-3-16 14:56
感谢老马，资料十分有用，已经买了打印机，打算将所有能找到的都打印出来，方便学习。

同感，我也是这么做的。

2015年5月1日，Exelixis’ cabozantinib received Fast Track designation by US FDA for Renal Cell Carcinoma treatment

upcoming 2015 Annual Meeting of the American Society of Clinical Oncology (ASCO). The meeting, which will be held from May 29 to June 2, 2015 in Chicago, Illinois.
Abstract 8003: “Cabozantinib (C), erlotinib (E) or the combination (E+C) as 2nd or 3rd line therapy in patients with EGFR wild-type (wt) NSCLC: a randomized phase 2 trial of the ECOG-ACRIN Cancer Research Group (E1512).”
Dr. Joel Neal, Stanford University Medical Center, Palo Alto, CA
Oral Abstract Session: Lung Cancer – Non-Small Cell Metastatic
Sunday, May 31, 8:00–11:00 a.m., N Hall B1 (talk from 8:36-8:48 a.m.)
[Note: This is an NCI-CTEP study.]
Abstract 8007: “Phase II study of cabozantinib for patients with advanced RET-rearranged lung cancers.”
Dr. Alexander Drilon, Memorial Sloan Kettering Cancer Center, New York, NY
Oral Abstract Session: Lung Cancer – Non-Small Cell Metastatic
Sunday, May 31, 8:00–11:00 a.m., N Hall B1 (talk from 10:12–10:24 a.m.)
[Note: This is an Investigator-Sponsored Trial.]
Abstract 8021: “Response to crizotinib and cabozantinib in stage IV lung adenocarcinoma patients with mutations that cause MET exon 14 skipping.”
Dr. Paul Paik, Memorial Sloan Kettering Cancer Center, New York, NY
Poster Session: Lung Cancer
Monday, June 1, 8:00–11:30 a.m., S Hall A (Poster 343); discussed later in the day, from 3:00-4:15 p.m., in E Hall D2
[Note: This is an Investigator-Sponsored Trial.]
Abstract 8087: “Biomarker analysis of a phase II trial of cabozantinib and erlotinib in patients (pts) with EGFR-mutant NSCLC with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) resistance: A California Cancer Consortium Phase II Trial (NCI 9303).”
Dr. Karen Reckamp, City of Hope Cancer Treatment Center, Duarte, CA
Poster Session: Lung Cancer – Non-Small Cell Metastatic
Monday, June 1, 8:00–11:30 a.m., S Hall A (Poster 411)
[Note: This is an NCI-CTEP study.]
Abstract TPS9088: “Phase 2 study of cobimetinib in combination with vemurafenib in active melanoma brain metastases (coBRIM-B).”
Dr. Melissa K. Yee, University of Pittsburgh Cancer Institute, Pittsburgh, PA
Poster Session: Melanoma/Skin Cancers
Monday, June 1, 1:15 p.m. – 4:45 p.m., S Hall A (Poster 326b)
[Note: This is a Trials in Progress abstract.]

