Adjuvant Pembro Success in Early Melanoma Raises Questions

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Adjuvant pembrolizumab (Keytruda) following complete melanoma resection could soon move to an earlier stage in the management of high-risk disease, suggest results from KEYNOTE 716. However, the results raise many questions, says an expert invited to discuss the new data.

Adjuvant pembrolizumab is already approved in the USA for use in patients with melanoma with lymph node involvement following complete resection, having been shown to prolong both recurrence-free and distant metastasis-free survival (DMFS) in stage 3 melanoma.

This latest trial involved patients with slightly earlier disease, those with resected stage 2 and 2 melanoma. These patients are at “high risk” of disease recurrence and have similar outcomes to stage 3 and 3 melanoma patients, explained study presenter Jason J. Luke, MD, director of the Cancer Immunotherapeutics Center at UPMC Hillman Cancer Center, Pittsburgh, Pennsylvania.

Results from the KEYNOTE-716 trial shown that adjuvant pembrolizumab is also beneficial in this earlier stage disease: it improved recurrence-free survival (RFS) by 35% and improved distant metastasis-free survival by 40% compared with placebo.

Adjuvant pembrolizumab is an “effective treatment option with a favorable benefit risk profile for patients with high-risk stage 2 melanoma,” Luke concluded.

The manufacturer, Merck, has said that these new results have already been accepted for priority review by the US Food and Drug Administration, making it likely that the indication will be extended to include patients with earlier disease.  

Luke presented the results at the European Society of Medical Oncology 2021 annual meeting.

Invited discussant Omid Hamid, MD, chief of research/immuno-oncology, The Angeles Clinic and Research Institute, a Cedars-Sinai Affiliate, Los Angeles, California, said that Luke’s presentation was “amazing.”

However, these new results have “sabotaged how we think about how we treat our patients and how we’re going to think about what we do in the future.”

Hamid noted that the incidence of stage 2B and 2C melanoma is “equal” to that of stage 3 disease, “so with a proposed approval” of pembrolizumab in this earlier setting, “we will have a lot more patients” to treat earlier in their disease course.

Of course, this raises the inevitable question of how to treat these patients when they relapse, and how to treat these patients in the metastatic setting “having already exhausted single-agent PD-1 therapy,” he commented.

Hamid said that the current results also reveal the “current problem” with adjuvant therapy, which is that “we don’t know who benefits,” and there is a subset patients who “never recur” even if they are untreated.

So the questions are: “How come all get treated? What about the risks of toxicity? The costs? And where do we fit these patients into clinic?”

As with so many presentations of immunotherapy trial data, the need for biomarkers was raised, with Hamid emphasizing the need for predictive biomarkers that could exclude patients, and save them from toxicity.

He noted that there were data with another checkpoint inhibitor, nivolumab (Opdivo) in the adjuvant setting (from the CheckMate 238 trial) that suggested higher tumor mutation burden and tumor interferon-gamma levels could play a role, and he hopes that similar data may be  available from this latest trial.

Also, there are ongoing and upcoming trials in patients with stage 2B and 2C melanoma that may answer some of the outstanding questions, including a study of neoadjuvant PD-1 blockade before resection, and the DETECTION trial, which is exploring circulating tumor DNA-guided therapy postsurgery.

Then there is the NivoMela trial that will look at nivolumab in stage 2A as well as 2B and 2C disease, while the REFINE trial will assess whether giving immunotherapy less often to patients with advanced cancer, including those with melanoma, results in fewer side effects while continuing to be effective.

The current results also raise the question of whether to go “earlier and earlier” with adjuvant immunotherapy into “poor risk” stage 1 melanoma, which is already being tried in the United States, although there is “no clear understanding of what to do for those patients.”

Overall, Hamid said that the results of KEYNOTE-716 have “created more questions than answers,” including its impact on the inclusion criteria for 3/4 clinical trials, “which now exclude patients who have received adjuvant therapy within 6 months.”

“That will have to change,” he suggested.

Some of the questions raised by Hamid were discussed on social media, sparking a lively Twitter debate on how best to take the results forward and into the clinic.

