Interim efficacy and safety results from the phase 2 LAPACT trial and health-related quality of life

Clinical Expert Commentaries   published on March 7, 2018
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Philip A. Philip, MD, PhD, FRCP, FABC
Professor of Oncology, Pharmacology and Medicine
Kathryn Cramer Endowed Chair in Cancer Research
Vice President of Medical Affairs
Department of Oncology
Karmanos Cancer Institute
Wayne State University School of Medicine
Detroit, Michigan
Interim efficacy and safety results from the phase 2 LAPACT trial and health-related quality of life

Hi, welcome to Partners in Pancreatic Cancer. My name is Dr. Philip Philip. Today I will be providing highlights from two abstracts presented this year at the 2017 ESMO Congress held in Madrid, Spain.

The first one will be nab-paclitaxel plus gemcitabine in patients with locally advanced unresectable pancreatic cancer. This was an interim analysis of efficacy and safety data from a phase II trial, called LAPACT, which was completed recently. I am going to first discuss with you the nab-paclitaxel/gemcitabine combination in patients with locally advanced unresectable disease. The treatment options for this group of patients are very limited and we do not have good FDA-approved regimens for this. The question was, does this combination of gemcitabine/nab-paclitaxel (which is used in metastatic disease) also work in this setting? As you know, in metastatic disease, the phase III trial, also called the MPACT trial, tested the combination in patients who were purely metastatic. They did not include any patient with locally advanced disease. In that trial, there was more than three-fold shrinkage of the primary pancreatic tumor with the combination, suggesting that using this combination may also be beneficial in patients who have purely localized unresectable pancreatic cancer. This was the interim analysis from an international multicenter prospective phase II study which was presented at ESMO, and I want to share with you some of the data that was presented in the abstract and the main salient features from the presentation. These were patients who were naive to any treatment and they had locally advanced unresectable disease. Their ECOG performance status was favorable at 0 or 1. They received six cycles of the combination which was cycled every four weeks. This was the standard nab‑paclitaxel 125 mg/m2 weekly, three weeks on and one week off; and gemcitabine 1000 mg/m2 weekly, three weeks on and one week off. After the initial induction phase, the doctors were allowed to decide what was best for the patient. If the patient had progressive disease, they were withdrawn from the trial. Those that did not have progressive disease had the option of going to surgery, if they had a very good response to the point where they can be resectable. That is a difficult thing to see in this type of tumor; but still if they had that option, they went into surgery if they had a good response. Some patients ended up getting chemotherapy radiation treatment or concurrent chemoradiation, while some patients simply continued on the same treatment.

A total of 101 patients were enrolled who received the combination. The patients were a bit older than those who went on the MPACT trial, so the median age was 65 years of age. The median time from primary diagnosis to first dose was 27 days. A total of 60 patients, which makes 59% of the population treated, managed to complete the induction phase, so that is a good number. Among the 93 evaluable patients, the disease control rate was 82%. The partial response rate was 34%. Those patients who attained a stable disease for 16 weeks or longer were 43%; 12% of the patients had stable disease for less than 16 weeks, and 5% of the patients had progressive disease. The most frequent reason for discontinuing the treatment during the induction phase was adverse events. Those patients comprised 18% of the people treated, and 5% of the patients were removed from the treatment during the induction phase because of the physician's decision, who he thought should not be continuing on the treatment any longer. We always see these things happen if the patient's performance status, for example, is worsening. This could be a reason why a doctor will decide not to continue with the treatment. If we look at the most common adverse events, in this case we are talking about grade 3 or 4, neutropenia in 37% of the patients, again as we expect, and anemia in 9% of the patients. If we look at the neuropathy, which will be a side effect with the nab-paclitaxel and we focus on grade 3 or 4 neuropathy, it was seen in only 4% of the patients which is less than what we have seen in the MPACT trial. Collectively, these results show that the combination is well tolerable and also is a promising combination to take it further. One of the things which we also learned from this trial, and was not a primary endpoint obviously, was the ability of the combination to take patients to surgery, to see if they are resectable, and also if it is going to be a safe surgical procedure. I can tell you that from our interim analysis, 16% of the patients could undergo surgery. Almost half had R0 resections. This is something that adds to the interest we will have in this regimen in the setting of locally advanced unresectable disease. This is a single‑arm trial and the numbers are not that high, but certainly having a percentage of 16% going to surgery is also very encouraging.