Outcome of combined bevacizumab and irinotecan for patients with progressive brain metastases from non-small cell lung cancer (NSCLC).
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
e19059
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr e19059)
Author(s): Evelyn M Brosnan, Camilo E. Fadul, Konstantin H. Dragnev, Melissa C Davis, Khushboo A Shah, Clifford J Eskey; Dartmouth Hitchcock Medical Center, Lebanon, NH; Dartmouth Hitchcock Medical Ctr, Lebanon, NH; Dartmouth Hitchcock Medcl Ctr, Lebanon, NH; Dartmouth Hitchcock Medical Center, lebanon,, NH
Abstract Disclosures
Abstract:
Background: About 30-44% of patients with non-small cell lung cancer (NSCLC) will develop brain metastases, with a median survival if untreated of less than 3 months. Treatment options are limited to surgery, whole brain radiation therapy (WBRT), and stereotactic radiosurgery (SRS). As more effective treatments for systemic disease are available, the brain is a frequent site of progression that after radiation is especially difficult to treat. Brain re-irradiation for recurrent disease is associated with prohibitively high risks for complications. New treatment options are desperately needed. We report the results of combination therapy with bevacizumab and irinotecan in patients with NSCLC who have developed progressive brain metastases.Methods: This is a retrospective study between 2011 and 2014, of 8 patients with brain metastases from NSCLC who were treated with bevacizumab and irinotecan, after progression of disease in the brain despite WBRT or SRS radiation. Brain MRI was used to measure response after 2 to 4 doses of therapy. Adverse effects, number of cycles, progression free survival (PFS) and overall survival (OS) were recorded. Results:Median shrinkage of lesion size was 53% (range 22-100%) after a median of 2.5 doses. The PFS median from start of therapy was 4 months (range 1-14). The OS was 5.2 months (range 1-23). The regimen was well tolerated. None of the patients had intracranial or systemic bleeding and the most common side effects were fatigue, nausea and diarrhea. Conclusions:Combination therapy with bevacizumab plus irinotecan for progressive brain metastases after radiation results in more than 50% response rate and appear to extend survival in this small retrospective cohort, lending support for further exploration in a randomized clinical trial.

Clinical activity and safety of PF-06463922 from a dose escalation study in patients with advanced ALK+ or ROS1+ NSCLC.
Sub-category:
Lung Cancer—Non-Small Cell Metastatic
Category:
Lung Cancer—Non-Small Cell Metastatic
Meeting:
2015 ASCO Annual Meeting
Abstract No:
8018
Poster Board Number:
Board #340
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8018)
Author(s): Alice Tsang Shaw, Todd Michael Bauer, Enriqueta Felip, Benjamin Besse, Leonard Philip James, Jill S. Clancy, Ganesh Mugundu, Jean-Francois Martini, Antonello Abbattista, Benjamin J. Solomon; Massachusetts General Hospital Cancer Center, Boston, MA; Sarah Cannon Research Institute / Tennessee Oncology, PLLC., Nashville, TN; Vall d'Hebron University Hospital, Barcelona, Spain; Gustave Roussy, Villejuif, France; Pfizer, New York, NY; Inventiv Clinical, Princeton, NJ; Pfizer, San Diego, CA; Pfizer, Milan, Italy; Peter MacCallum Cancer Centre, East Melbourne, Australia
Abstract Disclosures
Abstract:
Background: Anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) fusions define 2 molecular subsets of patients (pts) with non-small cell lung cancer (NSCLC). PF-06463922 is a selective, brain-penetrant ALK/ROS1 tyrosine kinase inhibitor (TKI) with potent activity against de novo fusions as well as resistance mutations, including ALKG1202R, that arise during treatment with other TKIs. Methods: In an ongoing phase I portion of a phase I/II study, pts had ALK+ or ROS1+ NSCLC, with or without central nervous system (CNS) metastases, and were TKI-na&#239;ve or had disease progression after prior treatment with 1–2 TKIs. Tumor tissue (archival sample or de novo biopsy) was required for enrollment. A continual reassessment method was used to estimate the maximum tolerated dose (MTD) and identify the recommended phase II dose (RP2D). PF-06463922 was administered on day –7 and then once daily (QD) starting day 1. Primary objective was to estimate the MTD and identify a RP2D. Other objectives included efficacy, safety, pharmacokinetics (PK), effect on cognitive function, effect on cytochrome P450 (CYP) 3A4 activity, biomarkers of drug response/resistance, and intracranial antitumor activity.Results: 18 ALK+ and 4 ROS1+ pts (CNS metastases, n = 17; prior ALK TKIs, n = 19) were enrolled across 7 dose levels (10–200 mg QD). Of 15 patients evaluated for efficacy, 6 (40%) had either confirmed or unconfirmed partial responses, 5 of whom previously received 1–2 TKIs and had progression following crizotinib +/- ceritinib; intracranial responses were observed in 5 pts. Common treatment-related adverse events (AE) were hypercholesterolemia and peripheral neuropathy (23% each). The most common grade ≥ 3 treatment-related AE was hypercholesterolemia (14%). One dose-limiting toxicity occurred in a pt who received < 16 of 21 planned 200 mg QD doses due to grade 1/2 CNS effects. PK analysis showed a dose-proportional increase in exposure with a half-life of 20–28 h and moderate CYP3A4 induction. 20 pts remain on treatment. ConclusionsF-06463922 was well tolerated and had clinical activity in pts with ALK+/ROS1+ NSCLC, most of whom had CNS metastases and received ≥ 1 prior TKI. Identification of MTD and RP2D is ongoing. Clinical trial information: NCT01970865

