Patients with locally advanced esophageal cancer who have residual disease following chemoradiotherapy (CRT) and surgery should be offered nivolumab (Opdivo), says a rapid update to American Society of Clinical Oncology (ASCO) guidance.
This could transform the treatment of “about 75%” of patients with ongoing disease despite CRT and surgery, co-author of the guidelines update, Wayne L. Hofstetter, MD, University of Texas MD Anderson Cancer Center, Houston, told Medscape Medical News.
Previously, patients were simply offered surveillance.
The Rapid Recommendation Update, published in the October 1 issue of the Journal of Clinical Oncology, comes in response to data from the double-blind, phase 3 randomized controlled CheckMate 577 trial.
This compared adjuvant nivolumab with placebo following neoadjuvant chemoradiation therapy in 794 patients with resected esophageal or gastroesophageal junction cancer.
Results presented at the ESMO Virtual Congress 2020 showed that nivolumab significantly increased median disease-free survival (DFS) to 22.4 months vs 11.0 months with placebo (hazard ratio 0.69, P = .0003), as reported by Medscape Medical News,
Treatment-related adverse events leading to discontinuation were reported in 9% of nivolumab and 3% of placebo patients.
An ASCO Expert Panel reviewed these latest data and concluded that, following neoadjuvant CRT and surgery, nivolumab should be offered to patients with locally advanced esophageal carcinoma who have good performance status and do not have a pathological complete response.
This is a significant change, as the 2020 ASCO guidelines for locally advanced esophageal cancer did not include recommendations for further treatment of patients with residual disease.
As the authors point out, the “previous standard of care for this patient population was surveillance.”
The question at that time therefore was: “What else can we do to prevent the cancer coming back?” said Alok A. Khorana, MD, Taussig Cancer Institute and Case Comprehensive Cancer Center, Cleveland Clinic, Cleveland, OH, who was not involved in developing the guideline update.
He told Medscape Medical News that “many clinicians would empirically give a different type of chemotherapy or try something else postoperatively but without any data.
“I think this study shows that, in people with an incomplete response you add nivolumab for a prolonged period after the surgery…which is a big advance for the field.
“It brings immunotherapy to a fairly large population,” he said, adding, “Obviously, I welcome this update.”
“I think it’s important that ASCO and other guidelines update when there’s practice-changing data and I definitely agree that this specific trial is practice-changing,” he said.
There were some qualifications, however, some of which echo concerns that were raised when the study results were presented last year.
The study quality was downgraded by the panel from high to moderate “because the number of events needed to report on secondary outcome overall survival has not yet been achieved.”
In addition, the update notes that a recommendation on the use of nivolumab following treatment with perioperative chemotherapy cannot be made because of a lack of supporting data.
It also highlights a post hoc analysis showing that the degree of response to nivolumab following CRT and surgery appears to be related to an individual’s level of programmed death ligand 1 (PD-L1) expression.
Patients with a combined positive score (CPS) of 5 or higher had a hazard ratio for disease-free survival vs placebo of 0.62, while those with a CPS score less than 5 had a hazard ratio of 0.89.
“This exploratory analysis suggests that future studies may define biomarkers, such as PD-L1 CPS, and/or a subgroup that will benefit from adjuvant nivolumab,” the authors state.
Khorana said, however, that whether this means nivolumab will end up being recommended only in patients with a CPS score of 5 or higher is a “billion dollar question.”
“We don’t want to subject people to months and months of immunotherapy if they don’t really need it,” he said.
However, he underlined that the study was not designed around a biomarker for response.
Moreover, while the post hoc analysis the authors presented “showed the hazard ratio is better” in patients with CPS of 5 or higher, “there was still a benefit for people” in those with lower scores.
Hofstetter agreed, saying that “the data as it stands now shows that progression is slower in those who have gotten nivolumab in all comers, including those with a CPS less than 5.”
Although he nevertheless noted that there are “other studies suggesting that patients CPS less than 5 may not be benefiting as much from immunotherapy.”
This still leaves the question as to whether CPS is sufficiently predictive to qualify as a biomarker.
“Ideally, yes, we want a biomarker,” Khorana said, adding: “Is CPS a biomarker? Is something else a biomarker? Is there a different biomarker that we don’t know right now?”
“I don’t know the answers to those questions, and in terms of drug development it’s really a shame that this has not been sorted out,” he commented. “There are perverse market incentives where, if you don’t have a biomarker, then the market is bigger than if you do.”
“Somehow that has to be factored in in terms of drug development,” Khorana added, saying that biomarkers should be looked at when trials are being developed and drug companies should “not rely on post hoc analyses.”
Other potential issues raised about the CheckMate 577 data when they were presented last year include whether preoperative chemoradiation can be considered a standard of care, and whether disease-free survival is a reasonable endpoint.
Hofstetter said both of those are “valid points.”
“Because the study was done in patients who received chemoradiation, which is more a standard in some institutions and not others, we don’t have data for patients who have received chemo followed by surgery.”
Hofstetter continued: “The problem with that is…there are current studies showing there may be efficacy with chemo and surgery above and beyond surgery alone.
“There are other studies showing there may be equipoise between chemoradiation and surgery and chemo and surgery.”
“So to dictate [that] it has to be chemotherapy and radiation followed by surgery and then immunotherapy does eliminate a certain proportion of patients who are treated with chemo alone up front.”
Turning to the question of disease-free survival, Hofstetter said that the study was designed to measure that “because it’s a sooner endpoint, so the expectation is that there will be a longer endpoint…for overall survival”.
This “will help us a little bit more in terms of understanding if this is helping with overall survival or just lengthening out the time to when patients recur.”
The study had no specific funding. Co-author of the guidelines update Manish Shah, MD, reports relationships with Merck, Oncolys BioPharma, and Bristol-Myers Squibb. Hofstetter and Khorana have disclosed no relevant financial relationships.
J Clin Oncol. Published in October 1 issue. Full text
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