Following in the footsteps of positive results for the drug nivolumab, another anti-PD1 antibody, lambrolizumab (formerly MK-3475), is also showing promising activity in melanoma. At the annual meeting of the American Society of Clinical Oncology, Antoni Ribas, MD, PhD, of the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles, presented data from a large, 1,000-plus patient phase I trial that also included other cancer types.
Of the 135 metastatic melanoma patients treated with lambrolizumab at different doses, 38% had their tumors shrink in volume by at least 30%. The responses are durable thus far—after an average of 11 months of follow-up, 81% (42 of 52) of the patients who responded continued to respond as of March, 2013.
Patients who had previously been treated with ipilimumab, an immune checkpoint antibody approved for melanoma treatment since 2011, were analyzed in a separate cohort in this study and found to have a similar rate of response (38%) as those who had not been exposed to ipilimumab. The separate analysis was to help researchers understand whether patients are able to respond to an immunotherapy after failing a previous one. The results here (as well as data from other studies with ipilimumab and nivolumab) suggest that failing one immune checkpoint antibody therapy does not necessarily predict a failure to respond to a different antibody in this drug class.
Lambrolizumab, like nivolumab, blocks activity of the programmed death 1 (PD-1) molecule, an immune checkpoint receptor found on a type of white blood cell called a ‘T cell.’ T cells fight infections in our bodies and also facilitate the body’s attack on tumors.
The PD-1 molecule on T cells interacts with another molecule, the programmed death 1 ligand (PD-L1) that fits with PD-1 like a lock and key. This interaction helps to modulate the immune response of T cells to various stimuli, including infections. PD-L1 is found on cells throughout the body, but tumor cells can also express PD-L1, resulting in a dampened response of the immune system to the tumor. Anti-PD1 antibodies block the interaction between PD1 and PD-L1 to boost T-cell activity in response to tumors.
Patients were treated either every 2 or every 3 weeks with two different doses (2 mg/kg or 10 mg/kg). Patients treated at the 10 mg/kg dose every 2 weeks had the highest rate of response: 52%.
Nikhil Khushalani, an associate professor of oncology, section chief for melanoma at the Roswell Park Cancer Institute in Buffalo, New York, (who was not associated with the study) highlighted the rapid responses seen in patients, even those who have many and large tumors. Khushalani said he was also impressed by the length of time patients responded and continue to respond to the treatment.
Thus far, lambrolizumab therapy appears to have a lower rate of toxicities and a different spectrum of toxicities compared with those seen in ipilimumab trials, but larger trials are needed to confirm this observation. Of the patients treated with at least one dose of the antibody, 79% had a drug-related toxicity. Of these, 13% (17 patients) had what were considered to be high-grade toxicities. The most common high-grade toxicities were skin rash in three patients, increased liver enzymes in two patients, renal failure in two patients, and fatigue in two patients. Patients who were previously treated with immunotherapies, including ipiliumab, did not have higher rates of adverse events.
Often, the patient population within a clinical trial does not reflect the types of patients seen in practice. However, according to Khushalani , the patients in this trial appear to represent the types of advanced-disease patients clinicians treat regularly. “The patient cohort is accurately representative of the types of patients we see in our practice with nearly three-quarters having metastatic disease involving sites such as the lung,” he said.
Based on these results, a phase II randomized trial is now testing lambrolizumab in advanced melanoma patients who have previously been treated with other therapies, including ipilimumab. The trial will compare the immunotherapy antibody to standard-of-care chemotherapy. A phase III trial will compare lambrolizumab to ipilimumab in metastatic melanoma patients who have not been previously treated for their metastatic disease. According to Ribas, the trial is slated to begin in a few months.
Other related antibodies are also in different stages of clinical trials. Nivolumab is currently being tested in several phase III trials for advanced melanoma. Based on promising results of a phase I trial (link), one of these phase III trials is now evaluating whether nivolumab in combination with ipilumumab is better than each antibody alone. A related antibody that targets a related molecule PD-L1, MPDL3280A, is in phase I for multiple, advanced solid tumor types, including melanoma.
Immune checkpoint-blocking antibodies are seen as a promising class of drugs for certain cancer types. Still, many questions remain about these agents as treatments for cancer. Because it is not clear which patients respond to these agents, researchers are also studying factors that can help identify melanoma patients who are likely to respond to these immunotherapies. Whether these agents will work better in combination with targeted agents or other immunotherapies also remains to be seen. One early-stage trial is underway, testing MPDL3280A in combination with vemurafenib, a BRAF inhibitor approved for BRAF-mutated metastatic melanoma.
While targeted agents can result in rapid responses, immunotherapy is seen as a way to provide longer-term control of disease for patients. Khushalani believes immunotherapies should be considered as the first line of therapy over targeted agents to offer patients the best chance at durable control of disease. Still, treatment choices should be individualized, and which patients should ultimately receive immunotherapy is still an open question that ongoing research is attempting to answer.