ASCO 2023 Round Up containing 22 chapters.
Chapter 16 of 22.
ASCO 2023 Round Up containing 22 chapters.
Chapter 16 of 22.
ASCO 2023 Round Up containing 22 chapters.
Chapter 16 of 22.
ASCO 2023 Round Up containing 22 chapters.
Chapter 16 of 22.
Astrazeneca appears to have teased out a positive result for Imfinzi in ovarian cancer – a setting that so far has proved intractable for anti-PD-(L)1 drugs. The data, toplined positive in April, concern the Duo-O study of an Avastin/Imfinzi/Lynparza triplet, and have just been presented at an Asco late-breaker.
The result is notable for having apparently succeeded where other PD-(L)1/Parp inhibitor combinations have failed, and one reason for this might be Astra’s exclusion of Brca-positive patients, who would normally be expected to do well on Avastin/Lynparza alone. Still, questions will remain about Imfinzi's contribution, the breadth of the effect, and the robustness of a progression-free survival endpoint.
Debate continues about the validity of PFS in ovarian cancer, and there have been cases where a clinical benefit on PFS has been followed by a clearly negative result in terms of overall survival. This has, for instance, seen use of GSK’s Parp inhibitor, Zejula, narrowed in ovarian cancer maintenance.
Complexities
Duo-O had a complex three-arm design, and included two settings. Active cohorts comprised chemo/Avastin/Imfinzi first line followed by Avastin/Imfinzi with or without Lynparza in the maintenance setting; this was compared against a control cohort of chemo/Avastin followed by Avastin maintenance.
A further crucial twist is that the trial enrolled Brca-negative patients only, and its PFS endpoint was split between two co-primaries: an effect in all-comers, and in Brca-negatives who were nevertheless positive for some other type of HRD mutation.
The good news is that the Avastin/Imfinzi/Lynparza maintenance triplet met both co-primaries, with p<0.0001. The bad that Avastin/Imfinzi had no advantage over control at all.
The survival curves reveal another nuance. It might have been assumed that HRD-positive patients are driving the all-comers benefit, but in fact in HRD-negatives, some 60% of the Duo-O Brca-negative population, the triplet also beat control.
PD-(L)1 + Parp inhibition in ovarian cancer | |||||
---|---|---|---|---|---|
Trial | Setting | Active treatment | Comparator | Note | Brca restriction? |
Roche | |||||
WO39409* | ≥2L | Tecentriq + Rubraca | Uncontrolled | Ended 2020 after Covid-related protocol amendment, no data reported | None in ovarian cancer cohort |
Merck KGaA/Pfizer | |||||
Javelin Ovarian Parp 100 | 1L & maintenance | Chemo + Bavencio, then Bavencio + Talzenna | Chemo +/- Avastin, then Talzenna or Avastin | Discontinued after failure of Javelin Ovarian 100 trial | None evident |
Merck & Co and/or Astrazeneca | |||||
Duo-O | 1L & maintenance | Chemo + Avastin + Imfinzi, then Avastin + Imfinzi +/- Lynparza | Chemo + Avastin, then Avastin | Maintenance triplet positive for PFS in HRD+ves, all-comers & HRD-ves | Must be Brca-ve (including other HRD+ves) |
Keylynk-001 | 1L & maintenance | Chemo + Keytruda, then Lynparza | Chemo +/- Keytruda, then placebo | PFS in PD-L1+ves & all-comers are co-primaries**; ends Oct 2023 | Must be Brca-ve |
Bristol Myers Squibb/Pharma& (ex Clovis) | |||||
Athena-Combo | 1L maintenance | Opdivo + Rubraca | Opdivo or Rubraca or placebo | PFS primary, data were due Q1 2023*** | None evident |
Note: *not phase 3; **earlier PFS & OS were co-primaries; ***forecast made by Clovis, which later entered bankruptcy and sold Rubraca to Pharma& for $70m. Source: company statements & clinicaltrials.gov. |
That Parp inhibition should work in patients with no HRD mutation seems counterintuitive. Presenting Duo-O at a pre-Asco press briefing, Memorial Sloan Kettering’s Dr Carol Aghajanian suggested that these patients might not be HRD-negative at all, since the tests on which their HRD status was based “are imperfect”.
