2015年10月26日，欧洲药品质量管理局人用药品委员会（CHMP）推荐其溶瘤免疫疗法Imlygic用于治疗恶性黑色素瘤。
Imlygic是一类极具潜力的溶瘤免疫疗法，主要通过局部注射给药，从而导致肿瘤细胞死亡.
安进研发副总裁Sean Harper表示：“我们非常高兴地看到CHMP能够给予Imlygic积极推荐，如果将来能够被欧洲药品质量管理局批准，我们期待着继续与监管部门合作，将这一创新性药物尽快带给患者。”
转移性黑色素瘤至今仍是最难治愈的肿瘤之一，通常需要使用多种治疗方法。尽管黑色素瘤的研究已经取得了许多进展，然而恶性黑色素瘤患者的五年生存期仍然处于极低水平，患者迫切需要新的治疗方法来对抗这一恶性肿瘤。
此次CHMP的积极推荐意见主要是基于一项III期临床试验，该实验评估了Imlygic在治疗IIIB、IIIC及IV期黑色素瘤患者方面的安全性和有效性。
在这项由436名黑色素瘤患者参与的临床试验中，Imlygic显着地提高了患者的持久响应率（DRR），这一指标是指患者用药后持续出现六个月及以上完全或部分响应的比率。
黑色素瘤是一种黑色素细胞不受控增殖的皮肤癌，而黑色素细胞主要负责皮肤色素沉着。
黑色素瘤是恶性程度最高的皮肤癌，2012年，多个欧洲国家中大约有56000名患者，当年造成了接近10000人死亡。
安进目前是肿瘤免疫治疗的研发者之一，与多家公司有合作关系，包括与默沙东合作研发Keytruda (pembrolizumab)，以及与罗氏合作研究Imlygic与罗氏的PDL-1抑制剂atezolizumab的联合用药
New Drugs Online Report for talimogene laherparepvec
Information
Generic Name: talimogene laherparepvec
Trade Name: Imlygic
Synonym: Oncovex GM-CSF, JS1/34.5- /47-/GM-CSF vaccine, TVEC, T-Vec
Entry Type: New molecular entity
Development and Regulatory status
UK: Recommended for approval (Positive opinion)
EU: Recommended for approval (Positive opinion)
US: Launched
UK launch Plans: Available only to registered users
Actual UK launch date:
Comments
Oct 15: Amgen plans to launch in the US within a week under the brand name Imlygic [20].
30/10/2015 09:16:02
Oct 15: US FDA approves Imlygic (talimogene laherparepvec) for melanoma lesions in the skin and lymph nodes [19].
28/10/2015 08:56:10
Oct 15: EU positive opinion for treatment of adults with unresectable melanoma that is regionally or distantly metastatic (Stage IIIB, IIIC and IVM1a) with no bone, brain, lung or other visceral disease. This is the first oncolytic immunotherapy medicine recommended for approval in the EU [18].
23/10/2015 13:53:21
Apr 15: A panel for the US FDA voted 22:1 to approve talimogene laherparepvec (T-vec) monotherapy despite previous concerns about drop-out rates of the pivotal study. Regarding these issues, the committee concluded that, “any bias that might have occurred in the study conduct would not change the study results sufficiently to alter the overall interpretation that talimogene laherparepvec had an effect on durable response rate” [16].
05/05/2015 11:02:18
Apr 15: Amgen filed a BLA based on data from a Phase III study of T-Vec called OPTiM in which T-Vec “demonstrated a significant extension in durable response rates (DDR),” which was its primary endpoint, as well as a 4.4 month overall survival (OS) as a secondary endpoint which was not considered to be clinically significant. A US FDA advisory committee raised concerns about this study of T-Vec in an internal review. The committee expressed concern about the 278 pts who dropped out of the study, questioning whether the investigators biased their decisions in favour of positive outcomes. Additionally, the committee questioned whether the systemic response observed was direct evidence of the drug’s effect. It also questioned whether there was investigator bias affecting the final results concerning overall survival. The FDA will vote at the end of April on whether T-Vec should receive approval to treat melanoma [15].