Florentia Dimitriou, MD, a dermatology consultant in the Skin Cancer Clinic, University Hospital Zurich, Switzerland, said the data were “great” but she was “still unclear” over who needs adjuvant immunotherapy in this setting.

She also emphasized that, for her, that the greater RFS benefit seen in T3b than in T4b disease “doesn’t make sense,” and she also highlighted the finding of long-term toxicity in approximately 18% of patients.


Luke replied that he agrees that the T3b/T4b results are puzzling but he said the event rate was “low” and the data are “immature,” and that he hopes to have “more info soon.”

He acknowledged that around 18% of patients on pembrolizumab went on receive hormone therapy for adverse events, including 13.9% due to hypothyroidism, and others including hypophysitis, adrenal sufficiency, and type 1 diabetes. However, he also pointed out that about 5% of patients in this study had background thyroid issues. The risks and benefits of treatment need to be discussed with patients, he added.

Over a series of tweets, Rebecca J. Lee, PhD, NIHR clinical lecturer in medical oncology at the University of Manchester, UK, said “we need to know more” about the distant metastasis-free survival results, and that results for overall survival are “really” needed.

She also emphasized the need for biomarkers to identify those patients who are likely to benefit, and whether benefit can be upfront or early on in treatment.” Lee added that, as endocrine thyroid toxicity occurs after a median of 3.3 months, “pre-treatment biomarkers will be more important than on-treatment biomarkers in this setting.”



Details of the Results in Earlier Stage Disease

The KEYNOTE-716 trial enrolled patients with newly diagnosed, resected, high-risk stage 2 melanoma aged ≥ 12 years and with a good performance status. The majority (~64%) had stage 2B melanoma, with the rest stage IIC. T3b disease was present in 41% of patients, 23% had T4a disease, and 35% T4b disease.

Patients were randomized to receive pembrolizumab or placebo.

In a subsequent part of the study, patients with recurrence will be unblended, with either crossover from the placebo to active treatment group or rechallenge with pembrolizumab for up to 2 years.

Presenting the first part, Luke said that, of 487 patients assigned to pembrolizumab, 483 started treatment, of whom 206 have completed treatment, 133 are still on therapy, and 144 have discontinued.

In the placebo group, 489 patients were assigned and 486 began treatment. Of those, 229 completed treatment, 152 are still ongoing, and 105 discontinued.

The two groups were well balanced in terms of their baseline characteristics. The median age was approximately 60 years, with only one patient enrolled who was aged 12-17 years.

At 12 months, the study met its primary endpoint.

Relapse-fee survival was 90.5% in patients treated with pembrolizumab versus 83.1% in the placebo group, at a hazard ratio for recurrence of 0.65 (P = .00658).

“Despite this trial hitting this primary endpoint very early, there are a number of patients who are censored later in the curves,” Luke said, adding that “we will continue to see these data mature.”

“In fact, it’s our full expectation that curves will continue to separate over time.”

When looking at key subgroups, Luke showed that the results favored pembrolizumab when stratifying patients by age, gender, race, and performance status.

Interestingly, patients with T3b disease did a lot better on pembrolizumab compared with those who had T4b disease, at a hazard ratio for recurrence of 0.44 versus 0.94.

Data on recurrence patterns revealed that 11.1% of patients taking pembrolizumab had an event, with 6.4% experiencing skin and/or lymph node regional recurrence and 4.7% distant recurrence.

In the placebo group, 16.8% of patients had a recurrence event, with 8.4% having a loco-regional recurrence and 7.8% a distant recurrence.

Luke explained that this equates to an approximate 40% reduction in distant recurrence with pembrolizumab over placebo.

Finally, the researchers examined change in global health status on the EORTC QLQ-C30 quality of life score. Examining mean change over time, they found that there were no clinically meaningful changes, and the scores in the pembrolizumab and placebo groups tracked each other during the course of follow-up.

Quality of life was therefore “only minimally changed,” Luke said.

The study was funded by MSD. Luke and Hamid have declared relationships with multiple companies.

ESMO Congress 2021. Abstract LBA3. Presented September 18, 2021.

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