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Friday, May 17, 2013

ONLINE FIRST: Immunotherapy Poised to Change 'Treatment Paradigm' in Melanoma, Other Solid Tumors



After years of lukewarm results with immunotherapy, researchers took a big step forward recently with ipilimumab, the first therapy designed to relieve a checkpoint or brake intrinsic to the immune system. Now, two studies that will be presented at the American Society of Clinical Oncology Annual Meeting suggest the step forward has turned into a leap forward with new agents aimed at another immune system checkpoint and a combination of two checkpoint-targeted antibodies.


In a large Phase I study of an anti-PD-L1 antibody, MPDL3280A (Abstract 3000), investigators saw no major safety concerns and a 21 percent response rate in patients with locally advanced or metastatic solid tumors, researchers reported during a news conference this week. In a separate Phase I trial, nearly half of the patients treated with a combination of ipilimumab, which blocks the CTLA-4 receptor, and nivolumab, which blocks the PD-1 receptor, showed objective responses -- and 90 percent of those patients were still responding at the last data check.


"You can see why we are all so excited about this," said ASCO President Sandra M. Swain, MD. "Because, after years of not really having success in immunotherapy, we have now heard two presentations showing great, great improvements and progress -- especially this last one," she said, referring to the ipilimumab-nivolumab combination.


"This combination led to rapid, lasting, and profound tumor shrinkage... I think this is really, truly remarkable. This kind of responses have not been seen with immunotherapy before."


PD-L1 Blockade Triggers Responses in Multiple Tumor Types

The Phase I study of MPDL3280A enrolled 171 patients, with 140 evaluable for response, reported Roy S. Herbst, MD, PhD, Ensign Professor of Medicine at Yale Cancer Center and Chief of Medical Oncology at Smilow Cancer Hospital. The trial is the first in-human study of MPDL3280A, a monoclonal antibody that binds to the ligand of the PD-1 receptor (PD-L1). Tumor cells express PD-L1 on their surface, which allows them to evade the immune system, by essentially turning off the T cell response. The antibody blocks that evasion system.


The researchers used a standard 3+3 Phase I trial design with expansion cohorts. The majority of patients were treated at the two highest doses, 15 mg/kg (n=57) and 20 mg/kg (n=67), with all patients receiving the drug intravenously every three weeks.


There were no dose-limiting toxicities. Overall, 43 percent of patients experienced some Grade 3 or 4 adverse event, but the investigators judged that only 13% were likely due to the study drug, Herbst said. The most common Grade 3 or 4 adverse events were hyperglycemia, which affected five percent of patients, followed by fatigue (4%), increased ALT (3%), dyspnea (3%), and hypoxia (3%). Moreover, two percent of patients developed Grade 3 or 4 immune-related events, based on investigator assessment, but only one patient discontinued treatment and that was due to elevated liver enzymes.


Of the 140 evaluable patients, 29 (21%) showed an objective response to MPDL3280A. When the response assessment was limited to just the 36 patients whose tumors appeared to be PD-L1 positive, based on a companion diagnostic in development, the response rate rose to 36 percent.


However, nine (13%) of the 67 patients whose tumors appeared to be PD-L1 negative, based on the companion diagnostic, also showed objective responses to the drug. Based on that observation, Herbst noted that the diagnostic test was still "in evolution," saying that either the cutoff value used in the diagnostic needs to be re-evaluated or a more sensitive diagnostic test is needed.


"Importantly -- and I've seen this in my own patients -- these responses tend to occur quite quickly and they also tend to be durable responses," he said. At the last data analysis in January, 26 of 29 patients were continuing to respond to treatment, with a time on study ranging from three to more than 15 months.


Additionally, the therapy appears to work in a variety of solid tumors, including non-small cell lung cancer, head and neck, colorectal, kidney and gastric cancer.


ASCO President-Elect Clifford A. Hudis, MD, noted that whereas Phase I trials have historically been used to establish the safety of a drug before moving it forward to test for efficacy, this study has already shown both safety and significant evidence of efficacy.


"The clearest indications of activity were in those patients with non-small cell lung cancer as well as melanoma, and also in patients who had tumors that tested positive for the PD-L1 marker," he said.


"This agent targets the PD-L1 protein on the surface of tumors cells, and unblocks a checkpoint in the immune response pathway. It allows the body's natural immunity to turn on and amplify and ramp up to target that patient's cancer. So this is really the beginning of an exciting, we think, new chapter of cancer."


