Highlights from promising immuno-oncology candidates are being presented at the American Society of Clinical Oncology's 49th annual meeting in Chicago.
IHS Global Insight perspective | |
Significance | Highlights in metastatic melanoma from US pharmaceutical firms at the American Society of Clinical Oncology meeting include Amgen's late-stage talimogene laherparepvec, Bristol-Myers Squibb's Yervoy + nivolumab combination regimen, and Merck & Co.'s lambrolizumab. |
Implications | All three candidates from a new class of oncology drugs harnessing the immune system demonstrated robust results in metastatic melanoma. |
Outlook | IHS Global Insight anticipates strong performance for the new class of immuno-oncology candidates if and when they reach the market, as they seem to demonstrate significant improvements over existing treatments, particularly for metastatic and virulent forms of cancer. |
The American Society of Clinical Oncology (ASCO)'s 49th annual meeting in Chicago, which began on 31 May, has seen some positive results highlighting new drugs and combination drug candidates as potential treatment for metastatic melanoma, one of the most aggressive forms of cancer. The conference highlights from US pharmaceutical firms include Amgen's late-stage talimogene laherparepvec, Bristol-Myers Squibb (BMS)'s Yervoy + nivolumab combination regimen, and Merck & Co.'s lambrolizumab.
Amgen's talimogene laherparepvec
Amgen's investigational melanoma candidate is in late-stage development. The US biopharmaceutical firm presented results investigating talimogene laherparepvec's safety and efficacy in more than 400 patients with unresected stage IIIB, IIIC, or IV melanoma in comparison to granulocyte-macrophage colony-stimulating factor (GM-CSF) treatment. The global, randomised, open-label Phase III study demonstrated a statistically significant difference in durable response rate (DDR), measured as the rate of complete or partial response over a continuous six-month period, with talimogene laherparepvec (16%) compared to the CM-CSF group (2%), thus meeting its primary endpoint. The overall response rate with talimogene laherparepvec was 26% compared to 6% in the CM-CSF arm, with a trend towards overall survival (0.79) noted at an interim period.
The talimogene laherparepvec DRR rates for the various stages of advanced melanoma were 33% in stage IIIB/IIIC, 16% in stage IVM1a, 3% for stage IVM1b, and 8% for stage IVM1c, whereas the GM-CSF arm did not see rates higher than 4% in any of the stages. Common adverse events include fatigue, chills, and pyrexia. Serious adverse events occurring in 26% of talimogene laherparepvec patients and 13% in GM-CSF, include disease progression, cellulitis, and pyrexia.
Talimogene laherparepvec's mode of action is through two mechanisms: the first through localised termination of tumour cells, and the second by stimulating a systemic anti-tumour immune response in the body. The candidate is injected into tumour tissue and facilitates replication of viral components until the cell ruptures, releasing the virus along with GM-CSF that the virus was engineered to produce. GM-CSF is a white-blood-cell growth factor that leads to heightened activation of the immune system against tumour cells throughout the body.
BMS's Yervoy and nivolumab
BMS announced detailed results for its combination regimen of cancer drug Yervoy (ipilimumab) with new candidate PD-1 receptor blocker nivolumab, licensed by BMS from Ono Pharmaceutical Co. (Japan), for the treatment of patients with advanced melanoma. Some data from the promising study was released in advance of the conference (see United States: 17 May 2013: BMS's investigational immune-oncology treatment yields positive results in early stage melanoma trial). The Phase I, Study 004 trial enrolled 86 patients and evaluated the combination regimen either concurrently (53) or sequentially (33). The concurrent arm received 1mg/kg nivolumab and 3mg/kg Yervoy, with 53% (nine out of 17 patients) demonstrated an objective response (OR) based on model World Health Organization (mWHO) criteria, seeing at least 80% reduction in tumour size at 12 weeks, and three complete responses (CR). Overall, the concurrent arm demonstrated a 40% OR rate (21 patients out of 52), and 31% saw tumour shrinkage by at least 80%, and five CRs. ORs lasted between 6.1–72.1 weeks at the time of analysis.
The estimated one-year survival rate in the concurrent group is approximately 82%, although median overall survival has not been reached at the 13-month follow up. With regards to safety and tolerability, grade 3–4 adverse events were reported in 53% of patients in the concurrent arm, although no treatment-associated deaths were reported. Most common adverse events in the concurrent arm included reports of rash (55%), pruritus (47%), fatigue (38%), and diarrhoea (34%). The Phase I data is published in The New England Journal of Medicine, with a Phase III trial evaluating nivolumab in combination with Yervoy in advanced melanoma currently under way, according to BMS.
