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A New Therapy for Melanoma

Reporter  Larry H Bernstein, MD

S Andrews, R Holden.  Characteristics and management of immune-related adverse effects associated with ipilimumab, a new immunotherapy for metastatic melanoma. Cancer Management and Research (Dovepress: open access) 11 Sept, 2012; 4:299-307.

This report is an immediate followup to a post on Ulcerative Colitis, a chronic inflammatory condition of the colonic mucosa that is now ready for phase 3 clinical trial with a breakthrough drug that blocks the action of “T-cell lymphokine” activity of IL-2, 4, 7, 15 and 21.  This also deals with a breakthrough immunotherapy for a common skin malignancy, melanoma, the sixth most common cancer (bearing no ontogenetic resemblance to the GI disease), that accounted for 8790 in the US in 2011. Approximately 84% of cases present with local disease (stages I and II), 8% of patients have regional disease, and only 4% show distant metastases, with 4% being unstaged. Melanomas characteristically occur after puberty.    Lesions that are by all means identical to melanoma behave as a benign pigmented mole in a child.  The melanoma is a raised pigmented lesion that when it invades deeply through the dermal layer and metastasizes, would be identify this late stage for treatment of the disease.  Stage IV disease is defined as distant skin involvement, soft tissue involvement, lung, and/or visceral sites.  Survival rates are highly dependent on the stage of metastatic disease,  with stage IV melanoma patients showing 15% survival rate at 5 years, but the survival rate drops to 3% at 5 years with brain metastasis. The therapeutic options for extensive disease or for metastatic disease have been until recently limited to entry into a clinical trial, treatment with dacarbazine or high-dose interleukin-2 was the only therapy approved by the US Food and Drug Administration (FDA) with no survival benefit and greater toxicity of combination sequential therapy of dacarbazine + other  drugs.

Vemurafenib (Zelboraf®, Genentech, South San Francisco, CA) is a BRAF inhibitor that has demonstrated activity in patients with metastatic melanoma who harbor the V600E BRAF mutation. Recent interim results of a Phase III study have reported 6-month overall survival of 84% (95% confidence interval 78–89) in patients receiving vemurafenib compared with 65% in the dacarbazine arm (95% confidence interval 56–73) of the study.14 The rate of progression-free survival was also improved in the vemurafenib arm, and this agent has received approval from the FDA for the treatment of patients with unresectable or metastatic melanoma whose tumors harbor the V600E mutation.  However, the long-term efficacy and safety of vemurafenib has yet to be determined.  Introduce Ipilimumab (Bristol Myers Squibb), the first drug approved for the treatment of melanoma by the FDA which has shown a survival benefit in a randomized Phase III study.

Mechanism of Action:  Ipilimumab is a monoclonal antibody that blocks cytotoxic T lymphocyte antigen-4, an inhibitor of T cell activation, thereby potentiating an immune response.  It’s unique mechanism of action differentiates it from chemotherapies, in that it targets the immune system rather than directly targeting the tumor itself.  Recall that in the previous GI inflammatory case the target was T-lymphocytes 2, 4, 7, 15, and 21. So this treatment is more narrowly focused.

Most recent Pase III Trial Result:  A Phase III study of ipilimumab in treatment-naïve patients with unresectable stage III or IV melanoma was recently published.  This study was done using a higher, experimental dose of ipilimumab at 10 mg/kg in combination with dacarbazine compared with dacarbazine alone. The combination arm of the study showed significantly higher survival rates in patients who received dacarbazine alone at one year (47.3% versus 36.3%), 2 years (28.5% versus 17.9%), and 3 years (20.8% versus 12.2%, hazard ratio for death 0.72; P , 0.001). The study confirmed the overall survival benefit of ipilimumab and it demonstrated an acceptable safety profile.