Relieving Two Checkpoints Is Better than One

In the other study,

Jedd D. Wolchok, MD, PhD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, reported the results of a Phase I combination trial designed to improve responses seen with two immunotherapy checkpoint drugs in patients with advanced melanoma (Abstract 9012).


Ipilimumab is approved for use in this patient population, but the objective response rate is only about 11 percent. Researchers are still testing single-agent nivolumab, which blocks the PD-1 receptor on T cells; early data suggests that the nivolumab monotherapy response rates are around 41 percent, he said. When used as monotherapy, neither drug triggers complete responses in more than three percent of patients.


"Both drugs relieve molecular brakes on the immune system, brakes that prevent the full and persistent activation of the immune system," Wolchok said. However, the drugs work in different ways, with ipilimumab inhibiting the CTLA-4 receptor on the surface of T cells and nivolumab blocking the PD-1 receptor on T cells. Preclinical studies have suggested that the combination will produce better results than either agent alone.


To test that possibility, Wolchok and colleagues are testing several doses and two different schedules, concurrent dosing and sequential dosing. In the concurrent treatment arm, patients receive nivolumab plus ipilimumab every three weeks for four doses, followed by nivolumab alone every three weeks for four doses, and then starting at week 24 patients receive one combination dose every three months. Patients were eligible for the sequential treatment arm if they had received standard ipilimumab treatment outside of this trial and did not show significant tumor shrinkage on CT scans; once enrolled in this trial the patients received nivolumab every two weeks.


As of February 2013, 86 patients were enrolled in the trial and evaluable. "Both the concurrent and sequential treatments had side effects that were manageable and generally reversible using standard algorithms that have been developed to manage side effects of each medicine alone," he said. "In general, we weren't surprised by the severity of the side effects and we didn't see anything new."


Adverse events were more common in the concurrent dosing cohort, with 28 of 53 patients (53%) developing Grade 3 or 4 adverse events. The most common adverse events were enzyme elevations, including ALT (11% of patient affected), AST (13%), and lipase (13%). The investigators saw inflammatory adverse events more rarely, affecting the eye, lung, and colon; all of these were reversible, and there were no treatment-related deaths on the study.


In the sequential treatment arm, six (18%) of 33 patients developed Grade 3 or 4 side effects due to treatment. The most common adverse event was lipase elevation, which occurred in two patients (6%).


Of all 52 evaluable patients treated in the concurrent treatment arm at any dose, 21 (40%) have had an objective response, 16 (31%) had greater than 80% tumor shrinkage at week 12, and approximately 17% had complete responses. Of the 17 concurrent cohort patients treated with 1 mg/kg nivolumab and 3 mg/kg ipilimumab, nine patients (53%) showed an objective response and seven (41%) had more than 80% tumor shrinkage at week 12.


"What was unique in our experience was that most of these patients had rapid and deep regressions, with many showing more than 80 percent tumor regressions by the time of the first scans," Wolchok said.


When the definition of response was broadened to include slow responders and those with stable disease on CT scans, the disease control rate was 65 percent with the concurrent combination therapy, he said.


 Patients in the sequential therapy arm also showed objective responses, with six of 16 patients (38%) treated with 1 mg/kg nivolumab showing objective responses, four of which had greater than 80 percent tumor shrinkage at week 12. In the 3 mg/kg arm, which was initiated later than the lower-dose arm, 14 patients are evaluable but none have yet shown an objective response.


"The important result [in the sequential cohort] is that there were responses noted, even in patients who had shown growth or progression of disease on ipilimumab," Wolchok said. "This indicates that even when one immunotherapy does not provide a response, patients can still respond to another immune modulator. This further supports the importance of studying combination therapy with medicines targeting distinct pathways."


When asked whether the combination may shift patients from an unresectable disease category into a resectable one, he said most of the patients in the current trial had metastatic disease so this still wasn't an option. However, in a few patients who had tumors readily accessible on or under the skin, the researchers obtained tumor samples: "In a few instances, [the surgeons] removed what they thought was a tumor, but instead what was inside this lump was a collection of immune cells that had been attracted there by the immunotherapy. So there was no viable melanoma left."


"This study is clearly proof of principle that concurrent use of two immune checkpoint antibodies can change the treatment paradigm for advanced melanoma," Swain concluded.


A Phase III trial will start sometime this year to compare the efficacy of concurrent nivolumab plus ipilimumab versus each agent as monotherapy in advanced melanoma patients. The combination is also being tested in non-small cell lung cancer and renal cancer.