JCO Article Insights: Use of Independently-Assessed vs Investigator-Assessed DFS in the APACT Trial

Journal of Clinical Oncology (JCO) Podcast

In this JCO Article Insights episode, Emily Zabor interviews Dr. Gulam Manji from Columbia University Irving Medical Center. Dr. Manji provides insight into his editorial published in the April 10, 2023 JCO issue: "Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” (10.1200/JCO.23.00039). His editorial focuses on the JCO Original Report, “Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial” by Tempero, et al on the APACT Trial.

TRANSCRIPT

The guest on this podcast episode has no disclosures to declare.

Emily Zabor: Welcome to this JCO Article Insights episode for the April issue of JCO. This is Emily Zabor, one of JCO's editorial fellows. And today I am interviewing Dr. Manji from Columbia University on their editorial titled “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?”

Dr. Manji, welcome to our podcast. You wrote this editorial to accompany the article, “Adjuvant Nab-Paclitaxel plus Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results from a Randomized Open-label Phase III Trial by Dr. Margaret Tempero and Colleagues.” That trial, called the APACT Trial, investigated the efficacy and safety of adjuvant nab-paclitaxel plus gemcitabine compared to gemcitabine alone in patients who had undergone resection for pancreatic ductal adenocarcinoma. So I wanted to ask if you could start by giving listeners a quick overview of the study design and the main findings from that trial.

Dr. Gulam Manji: Yeah, sure, Emily. So, as you pointed out, it was a randomized phase III study in patients who had resected pancreatic carcinoma. The primary endpoint was independently assessed disease-free survival. Additional endpoints included investigator-assessed disease-free survival, overall survival, and safety. And we'll get back later on as far as the importance of investigator-assessed versus independently-assessed disease with survival because I think that that's the main point of discussion for today. The enrollment criteria were fairly stringent and included patients with macroscopic complete resection, ECOG performance status of either 0 or 1, and the peripheral tumor markers of CA 19-9 being less than 100. And patients were required to initiate adjuvant chemotherapy within 12 weeks. Patients received standard gemcitabine at 1000 milligrams per meter square, either with or without nab-paclitaxel of 125 milligrams per meter square once weekly for three weeks during every four-week cycle.

Emily Zabor: Great. So I think that the main thing that we wanted to talk about today, and one of the main points you discuss in your editorial is the difference between the primary endpoint of independently assessed disease-free survival and the secondary endpoint of investigator-assessed disease-free survival. So can you describe the difference between those endpoints, how they were defined, and how they differed?

Dr. Gulam Manji: Sure. So, independently-assessed DFS was determined by a radiologist who was blinded to treatment assignment, and new lesions followed RECIST 1.1 criteria. In contrast, the investigator-assessed recurrence was determined by the treating physicians using all available clinical information. So that could be abdominal pain, anorexia, probably elevation of peripheral tumor markers. And the other important aspect to the study is that the independent review was not performed in real-time to confirm investigator assessments. So patients who started subsequent therapy after recurrence by treating investigators were censured for the independently-assessed DFS analysis. So in this trial, 866 patients were randomized. And patients who are randomized to the experimental arm had a median independently assessed DFS of 19.4 months, while patients randomized to the control arm, which was gemcitabine alone, had a median DFS of 18.8 months. Now, when we compare that to the investigator-assessed DFS, the data looks quite different. Where the DFS was 16.6 months in the experimental arm compared to 13.7 months in the control arm. That is consistent with the five-year follow-up looking at the median overall survival, which was 41.8 months for the combination arm compared to 37.7 months for the gemcitabine alone arm.

Emily Zabor: Okay, so there's some really interesting differences there. And I noticed that there were only 439 events according to the independently-assessed DFS versus 571 according to the investigator-assessed DFS. So that's a big difference in the number of events that I guess is coming from that additional censoring that was occurring due to the delay in the independently assessed endpoint. Is that right?

Dr. Gulam Manji: Exactly. So you could envision a scenario where patients received chemotherapy and then on the investigator-assessed DFS, the investigators decided that the patient had recurred. However, that patient probably did not meet the RECIST or radiological criteria to determine that that patient had recurred. And hence, since it was not done in real-time, there was censoring that occurred for the independently-assessed DFS. So that's the reason why there was a difference in that number as you pointed out.

The decision to use independent DFS, disease-free survival, really was to remove investigator-associated bias and increase rigor to the study, which is commendable. However, unfortunately, that's not how we normally treat patients with aggressive cancer who have undergone surgical reception. And knowing that imaging modality is limited in identifying those patients, particularly in those that have peritoneal disease, or even more importantly, the patients who have recurrence within the surgical bed, I think is the issue.

Emily Zabor: Right. So the motivation behind selecting that endpoint was really good and well-motivated. Everybody wants to reduce bias and make sure we're taking out those kind of more subjective parts of identifying that. But it, unfortunately, missed some events as a result.

Dr. Gulam Manji: Correct. I think that it delayed those events and that's what compromised the analysis because it was the limitations of the available modalities to determine when recurrence occurs.

Emily Zabor: So how do these different definitions compare to other trials or previous trials?

Dr. Gulam Manji: So previous trials that I'm aware of, it was the investigator-assessed DFS that had been used. And when you look at the data that was used in this trial, that concurs with what has historically been seen. And what I mean by that is that the original assumptions regarding DFS when this trial was being designed, used historical outcomes. Investigators see that DFS with adjuvant gemcitabine ranged anywhere from between 13.4 to 14.3 months. And the study had aimed to achieve a DFS improvement from 13.5 to 18.5 months. When you look at the investigator-assessed DFS, the ballpark of gemcitabine is very much in line with the previous historical data. So I think that the key discrepancy between the two DFS endpoints was likely a delay in accurately assessing disease recurrence when using the blinded radiological modality alone. And the second thing is, as you pointed out, a greater proportion of patients who were censored for independent assessments compared with those for investigator assessments was different. So that was between 40% versus 34%. So those two points, I think, were the key points that show the difference between independent versus investigator-assessed DFS and also that the independent-assessed DFS was not done in real-time.

