Skin Conditions, General | September 1, 2015 | Author: The Super Pharmacist
Melanoma is a particularly aggressive form of skin cancer that arises from cells containing the pigment, melanin. Rarely, melanoma can occur from melanin-containing cells in the eyes or the intestines. Melanoma that is contained within the superficial layers of skin can often be surgically removed and, with certain adjunctive treatments, can be more or less cured. Malignant melanoma, on the other hand, is very difficult to treat. The prognosis for malignant melanoma depends on the thickness of the original tumor, the speed at which the cancer cells divide, and the extent that the cancer cells have spread throughout the body. Treatment options are limited and prognosis is poor if melanoma cannot be surgically removed or it has spread throughout the body. Traditional treatments for malignant melanoma include radiation therapy and chemotherapy intended to kill cancer cells.
The Australian government earmarked $57 million to include an immunotherapeutic drug called pembrolizumab (Keytruda) to the national registry. Keytruda is one of the first of its kind in a new class of drugs that operate through mechanism called immune checkpoint blockade.
Under normal circumstances, immune system cells called T cells are activated to participate in an immune response. Some activated T cells become killer T cells that find and destroy abnormal cells within the body. Ideally, the immune system would identify melanoma cancer cells as abnormal, activate T cells to attack them, and kill the cancer cells directly.
As you might imagine, having a body full of killer T cells can create its own problems. Indeed, experiments in mice have shown that too many killer T cells can be deadly.
The immune system has an elegant way of keeping the number of killer T cells in check, namely immune checkpoints. Immune checkpoint receptors such as CLTA-4 and PD-1 are present on T cells and keep killer T cells from being over-activated. In this way, a number of T cells can be activated to fight infection, but the total number of T cells is kept under control so as not to overwhelm the body. In other words, immune checkpoint receptors keep activated T-cell numbers in check.
In inoperable or metastatic melanoma, the immune checkpoint system does not do the cancer patient any favors. The immune checkpoint system keeps killer T cells from mounting an effective attack against cancer cells in the body. Immune checkpoint blockade is a way for physicians to release the controls on the T cells and allow them to attack cancer cells more aggressively. While the precise mechanism of action is significantly more complex than described, in essence drugs such as pembrolizumab (Keytruda) release natural controls on T-cell function so that they can gain the upper hand on cancer cells.
Pembrolizumab (formerly lambrolizumab) is a monoclonal antibody that is highly selective for the PD-1 receptor. By blocking the PD-1 receptor and pathway, pembrolizumab reverses the suppression of T cells and induces antitumor responses. Pembrolizumab is intended for people with inoperable or metastatic melanoma who have failed to achieve the benefit from another immunotherapeutic agent called ipilimumab. Likewise, individuals who are BRAF V600 mutation positive must have also failed to achieve a benefit from a BRAF inhibitor. Nevertheless, it is impressive effects in this deadly disease may make it useful in patients with inoperable or metastatic melanoma earlier in their treatment. Notably, pembrolizumab has been studied in people with melanoma who have never taken ipilimumab Pembrolizumab drug is given intravenously, over a period of 30 min., every three weeks. The drug continues to be administered until the melanoma progresses or the side effects become intolerable for the patient.
Pembrolizumab is associated with several serious side effects, some of which can be severe. Significant adverse reactions that may occur in over 10% of patients include:
Significant adverse reactions that may occur in less than 10% of patients include1:
Severe or life-threatening side effects occurring in less than 1% of patients include:
While the above listing of side effects is daunting, the side effects/adverse events must be balanced against the possible benefit of taking the drug. It is important to note that 83% of patients experienced one or more treatment related adverse events during clinical trials, though most people experience fatigue, itchiness of the skin, rash, diarrhea, and joint pain. No one in the trials of pembrolizumab has died from taking the drug. The safety profile is quite similar to that of ipilimumab.
Oncologists and researchers used several measures to determine the efficacy of a cancer-fighting drug. They use terms such as complete response, incomplete response, progressive disease, and stable disease. Obviously, complete response is better than incomplete response and stable disease is better than progressive disease.
These and other terms (e.g. immune related response), can be very technical and mean very little for patients. Therefore, we will use findings that have greater impact and meaning for patients with cancer. In a phase 1 trial, one out of three patients who were treated with pembrolizumab responded to the drug. Response means that the tumor disappeared or got significantly smaller. This response rate is especially impressive when you consider that half the patients included in the trial had already failed another immunotherapeutic drug, ipilimumab. After one year of taking the drug, 66% of had survived and after two years of taking pembrolizumab, approximately half of patients were still alive. Within the first 12 months of taking pembrolizumab, 35% of patients had no progression of their malignant melanoma. Pembrolizumab essentially doubles the rate of people who experience progression free survival at six months over chemotherapy alone (38% compared to 16%).
Immune checkpoints blockade appears to be an effective way to treat malignant melanoma. Patients who take pembrolizumab do significantly better in terms of response, progression free survival, and overall survival than patients who simply take chemotherapy alone. While the side effects can be significant and severe, for people who can tolerate pembrolizumab treatment, there appear to be significant treatment benefits.
Liu V, Mihm MC. Pathology of malignant melanoma. Surg Clin North Am. Feb 2003;83(1):31-60, v. doi:10.1016/s0039-6109(03)00003-3
Balch CM, Gershenwald JE, Soong SJ, et al. Final version of 2009 AJCC melanoma staging and classification. J Clin Oncol. Dec 20 2009;27(36):6199-6206. doi:10.1200/jco.2009.23.4799
Merelli B, Massi D, Cattaneo L, Mandala M. Targeting the PD1/PD-L1 axis in melanoma: biological rationale, clinical challenges and opportunities. Crit Rev Oncol Hematol. Jan 2014;89(1):140-165. doi:10.1016/j.critrevonc.2013.08.002
Postow MA, Callahan MK, Wolchok JD. Immune Checkpoint Blockade in Cancer Therapy. Journal of Clinical Oncology. January 20, 2015 2015. doi:10.1200/jco.2014.59.4358
Hamid O, Robert C, Daud A, et al. Safety and tumor responses with lambrolizumab (anti-PD-1) in melanoma. N Engl J Med. Jul 11 2013;369(2):134-144. doi:10.1056/NEJMoa1305133
Keytruda (pembrolizumab) [prescribing information]. Whitehouse Station, NJ: Merck; June 2015.
Robert C, Ribas A, Wolchok JD, et al. Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet. Sep 20 2014;384(9948):1109-1117. doi:10.1016/s0140-6736(14)60958-2
Ribas A, Puzanov I, Dummer R, et al. Pembrolizumab versus investigator-choice chemotherapy for ipilimumab-refractory melanoma (KEYNOTE-002): a randomised, controlled, phase 2 trial. Lancet Oncol. Aug 2015;16(8):908-918. doi:10.1016/s1470-2045(15)00083-2
Robert C, Schachter J, Long GV, et al. Pembrolizumab versus Ipilimumab in Advanced Melanoma. N Engl J Med. Jun 25 2015;372(26):2521-2532. doi:10.1056/NEJMoa1503093
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. Jan 2009;45(2):228-247. doi:10.1016/j.ejca.2008.10.026
Daud A, Ribas A, Robert C, et al. Long-term efficacy of pembrolizumab (pembro; MK-3475) in a pooled analysis of 655 patients (pts) with advanced melanoma (MEL) enrolled in KEYNOTE-001. Paper presented at: ASCO Annual Meeting Proceedings2015.