28/04/2015 11:13:38
Feb 15: The FDA’s Cellular, Tissue and Gene Therapies Advisory and Oncologic Drugs Advisory Committees will jointly review the company’s Biologics License Application for talimogene laherparepvec for treatment of patients with injectable regionally or distantly metastatic melanoma. The meeting will take place on Apr 29 with a Prescription Drug User Fee Act (PDUFA) action date of Oct 27 [14].
12/02/2015 13:19:03
Sep 14: Filed to the EMA for the treatment of adults with melanoma that is regionally or distantly metastatic. [13]
03/09/2014 15:16:36
Jun 14: Amgen plan to file in the US in late 2014 [12].
09/06/2014 12:37:54
US filing expected mid 2011 (4).
23/03/2011 14:17:47
PIII trials in US underway with UK trials due to start later in 2009 (1).
16/04/2009 11:37:43
Trial or other data
May 15: Results of NCT00769704 published in the Journal of Clinical Oncology. Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC–treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred [17].
02/06/2015 09:31:03
Jun 14: Data from the 19 patients in a P1b combination study, presented for the first time at ASCO, showed no dose-limiting toxicities with talimogene laherparepvec in combination with ipilimumab (Abstract #9029). Additionally, tumors either shrank in size or were no longer detectable in 56 percent of patients when talimogene laherparepvec was given prior to and in combination with ipilimumab. The most common adverse events observed were chills, fevers, rash and fatigue [12].
09/06/2014 12:38:20
Apr 14: Top-line results from the primary overall survival analysis of a PIII trial in unresected stage IIIB, IIIC or IV melanoma compared to treatment vs subcutaneous GM-CSF showed that, while the primary endpoint of durable response rate was met the secondary endpoint of OS was not met, although there was a strong trend in favour of talimogene laherparepvec (p=0.051). The estimated OS hazard ratio and improvement in median OS were similar to that previously reported at the interim OS analysis [11].
06/04/2014 09:58:22
Mar 14: A pre-specified retrospective analysis recorded tumour-level responses from a pivotal PIII study of talimogene laherparepvec in patients with injectable unresected stage IIIB, IIIC or IV melanoma vs GM-CSF. Of the 295 patients treated with talimogene laherparepvec, ~4,000 tumour lesions were tracked for this analysis. Half the lesions were injected with talimogene laherparepvec at least once, while the rest were not, including visceral tumours. There was a ≥50% reduction in tumour size in 64% of injected tumours; one-third of uninjected non-visceral tumours and 15% of visceral tumours were reduced by ≥50%. There were 35 melanoma-related surgeries performed during this trial of which 30% successfully removed all residual disease [10].
17/03/2014 10:09:17
Nov 13: Pre-defined interim results from a pivotal PIII trial of talimogene laherparepvec (T-vec) vs GM-CSF in patients with unresected stage IIIB, IIIC or IV melanoma reported. Patients were randomized 2:1 to T-vec intralesionally every 2 weeks or GM-CSF sc for the first 14 days of each 28 day cycle. Treatment could last for up to 18 months. Median OS was 23.3 vs 19.0 months (HR = 0.79 [95% CI 0.61-1.02]; p=0.0746). Differences in survival rates were pronounced in the subset of patients with stage IIIB, IIIC or IV M1a disease (HR = 0.56, [0.38-0.81]) or who received T-vec as first-line treatment (HR = 0.49, [0.33-0.74]), each comprising approximately 50% of the study population. Mature OS data expected H1 2014. The most frequently AEs were fatigue, chills and pyrexia. The most common serious AEs include disease progression in both arms, and cellulitis and pyrexia in the T-vec arm. Serious adverse events occurred in 26 vs 13% of patients respectively [9].
19/11/2013 20:11:38
Mar 13: Amgen announces talimogene laherparepvec has met the primary outcome in the OPTiM trial (NCT00769704; n>400) with 16% of trial pts having a durable response rate (defined as the rate of complete or partial response lasting continuously for at least six months) vs. 2% of those on GM-CSF. Amgen also revealed a trend toward overall survival in favor of its virus vs. GM-CSF. Amgen plans to report more safety & efficacy data at the major annual ASCO meeting in May. Overall survival data are expected in late 2013 [8].