Emily Zabor: Yeah, that's really interesting and such a good point. And I think it really emphasizes how important it is to think carefully about these endpoint definitions in the design stage of these clinical trials and especially to think about when and why patients are getting censored and how that might impact the results.

So how do these results of this trial then, given the negative result of the primary endpoint, but that positive result on the secondary investigator-assessed endpoint, how do these fit in with other trials? And what do you think that means for patient treatment recommendations?

Dr. Gulam Manji: Excellent point. So just to be clear, the APACT study did fail to meet its primary endpoint and hence gemcitabine and nab-paclitaxel were not indicated for patients in the adjuvant setting. The current standard of care are either modified FOLFIRINOX or gemcitabine combination with capecitabine. And those two regimens really remain a standard of care for patients. So what I do is for fit patients, I prefer modified FOLFIRINOX. However, in patients who are not as fit, gemcitabine in combination with capecitabine is the alternative.

Now, one could envision a scenario where gemcitabine and nab-paclitaxel may become relevant. It is, but only when I'm really pushed to do so, where I feel like there is no other regimen available optimally for a patient. And one could envision a scenario where you could have a patient who does not have the performance status to tolerate modified FOLFIRINOX and then you start that patient on gemcitabine in combination with capecitabine. However, I have experienced that that combination results in significant myelosuppression in patients in the United States. And then we have to do significant dose reductions or interruptions.

Now, in that case, where I feel like I'm reducing the dose of capecitabine to a point where the patient may not be potentially benefiting from that regimen, it's impossible to determine what dose would be efficacious when you're doing those dose reductions. That is the only scenario where I may be able to be pushed to consider gemcitabine and nab-paclitaxel, but only after also discussing with the patient the results of the current data and there being limited efficacy.

Emily Zabor: That makes sense. So the treatment you would select would really depend on some patient characteristics and then how they do on the different treatments.

Dr. Gulam Manji: Correct.

Emily Zabor: So what do you think are the next steps for research in this area and in this disease?

Dr. Gulam Manji: I think that this clinical trial really demonstrated our inability to accurately pinpoint the time of disease recurrence using imaging modalities alone. And for patients who treat pancreas cancer, they would know that the recurrence patterns usually are either to the liver or to the peritoneum, or to the lung. However, in about 25% of the cases, the recurrence may be at the surgical site, and that's when things become tricky. After patients have undergone surgery, their scar tissue and the pancreas tumor is very dense, so it's difficult to determine that there's actually tumor growth. So that's where you really need help from other modalities. So should we get a PET scan? Is the patient symptomatic? Is a tumor marker going up in the absence of biliary obstruction? So all of those things need to be taken into account to truly pinpoint whether the patient has recurred or not. In peritoneal disease, you may need to ask the surgeons to help and have the patient undergo a laparoscopy to truly determine whether there is a peritoneal disease. And lastly, I think that incorporating ctDNA to better define whether there is a minimal residual disease will likely be a standard in the future.

Emily Zabor: I see. Yeah, that makes sense. Incorporating some ctDNA biomarker information along with these really detailed clinical and possibly imaging assessments to determine recurrence seems like it would be really important in future trials to make sure you're capturing all of those recurrences accurately.

Dr. Gulam Manji: Yeah, I think that that's critical before you can say that an adjuvant treatment is truly helping the patient.

Emily Zabor: That's great. Well, I really learned a lot reading this article and speaking to you today. But before we end, is there anything else you'd like to share with our listeners?

Dr. Gulam Manji: Yeah, so I think we know that for a majority of patients who undergo curative resection, unfortunately, the disease recurs. And I think that that implies that, really, pancreas cancer is a systemic disease at the time of diagnosis. And despite aggressive adjuvant therapy, the median DFS, OS, and five-year survival rate show that we are impacting only a subset of patients with six additional months of chemotherapy. So I think that identifying predictive markers of response to systemic therapy, better selection of patients for surgery, perhaps using total upfront neoadjuvant therapy, an institution of maintenance therapy, and patients who are at high risk for recurrence, perhaps using ctDNA as a marker to determine who those high-risk patients are, all leads to help better design and identify patients who should really be treated systemically and patients who should undergo surgery. And lastly, with some glimmers of success from personalized vaccines may be on the horizon. And I'm hoping in the near future to treat minimal residual disease so that we can get the best outcome with minimal toxicity for our patients.

Emily Zabor: That's great. That sounds like an exciting development for a disease that seems really tricky.

Dr. Gulam Manji: Agreed.

Emily Zabor: Well, thank you so much. It has been a pleasure speaking with you, Dr. Manji, and thank you so much for joining me today on this episode of JCO Article Insights.

This concludes the episode on the article “Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?” Thank you for listening and please tune in for the next issue of JCO Article Insights.

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Guest Bio: Dr. Gulam Manji, MD, PhD is a medical oncologist at the Columbia University Irving Medical Center in New York.

Articles:

Editorial: Adjuvant Gemcitabine and Nab-Paclitaxel Misses the Target in Pancreas Adenocarcinoma: Or Did an Effective Therapy Fall to the Definition of Recurrence?

Original Report: Adjuvant nab-Paclitaxel + Gemcitabine in Resected Pancreatic Ductal Adenocarcinoma: Results From a Randomized, Open-Label, Phase III Trial

Find more articles from the April 10 issue.