Where does this take us? Well, we need to consider this regimen as a treatment option for patients with locally advanced unresectable disease. We are trying to think more of the utility of this regimen in patients who have localized disease that is resectable or borderline resectable. Certainly, a combination that is well tolerated is something we would like to consider in a setting like this. In future trials that we are going to do with targeted agents, this regimen can form a safe and efficacious platform to add new drugs or targeted agents, or other types of treatment and even immunotherapy. We still have a lot of work to do, but at least we have identified a regimen that we can use as a platform for further development of systemic disease. It is very important for us to identify active systemic treatments in locally advanced unresectable disease because we can then start to think of better ways of trying to improve our local or regional therapy, which would be more beneficial if we are able to also control the systemic disease.

Now we are going to discuss the interim health-related quality of life results from the LAPACT trial, the phase II trial of nab-paclitaxel and gemcitabine. Just to remind you, I just discussed the LAPACT study in terms of the efficacy and toxicity in patients who have locally advanced unresectable pancreatic cancer. As you know, when we talk about a treatment in this setting, especially in patients with pancreatic cancer, it is very important for us to examine the disease burden, we know what that can do, and the cumulative toxicity which can happen from the chemotherapy and collectively how these impact the quality of life of the patients. At the end of the day, we want to make sure that we treat the patients and, as much as possible, do not negatively impact their quality of life. If we can improve it, that is even better. The whole idea of this analysis was to see how the combination affected the quality of life of the patients.

Remember we mentioned the schedule and dosing. Just to remind you, 125 mg/m2 of nab-paclitaxel given weekly, three weeks on and one week off; and gemcitabine 1000 mg/m2 given again weekly, three weeks on and one week off. The cycle is every four weeks. These were patients with locally advanced unresectable disease; and those were patients with favorable performance status, meaning it is either 0 or 1 on the ECOG scale. After patients received induction treatment, those who had progressive disease were removed. Those patients who were able to receive the induction treatment of six months and those who did not have any difficulty with the treatment and tolerated the treatment well, the option was to either go to surgery, if they had very good shrinkage of the tumor, or get chemoradiotherapy. Patients could also continue on the same treatment until disease progression. The objective of the study was simply to see how the treatment affected the quality of life of the patients. To achieve that, a tool was used which is known to most of you as the EORTC QoL-C30 tool, and also the QLQ-PAN26. Both were used at the time of the screening and the baseline. They were also used after starting the treatment, using the same tool repeatedly in patients on day 1 of each cycle, and then to follow up after the treatment was completed. This was a nice way of trying to see how the treatment is going to impact the patients, in terms of the treatment, and also in terms of how that interacts with the disease burden of the patients. Again, these are important aspects of our treatment in terms of what we do for the patients. We were looking at global health status, functional status and also symptoms. These were all put into various scales that were used not only at baseline, but to see how they compare as the treatment is going forward. Now I can tell you that the key finding from the abstract was that the quality of life was maintained during the treatment, so the good thing to hear, is that with the gemcitabine/nab-paclitaxel given over this induction period of time, really the patients did not have a major worsening in their quality of life. In fact, the quality of life was maintained. That is a good thing to know because it is always a concern in patients like those that we will be losing on the quality of life. In fact, as I mentioned during the other abstract, they found that 60% of the patients did complete the indication phase which was six months, so that is a good treatment for the patients.

There were also improvements in different dimensions of the quality of life. The majority of the patients had improvement in some aspects. In fact, more than 60% of the patients had improvement in one or more complete resolution of some of the measurements we had regarding, for example, anxiety, constipation, depression, nausea or pain during the induction phase. Again, to show that not only the quality of life was maintained, but there were some other aspects that we were following; and these were symptoms related to the disease or the treatment. With time, there was improvement in these parameters; but the greatest improvement in stability was seen in nausea, vomiting, financial difficulties, pain, and constipation. Most of these were important because they interfere with daily activities of the patient and their well-being. In the majority, we saw that there were improvements within a month of starting the treatment. It was encouraging that we have a regimen that we can give that has efficacy but at the same time maintains quality of life. At the same time, there are aspects of patient symptoms that can be improved by giving this treatment. As I mentioned to you earlier, this is very encouraging for us in terms of taking this regimen further in patients who have locally advanced disease but also in localized pancreatic cancer in general where it can be used maybe preoperatively, for example, in patients with borderline resectable disease. I have to stress that this study did not include patients with borderline resectable disease, they were only localized unresectable disease, but that will be something for the future. It also underscores the value of taking notice of the quality of life in patients we treat for pancreatic cancer, and also the value of getting supportive care involved earlier. The bottom line is that when it comes to gemcitabine and nab‑paclitaxel, we do find a regimen that is well tolerated and efficacious. We do not have major concerns about the quality of life being severely affected by this regimen.

Again, I thank you very much for viewing this activity.

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Last modified: February 14, 2018