Summary of pharmaceutical treatment options

• Dacarbazine has low toxicity, is well tolerated, minimally effective, and has limited progression-free survival

• High-dose interleukin-2 has high toxicity, is used in highly selected patients, and has limited efficacy

• Combination biochemotherapeutic regimens have not been shown to have an overall survival benefit, and have added toxicity

• Vemurafenib shows a rapid response, has improved 6-month overall survival and progression-free survival, but lacks durability

• Ipilimumab has a unique side effect profile, and has been shown to improve one-year and two-year overall survival.

Immune-related AEs with ipilimumab

The most common safety events associated with ipilimumab therapy are immune-related; a recent pooled analysis of 14 completed Phase I–III ipilimumab clinical trials showed that 64.2% of patients experienced an immune-related adverse event (AE) of any grade.20 Immune-related AEs are likely reflective of the immune-based mechanism of action of ipilimumab and may affect various organs. An overview of the rate of immune-related AEs associated with ipilimumab 3 mg/kg in the Phase III MDX010-20 registration trial is shown in Table 1 (Rates of immune-related adverse events from the MDX010-20 registration trial, which included previously treated patients with unresectable stage III or IV melanoma treated with ipilimumab 3 mg/kg alone, a control vaccine alone (glycoprotein 100), or a combination of both ipilimumab and glycoprotein 100).  The most common immune-related AEs included toxicities of the skin, gastrointestinal tract, endocrine system, and liver.  The majority of immune-related AEs initially manifest during induction phase; however, a minority occurs weeks to months after discontinuation of ipilimumab. Time to resolution of immune-related AEs experienced by patients varied from 4.3 to 7.7 weeks on average across all studies.

Zelboraf® (vemurafenib) package insert. South San Francisco, CA: Genentech USA Inc,; 2011.
Hodi FS, O’Day SJ, McDermott DF, et al. Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. 2010; 363:711–723.

Patterns of response with ipilimumab

In addition to the safety events, which may be tied to the unique mechanism of action of ipilimumab, unique clinical responses might also be reflective of the immune-related mechanism of action. (Table 2) Response patterns with ipilimumab include two standard responses that are commonly observed with other cytotoxic therapies, the first being an immediate decline in overall tumor burden with no new lesions and the second being stable disease. Stable disease in some patients on ipilimumab can be followed by a slow and steady decline in tumor burden.  However, throughout clinical development of ipilimumab, two additional, novel response patterns have been observed in patients, while still being shown to be associated with improved survival in patients. The first is a reduction in overall tumor burden in the presence of new lesions and the second is an initial increase followed by a steady decrease in tumor volume.

Patterns of response with ipilimumab

• Immediate response in baseline lesions, without the presence of new lesions

• Durable stable disease (SD), which may be followed by a slow, steady decline in total tumor burden

• Response after an increase in total tumor burden

• Response in presence of new lesions (which may have been present at baseline but were radiographically undetectable)

Notes: All patterns of response have been associated with response in patients and to improved survival.

Hoos A, Ibrahim R, Korman A, et al. Development of ipilimumab: contribution to a new paradigm for cancer immunotherapy. Semin Oncol. 2010;37(5):533–546.

Ibrahim R, Berman D, de Pril V, et al. Ipilimumab safety profile: summary of findings from completed trials in advanced melanoma. J Clin Oncol. 2011;29 Suppl:Abstract 8583.

Wolchok JD, Hoos A, O’Day S, et al. Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria. Clin Cancer Res. 2009;15:7412–7420.

Hoos A, Eggermont AM, Janetzki S, et al. Improved endpoints for cancer immunotherapy trials. J Natl Cancer Inst. 2010;102:1388–1397.

Conclusion

Ipilimumab is a novel immunotherapeutic agent approved by the FDA for unresectable and metastatic melanoma. Due to its characteristic and distinctive mechanism of action, ipilimumab elicits a number of specific immune-related AEs. Time to onset and resolution of ipilimumab-associated immune-related AEs follow a predictable temporal pattern but can vary from patient to patient.

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