BMS has reiterated its commitment to developing immuno-oncology, a fast-growing field in oncology focussed on utilising the body's own natural capabilities to target tumours through the immune system. BMS's nivolumab is currently in clinical development in seven "potentially registrational" trials evaluating its efficacy and safety in treatment of non-small-cell lung cancer (NSCLC), advanced renal cell carcinoma, and advanced melanoma. Yervoy, which is already approved for marketing in over 40 countries for melanoma, is now also in late-stage clinical development, with Phase III trials in adjuvant melanoma, NSCLC, and metastatic castrate-resistant prostate cancer under way (see United States: 28 March 2011: FDA Approves BMS' Yervoy for Treatment of Metastatic Melanoma).
Merck & Co.'s lambrolizumab
Merck & Co. also reported promising results from its PD-1 targeting candidate, lambrolizumab (MK-3475), from a Phase IB expansion study at ASCO, which was also published in The New England Journal of Medicine. The trial evaluated the safety and efficacy of lambrolizumab in patients with advanced (inoperable and metastatic) melanoma. The multi-centre, single-arm, open-label study enrolled 135 patients with advanced melanoma, and evaluated the overall response rate and response duration in three different groups, 10mg/kg every two weeks; 10mg/kg every three weeks or 2mg/kg every three weeks. Interim results demonstrated an average response rate of 38% across all dosage regimens, with the 10mg/kg every two weeks arm demonstrating the highest response rate (52%). The duration of confirmed responses after 12 weeks ranged from 20 days to eight months. Most common adverse events were grade 1 or 2, including fatigue (30%), rash (21%), pruritus (21%), and diarrhoea (20%); and 13% grade 3 or 4 events including fatigue (1.5%), rash (2%), and elevated aspartate transaminase (AST) levels (1.5%).
Based on these results, Merck will be initiating late-stage trials with lambrolizumab in advanced melanoma, and non-small-cell lung cancer in the third quarter of 2013, with early stage trials in triple-negative breast cancer, metastatic bladder cancer, and head and neck cancer. The US FDA granted Merck's lambrolizumab breakthrough therapy designation for advanced melanoma in April 2013 (see United States : 25 April 2013: Merck & Co.'s lambrolizumab granted "breakthrough" designation by US FDA for advanced melanoma).
Outlook and implications
The incidence of melanoma has increased over 200% in the last three decades, with an estimated 132,000 new cases registered each year around the world. The aggressive type of cancer represents only 5% of skin cancers; however, it is the major cause of death from skin cancer. Leading pharmaceutical companies are racing to bring promising new candidates to the market to address the rising occurrence of the disease, and the ASCO conference highlighted several novel candidates that further validate the efficacy of immuno-oncology treatments.
Amgen is pleased with the trial outcome, and anticipates obtaining the complete overall survival data later in the year. Amgen's executive vice president of research and development has stated that "these are the first data from a controlled trial of oncolytic immunotherapy to demonstrate activity in melanoma". Meanwhile, BMS has stated its investigational combination regimen is the first one to investigate two immune-checkpoint inhibitors that can reduce tumour cells' ability to evade the immune system. Nivolumab and Yervoy are monoclonal antibodies that target different receptors for distinct T-cell checkpoint pathways: PD-1 receptor involved in programmed cell death, and cytotoxic T- lymphocyte antigen-4 (CTLA-4). The firm finds the promising results could lead to further research in combination candidates that can target different immune checkpoints in a complementary manner. Similarly, Merck's PD-1 receptor inhibitor, lambrolizumab is capable of utilising the immune system to target and kill tumour cells. The firm's candidate is directly competing with BMS's nivolumab-Yervoy combination regimen, and both candidates seem to present very comparable and significant response rates of 52% and 53%, respectively. Additionally, lambrolizumab demonstrated complete responses in five patients, and BMS's combination regimen saw three complete responses so far in the most efficacious arms.
Oncology research has shown an increased interest in immuno-oncology candidates, which may become the next new wave of cancer drugs harnessing the body's own immune system in a targeted yet systemic manner. For metastatic and virulent forms of cancer, these therapies may demonstrate significant improvements over existing treatments, and it remains to be seen which of these and other high-potential candidates make it successfully through clinical development, with IHS Global Insight expecting strong performance from the new class of candidates in the oncology market.