CHICAGO—Though it's not a common occurrence, most oncologists have questioned if their patients with evidence of tumor growth while receiving immunotherapy aren't responding to treatment or just experiencing a “pseudo-progression.”
Walter Stadler, MD, FACP, the Fred C. Buffett Professor of Medicine and Surgery, Chief of the Section of Hematology/Oncology, and Director of the Genitourinary Program at University of Chicago Medicine, lead a discussion at the 2016 ASCO Annual Meeting on analyzing the definitive study of nivolumab in refractory renal cell cancer.
“It's an interesting discussion because the two groups investigated data from the same clinical trial but came to very disparate conclusions. The organizers gave me the title of Treatment Beyond Progression: Forward Progress or Simply Progression Confirmed? Now, the question in front of us is whether there is any value to treatment beyond progression of patients with metastatic renal cell cancer who are on therapy with nivolumab beyond standard RECIST-based criteria,” Stadler explained.
“The thought process here is that with pseudoprogression the growth we see on CT scans really reflects inflammatory infiltrate,” he clarified. “This eventually leads to tumor shrinkage and is a concept that has been around since initial investigations with CTLA-4 inhibitors and is also observed with PD-1 inhibitors.”
The trial under Stadler's discussion lead to FDA approval of nivolumab for renal cancer in the refractory setting. Patients were allowed to be treated beyond the standard RECIST-based progression. The FDA analysis focused only on five patients who had an initial progression and then had a response. He said it explained the difference between the 14 percent response rate beyond progression reported as a bottom line by the sponsor, who also analyzed patients whose best RECIST response was stable disease or response and 3 percent by the FDA. In either case, he recognized the number of patients affected by treatment beyond progression is small.
Stadler pointed out that the patients on treatment beyond progression were on treatment longer than those who were not treated beyond progression in the sponsor's analysis. Yet, he noted probable bias in the statistical comparison as physicians selected patients for ongoing therapy who they believed would do well. Therefore, he concluded treatment beyond progression does not necessarily lead to improved outcomes.
Questioning Tumor Shrinkage Terms
Patient selection wasn't the only aspect of the trial Stadler asked audiences to examine. He called upon oncologists to recognize the “arbitrary” nature of PR, stable disease, and progressive disease (PD).
PR, he noted, was categorized at one of the first ASCO meetings in the 1970s palpating hard spheres under a thin mattress. “As far as I can tell, PD criteria were simply made up,” Stadler remarked.
Stadler noted there's no concrete difference between the “magical 20 percent” growth point and, say, 19 percent growth.
Progression's Grey Area
There is a correlation between progression-free and overall survival in renal cancer treated with interferon-alfa and/or bevacizumab. At the same time, the vast majority of nivolumab-treated patients with radiologic PD are no longer benefiting from therapy and should probably be treated otherwise.
Stadler noted that patients showing “a little bit of progression” on scans shouldn't necessarily discontinue therapy if they're otherwise feeling well. Expert clinicians can define “a little bit of progression,” which includes things such as:
- minimal growth of small lymph nodes and possibly appearance of a sub-centimeter lung nodule 2 months after starting and the patient otherwise feels healthy; and
- ongoing slow growth over several months that crosses the “magical 20 poercent mark.” Conversely, the term does not coin a patient with 15 percent growth of multiple masses greater than 6 cm and corresponding weight lost and pain.
Refining Dosing & Scheduling
Stadler observed response rate and progression-free survival were similar in a small, randomized trial of nivolumab of 0.3, 2, and 10 mg/kg doses, yet the package insert recommends 3 mg/kg.
Also, in the original phase I trial of nivolumab, circulating lymphocyte PD1 occupancy was maintained for more than 57 days after a single infusion, and Stadler noted longer time points were not studied.
Stadler posed the question at hand: “Can we discontinue therapy in patients who are clinically benefitting?”
“At these kinds of drug costs of $65,000 to $100,000 per patient, I think we need to begin asking the sort of questions whether we can, or even should, discontinue some types of therapy,” he stated.
Though the studies focused on practice of treatment beyond progression, which is expensive, the number of patients impacted by this is small, and the real opportunity for cost savings lies in altering dosing and scheduling. Stadler also perceived increased concern for this issue among the 2016 ASCO audience.
To address the questions regarding dosing and therapy discontinuation, Stadler suggested randomizing patients to low and intermediate doses of nivolumab. He chose 4 months as an “arbitrary time frame” for patients to be treated with nivolumab. Physician choice should dictate treatment for those with true progressive disease, but those with RECIST-stable disease or better could be randomized to continuing the same dose or discontinuing therapy with survival as the primary endpoint. “I think this is an important question for the field,” he articulated.
To conclude his presentation, Stadler was clear that RECIST-based progression shouldn't be the only consideration, or “slavishly followed,” in treatment decision-making.
“RECIST guidelines really reflect the arbitrary nature of partial response and progression,” he shared. “Though these standards are fine for clinical trial purposes, we must recognize they may not be meaningful for the individual patient.”
Robin Hocevar is a contributing writer.