20/03/2013 17:04:50
Mar 13: Estimated study NCT00769704 completion date September 2014 [8].
11/03/2013 14:47:27
A complete analysis of the PIII trial is expected in 2013 and the company does not plan on reporting study data until then. The primary endpoint is a statistically significant improvement in durable response rate, defined as the rate of complete response or partial response lasting continuously for ≥6 months. The secondary endpoint is overall survival. Per study protocol, a predefined volume can be injected into multiple tumor lesions. The trial design has been questioned; GM-CSF as a comparator is atypical, dacarbazine is the normal comparator [7].
04/09/2012 11:09:46
July 11: Enrolment in phase III trial for malignant melanoma in USA, Canada, South Africa & United Kingdom (NCT00769704) completed. [5]
23/04/2012 09:48:52
June 11: Enrolment in an extension phase III trial for malignant melanoma (late-stage disease) in United Kingdom (NCT01368276) completed. This 12-month extension trial will assess the long-term safety of treatment with talminogene laherparepvec [5]
23/04/2012 09:48:42
Mar 11: Amgen has acquired the BioVex group [5].
21/04/2011 11:11:31
Jan 10: The US FDA agrees to allow pts who have not received prior treatment into the OPTiM trial [4].
23/03/2011 14:19:50
Jan 11: Amgen is to acquire BioVex, which will become a wholly owned subsidiary of Amgen [3].
25/01/2011 21:37:52
Results from PII study report at 2009 ASCO meeting - J Clin Oncol 27:15s, 2009 (suppl; abstr 9035) . 50 patients with advanced melanoma (stage IIIc and IV) with at least one injection accessible lesion received a single IT injection of 106 pfu/ml apportioned between ≤10 injectable tumours, followed 3 wks later by ≤24 sequential injections every 2 wks until clinically significant disease progression, or complete response (CR). The overall response rate was 26% (8 CR, 5 PR); 10 responses have been maintained for >6 months and 2 are ongoing at <6months, the longest currently being at 35 months from first dose. 93% of patients (14 of 15) with PR, CR or surgical CR remain alive. Kaplan Meier one year survival is 61%. The median OS is 16+ months. AEs were limited and generally involved transient flu-like symptoms [2].
04/11/2009 08:33:55
The OPTiM trial is a multi-national, open label, randomized PIII3 study designed to assess the efficacy and safety of treatment with OncoVEX (GM-CSF) vs. s.c. GM-CSF in patients with unresectable stage III (b-c) and Stage IV (M1a-c) disease. Patients will have received at least one prior therapy for active disease which includes any type of therapy including investigational drugs (1).
16/04/2009 11:42:26
Evidence Based eva luations
NIHR HSRIC http://www.hsc.nihr.ac.uk/topics/oncovex-gm-csf-for-malignant-melanoma-unresectable/
NICE scope http://www.nice.org.uk/guidance/indevelopment/gid-tag509/documents
References
Available only to registered users
Category
BNF Category: Other immunomodulating drugs (08.02.04)
Pharmacology: First-in-class oncolytic virus immunostimulant. Dual mechanism of action; attenuated herpes simplex virus (HSV) potentiates local anti-tumor effects & GM-CSF cytokine stimulates the immune system to kill melanoma cells at sites not infected with HSV.
Epidemiology: In 2008, the UK age-standardised incidence of melanoma for females was 16.5 and for males was 15.9 per 100,000 population. It has been estimated that the lifetime risk of developing malignant melanoma in 2008 was 1 in 61 for men and 1 in 60 for women in the UK. [6] Only one-third of advanced melanoma patients have some skin, soft tissue or nodal disease that is amenable to intratumoral injection [7].
Indication: Malignant melanoma
Additional Details: stage IIIc and IV disease - 1st & 2nd line therapy
Method(s) of Administration
Intratumoural
Company Information
Name: Amgen
US Name: Amgen
Further Information
Anticipated commissioning route (England) NHSE
High cost drug list? Awaiting Update
Tariff Chemotherapy is locally negotiated.
In NICE timetable: Yes
When: Jul / 2016
Note: www.nice.org.uk/guidance/indevelopment/gid-tag509
Implications Available only to registered users |
