My favorite company and molecule are on the move! I’m not sure how Dr J convinced regulatory to allow the company to add the Rollover Protocol, but I’m glad he and his team did for the sake of the patients. In that light (and since my expertise is not in medicine-drugs please bare with me), I have a question for the board:
Potential Scenario: Let’s suppose some of the patients in the 350 mg and the 700 mg arms had their first scan, which showed stable or shrinking disease but maybe not yet at the Partial or Complete stages, and also had up-regulation of PD-L1, so that they and their doctor then opted for getting an ICI in the EAP program (before Rollover was offered). With just a few doses given before the initial scan, maybe there hasn’t been enough doses of LL administered to the patient to have full effect on the disease as far as scans are concerned.
Question (1): How might this affect Clover? If some patients are seeing good results, and PD-L1 up-regulation, but not yet PR or CR, they might opt for an ICI (before the Rollover offered). This scenario might help the secondary DOR, DCR, and PFS, but would it hurt the primary ORR since this requires the RECIST 1.1 criteria to be met?
Question (2) Would this information—the patient history, say stable disease after initial dose of LL and combo, and up-regulation, and opting for an ICI through EAP or some other means (before Rollover)—be taken into account by regulatory?
Rollover Protocol: For both patients, and for trial success, this was an excellent idea. It provides the vehicle for any patients whose disease has progressed to remain in the trial and get an ICI and see if the LL plus ICI has the effect we think it will have. Perhaps one of the reasons Dr J was able to convince regulatory to accept this amendment was because of the PD-L1 up-regulation seen in patients, the potential to do good, and maybe because some earlier patients might have been opting for ICI via EAP or other means.
Of course this is just a potential scenario, and I have no knowledge of whether these were the reasons for the protocol. But I am wondering, to summarize my questions above, the following: (1) if pre-Rollover patients leaving the trial will affect ORR, and (2) if regulatory would take this type of scenario into account, that even though good things are happening (as evidenced by CtDNA, for instance), some of those good things might not show up in ORR if earlier pre-Rollover patients opted for an ICI?
The good news is I think we capture this traffic going forward in the Rollover Protocol and get the benefit of seeing LL plus Keytruda in action. This is a big plus for patients and the trial.
Plus now we have many potential success points in the trial: ORR-LL plus Combo, ORR-LL plus Keytruda, PD-L1 Up-regulation, CtDNA, CTCs and CAMLs, and DOR-DCR-PFS. I realize that only the ORR-LL plus Combo is primary, but the secondaries are also hugely important, especially PD-L1 Up-regulation, CtDNA, and PR and CR from LL plus Keytruda.
Food for thought. Of course, do your own due diligence, but I’m staying long and buying more.
Keep on keeping on and staying long for the long haul
KOKO&SLLH
Thanks, Ramjet
Potential Scenario: Let’s suppose some of the patients in the 350 mg and the 700 mg arms had their first scan, which showed stable or shrinking disease but maybe not yet at the Partial or Complete stages, and also had up-regulation of PD-L1, so that they and their doctor then opted for getting an ICI in the EAP program (before Rollover was offered). With just a few doses given before the initial scan, maybe there hasn’t been enough doses of LL administered to the patient to have full effect on the disease as far as scans are concerned.
Question (1): How might this affect Clover? If some patients are seeing good results, and PD-L1 up-regulation, but not yet PR or CR, they might opt for an ICI (before the Rollover offered). This scenario might help the secondary DOR, DCR, and PFS, but would it hurt the primary ORR since this requires the RECIST 1.1 criteria to be met?
Question (2) Would this information—the patient history, say stable disease after initial dose of LL and combo, and up-regulation, and opting for an ICI through EAP or some other means (before Rollover)—be taken into account by regulatory?
Rollover Protocol: For both patients, and for trial success, this was an excellent idea. It provides the vehicle for any patients whose disease has progressed to remain in the trial and get an ICI and see if the LL plus ICI has the effect we think it will have. Perhaps one of the reasons Dr J was able to convince regulatory to accept this amendment was because of the PD-L1 up-regulation seen in patients, the potential to do good, and maybe because some earlier patients might have been opting for ICI via EAP or other means.
Of course this is just a potential scenario, and I have no knowledge of whether these were the reasons for the protocol. But I am wondering, to summarize my questions above, the following: (1) if pre-Rollover patients leaving the trial will affect ORR, and (2) if regulatory would take this type of scenario into account, that even though good things are happening (as evidenced by CtDNA, for instance), some of those good things might not show up in ORR if earlier pre-Rollover patients opted for an ICI?
The good news is I think we capture this traffic going forward in the Rollover Protocol and get the benefit of seeing LL plus Keytruda in action. This is a big plus for patients and the trial.
Plus now we have many potential success points in the trial: ORR-LL plus Combo, ORR-LL plus Keytruda, PD-L1 Up-regulation, CtDNA, CTCs and CAMLs, and DOR-DCR-PFS. I realize that only the ORR-LL plus Combo is primary, but the secondaries are also hugely important, especially PD-L1 Up-regulation, CtDNA, and PR and CR from LL plus Keytruda.
Food for thought. Of course, do your own due diligence, but I’m staying long and buying more.
Keep on keeping on and staying long for the long haul
KOKO&SLLH
Thanks, Ramjet
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