Back to the Picasso trial for some perspective on Clover. It bothers me that the prime and pair idea failed with maraviroc and Keytruda. As noted in a recent post, chemo was not used in Picasso until patients finished the combination therapy, as a salvage effort. So that is likely part of the picture. In effect, maraviroc does prime or sensitize the tumors—but to chemo, not the ICI. And the proof of that is the excellent Disease Control Rate of 70% in the salvage patients, along with a then-respectable Overall Survival figure of 9.8 months. But what else is going on? Why didn’t a CCR5 inhibitor that works in HIV not prime cancer to respond to Keytruda?
Turns out the answer is pretty simple—maraviroc does not raise PDL-1 in the tumors! At least that’s what AI tells me. Apparently this has everything to do with the short half-life of maraviroc in the body, which logs in at 10.5 hours. So receptor occupancy fluctuates during the day as the liver processes and removes the drug from circulation… so if you don’t take your twice-a-day pills right on schedule, or miss a dose, the tumor has windows of opportunity to exploit and resist.
They tried to work around this by upping the dose significantly, in conjunction with something called CYP3A4 Inducers. For HIV, typically taken along with CYP3A4 Inhibitors, the usual dose is 150mg twice a day, for a total of 300mg. If you are not taking any other drugs processed by the liver you can safely take 600mg a day, in split doses. In the Picasso trial they tried up to 2,400mg a day, in split doses. Yikes! Maraviroc is a drug that is hard on the liver, so they would have had to monitor patients closely, and reduce dosage as needed. More windows of opportunity for the tumor, especially in the liver.
Well, it all makes sense now. Leronlimab is not only superior to maraviroc in terms of occupying the receptor exquisitely and competitively, but it’s long half-life means there are no gaps in coverage for a brain-fogged patient who gets confused about the dosing schedule. I was concerned that there might be some reason the prime and pair idea with leronlimab and an ICI might not work as effectively in mCRC as it did in TNBC, basically because maraviroc didn’t work in the Picasso trial. Now it is still an open question, in my mind at least, as to the level of effectiveness the LL/ICI pairing will have in various cancers… because there is no data yet, and cancer can be both tricky and harsh. I’ll just say, it would be unrealistic to expect, extrapolating from the 5 for 5 in TNBC, that we would cure 1,000 out of 1,000… even in TNBC. We can always dream big… even if we are still early in the leronlimab story.
One final thought—we usually think of “prime and pair” with leronlimab in terms of ICIs, but it is clear that P and P works for chemo as well. The combo creates an anti-cancer cascade, if you will—LL primes the chemo to more effectively kill cancer, which stimulates the release of antigens for the immune system to process, recognize, and dispatch any remaining cancer cells. While Taz appears to be the perfect companion for leronlimab in CRC, Cytodyn might want to search for other chemotherapies that would work well in specific cancers. I am really excited to see if we get any Complete Responses in the 700mg arm… and I’m talking without Keytruda! Perhaps with curative resection? And further down the line, we’ll see if the triplet leads to CRs in first or second-line indications. Looks likely to me. I-Spy, anyone? Pre Spy? The Man From Uncle?
Turns out the answer is pretty simple—maraviroc does not raise PDL-1 in the tumors! At least that’s what AI tells me. Apparently this has everything to do with the short half-life of maraviroc in the body, which logs in at 10.5 hours. So receptor occupancy fluctuates during the day as the liver processes and removes the drug from circulation… so if you don’t take your twice-a-day pills right on schedule, or miss a dose, the tumor has windows of opportunity to exploit and resist.
They tried to work around this by upping the dose significantly, in conjunction with something called CYP3A4 Inducers. For HIV, typically taken along with CYP3A4 Inhibitors, the usual dose is 150mg twice a day, for a total of 300mg. If you are not taking any other drugs processed by the liver you can safely take 600mg a day, in split doses. In the Picasso trial they tried up to 2,400mg a day, in split doses. Yikes! Maraviroc is a drug that is hard on the liver, so they would have had to monitor patients closely, and reduce dosage as needed. More windows of opportunity for the tumor, especially in the liver.
Well, it all makes sense now. Leronlimab is not only superior to maraviroc in terms of occupying the receptor exquisitely and competitively, but it’s long half-life means there are no gaps in coverage for a brain-fogged patient who gets confused about the dosing schedule. I was concerned that there might be some reason the prime and pair idea with leronlimab and an ICI might not work as effectively in mCRC as it did in TNBC, basically because maraviroc didn’t work in the Picasso trial. Now it is still an open question, in my mind at least, as to the level of effectiveness the LL/ICI pairing will have in various cancers… because there is no data yet, and cancer can be both tricky and harsh. I’ll just say, it would be unrealistic to expect, extrapolating from the 5 for 5 in TNBC, that we would cure 1,000 out of 1,000… even in TNBC. We can always dream big… even if we are still early in the leronlimab story.
One final thought—we usually think of “prime and pair” with leronlimab in terms of ICIs, but it is clear that P and P works for chemo as well. The combo creates an anti-cancer cascade, if you will—LL primes the chemo to more effectively kill cancer, which stimulates the release of antigens for the immune system to process, recognize, and dispatch any remaining cancer cells. While Taz appears to be the perfect companion for leronlimab in CRC, Cytodyn might want to search for other chemotherapies that would work well in specific cancers. I am really excited to see if we get any Complete Responses in the 700mg arm… and I’m talking without Keytruda! Perhaps with curative resection? And further down the line, we’ll see if the triplet leads to CRs in first or second-line indications. Looks likely to me. I-Spy, anyone? Pre Spy? The Man From Uncle?
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