AZD3759, an EGFR inhibitor with blood brain barrier (BBB) penetration for the treatment of non-small cell lung cancer (NSCLC) with brain metastasis (BM): Preclinical evidence and clinical cases.
Meeting:2015 ASCO Annual Meeting
Abstract No:8016
Poster Board Number:Board #338
Citation:
J Clin Oncol 33:5s, 2015 (suppl; abstr 8016)
Author(s): Dong-Wan Kim, James Chih-Hsin Yang, Kan Chen, Ziqiang Cheng, Lucy Yin, Paul David Martin, Zhenfan Yang, Haiyi Jiang, Myung-Ju Ahn; Seoul National University Hospital, Seoul, South Korea; Department of Oncology, National Taiwan University Hospital; Graduate Institute of Oncology & Cancer Research Center, National Taiwan University, Taipei, Taiwan; Innovation Center China, Innovative Medicines and Early Development, AstraZeneca, Shanghai, China; Innovation Center China, Innovative Medicines & Early Development, AstraZeneca, Shanghai, China; Innovation Center China, Innovative Medicines & Early Development, Shanghai, China; AstraZeneca, Alderley Park, Macclesfield, United Kingdom; AstraZeneca China, Shanghai, China; Sungkyunkwan University School of Medicine, Samsung Medical Center, Seoul, South Korea
Abstract Disclosures
Abstract:
Background: Increasing numbers of EGFRm+ NSCLC patients with BM have been reported, while effective treatment is lacking due to limited BBB penetration of currently available EGFR TKIs. Here we report preliminary data on AZD3759, an EGFR TKI with BBB penetration, for the treatment of BM.Methods: Preclinically, AZD3759 was assessed in both in vitro and in vivo assays, including MDCKII/Pgp and BCRP assays and CNS penetration in rats, mice and monkeys. PC-9 cells (Exon19Del) were transfected with luciferase and implanted through intra-carotid artery injection to establish a BM model in mice. Tumor growth was monitored weekly by a Xenogen Imaging System and the animal survival time was recorded. Blood and brain tissues were collected for pharmacokinetics, histopathology and pEGFR expression analyses. An ongoing, open label, dose escalation phase I study (NCT02228369; sponsor AstraZeneca) is investigating safety and tolerability of AZD3759 in patients with EGFRm+ advanced NSCLC. Results: AZD3759 has high passive permeability (29.5x10-6 cm/sec) and is not a substrate of the efflux transporters Pgp or BCRP at the BBB. In vivo, AZD3759 reached distribution equilibrium in rats, mice and monkey (Kpuu,brain and Kpuu,CSF > 0.5), suggesting BBB penetration. In the BM model, AZD3759 induced profound tumor regression and significantly improved animal survival. A correlation between free brain exposure and pEGFR modulation was also detected in tumor tissues on AZD3759 treatment. To date, 4 patients with measurable BM have been enrolled into 50mg bid and 100mg bid cohorts (3 patients and 1 patient, respectively). In the 2 evaluable patients with BM, one unconfirmed PR and one SD in the brain have been observed. Ctrough CSF concentrations of these patients were 7.7 and 6nM, respectively, close to the pEGFR IC50 of AZD3759. No DLTs were reported to date and two cases of grade I skin rash were observed. Conclusions: Preclinical and initial clinical evidence indicate that AZD3759 is an EGFR TKI with BBB penetration with potential to treat EGFRm+ NSCLC patients with BM. Updated clinical data will be shared at the meeting. Clinical trial information: NCT02228369