Duration of checkpoint inhibitor treatment the next milestone

Australian patients with metastatic melanoma will be among those helping to determine the optimal duration of treatment with immune checkpoint inhibitors (ICIs).

A prospective trial recruiting across multiple sites in Australia and Canada will compare continuous versus intermittent therapy with any approved and publicly funded PD-1 inhibitor.

STOP-GAP is just one of a number of trials worldwide that are now ready to test if the durable responses seen in many patients with ICIs can still be achieved with less therapy.

According to a review article in the Journal for ImmunoTherapy of Cancer, less therapy offers the potential to avoid unnecessary physical and financial toxicities associated with lengthy or indefinite treatment.

And there is mounting evidence from a number of studies that early cessation of treatment does not negatively impact clinical outcomes.

For example: “While treatment discontinuation due to adverse events makes outcome comparison challenging, evidence from the Keynote-006 trial suggests that some patients may continue to derive benefit from ICI therapy after discontinuation, suggesting durable benefits may be feasible from shorter courses of therapy than defined by current protocols,” it said.

The authors said DANTE, Safe Stop, STOP-GAP and PET-Stop will all address the question of early cessation of ICI in melanoma.

Discontinuation benefits

Associate Professor Matteo Carlino, an investigator on STOP-GAP, told the limbic he thought there would be huge benefits for patients receiving less treatment – including psychological benefits.

“I see a lot of people off drug and it allows them to transition into a different point in their illness,” he said.

Associate Professor Carlino, from Westmead Hospital and the Melanoma Institute Australia, said he was now seeing patients out to nine and ten years from the phase 1 trial of pembrolizumab in melanoma.

“None of them are on drug and there is a very clear and different psychology between someone getting drug and someone who has stopped getting drug and sees their cancer doctor every 6-12 months.”

“And I am all for getting a lot of them to stop seeing me at the ten year mark and more importantly, to stop scanning.”

“First of all you have to got to work out if it is safe. If giving less means people die, we are not going to give less. But once we work out it is just as efficacious to give less, the question then becomes how much less and how to identify people who can safely stop. That sort of work is slowly coming together but STOP-GAP will be the prospective way to answer that question.”

Associate Professor Carlino said the PBS indication for ICIs in melanoma had no limit on the duration of treatment.

“Technically for melanoma, you could go forever. Some of the other cancers have a two year limit on them and it often depends on the clinical trial where the evidence came from.”

Discussion with the patient

However he usually starts the conversation with melanoma patients by talking about the standard duration of treatment being 1-2 years, and that there were key decision points along the treatment journey where he might advise it was safe to stop.

“Often you are not discussing that at the beginning but you are discussing that when they have the first scan showing that things are working. So my next discussion is when people get towards the one year anniversary, I introduce the idea that if the scan shows nothing, we will consider stopping a bit earlier.”

“And then at the 1-year mark, I give them the option of stopping and discuss that over 2-3 visits because there is a fair bit of psychology about it.”

He said some patients will elect to stay on treatment figuring that the 2-hour visit every three weeks was not that big an impost while others were very happy to be guided by evidence that with a complete response on PET scan, they would likely do very well off treatment.

“Patients and oncologists are very cognisant of the fact that these drugs probably don’t need to be forever. We acknowledge that shorter durations are likely safe for at least a subset of patients and there is lots of work going into working out who they are. We think they are the people who’ve had side effects and people who have had a complete response. They are probably the two easiest to pick groups.”

“The other thing I do tell people is there is a fair bit of evidence that stopping in the setting of side effects is quite safe. And you need to broach that topic quite early because a lot of people fear reporting side effects because they think you’ll stop the drug that is keeping them alive.”

He said STOP-GAP will take years to deliver its findings.

“Because a lot of patients have a good prognosis, the results will take a while I think. Because if the drug reworks when you rechallenge, and we think that is the case, the outcome of harder endpoints like survival or secondary progression, will take longer.”

“STOP-GAP is just for melanoma but the idea is it would be informing other cancers. And you have to be a little bit cautious there because we can’t assume it is all the same but I imagine if STOP-GAP showed it was equally efficacious to stop early you would see a real push to answer that question in other cancers.”

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