Understanding the extent to which HRD-positives are actually responsible for any benefit is key to estimating the possible breadth of any label here. And of course nothing is yet known about OS, a secondary Duo-O endpoint that is still immature.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
Whether Imfinzi is active here goes to the heart of why Duo-O’s positive hit is unexpected. Immunotherapy has tended not to work in ovarian cancer: witness the failures of Roche’s Imagyn-050, Merck KGaA/Pfizer’s Javelin Ovarian 100 and Merck & Co’s Keynote-100 trials.
Next to test the theory will be Merck & Co’s Keylynk-001 trial, which tests Keytruda followed by Lynparza in the maintenance phase, and like Duo-O enrolled only Brca-negative patients. The Athena-Combo trial of Opdivo and Rubraca was to have read out in the first quarter, but its sponsor, Clovis, has gone out of business.
Astrazeneca appears to have teased out a positive result for Imfinzi in ovarian cancer – a setting that so far has proved intractable for anti-PD-(L)1 drugs. The data, toplined positive in April, concern the Duo-O study of an Avastin/Imfinzi/Lynparza triplet, and have just been presented at an Asco late-breaker.
The result is notable for having apparently succeeded where other PD-(L)1/Parp inhibitor combinations have failed, and one reason for this might be Astra’s exclusion of Brca-positive patients, who would normally be expected to do well on Avastin/Lynparza alone. Still, questions will remain about Imfinzi's contribution, the breadth of the effect, and the robustness of a progression-free survival endpoint.
Debate continues about the validity of PFS in ovarian cancer, and there have been cases where a clinical benefit on PFS has been followed by a clearly negative result in terms of overall survival. This has, for instance, seen use of GSK’s Parp inhibitor, Zejula, narrowed in ovarian cancer maintenance.
Complexities
Duo-O had a complex three-arm design, and included two settings. Active cohorts comprised chemo/Avastin/Imfinzi first line followed by Avastin/Imfinzi with or without Lynparza in the maintenance setting; this was compared against a control cohort of chemo/Avastin followed by Avastin maintenance.
A further crucial twist is that the trial enrolled Brca-negative patients only, and its PFS endpoint was split between two co-primaries: an effect in all-comers, and in Brca-negatives who were nevertheless positive for some other type of HRD mutation.
The good news is that the Avastin/Imfinzi/Lynparza maintenance triplet met both co-primaries, with p<0.0001. The bad that Avastin/Imfinzi had no advantage over control at all.
The survival curves reveal another nuance. It might have been assumed that HRD-positive patients are driving the all-comers benefit, but in fact in HRD-negatives, some 60% of the Duo-O Brca-negative population, the triplet also beat control.
PD-(L)1 + Parp inhibition in ovarian cancer | |||||
---|---|---|---|---|---|
Trial | Setting | Active treatment | Comparator | Note | Brca restriction? |
Roche | |||||
WO39409* | ≥2L | Tecentriq + Rubraca | Uncontrolled | Ended 2020 after Covid-related protocol amendment, no data reported | None in ovarian cancer cohort |
Merck KGaA/Pfizer | |||||
Javelin Ovarian Parp 100 | 1L & maintenance | Chemo + Bavencio, then Bavencio + Talzenna | Chemo +/- Avastin, then Talzenna or Avastin | Discontinued after failure of Javelin Ovarian 100 trial | None evident |
Merck & Co and/or Astrazeneca | |||||
Duo-O | 1L & maintenance | Chemo + Avastin + Imfinzi, then Avastin + Imfinzi +/- Lynparza | Chemo + Avastin, then Avastin | Maintenance triplet positive for PFS in HRD+ves, all-comers & HRD-ves | Must be Brca-ve (including other HRD+ves) |
Keylynk-001 | 1L & maintenance | Chemo + Keytruda, then Lynparza | Chemo +/- Keytruda, then placebo | PFS in PD-L1+ves & all-comers are co-primaries**; ends Oct 2023 | Must be Brca-ve |
Bristol Myers Squibb/Pharma& (ex Clovis) | |||||
Athena-Combo | 1L maintenance | Opdivo + Rubraca | Opdivo or Rubraca or placebo | PFS primary, data were due Q1 2023*** | None evident |
Note: *not phase 3; **earlier PFS & OS were co-primaries; ***forecast made by Clovis, which later entered bankruptcy and sold Rubraca to Pharma& for $70m. Source: company statements & clinicaltrials.gov. |
That Parp inhibition should work in patients with no HRD mutation seems counterintuitive. Presenting Duo-O at a pre-Asco press briefing, Memorial Sloan Kettering’s Dr Carol Aghajanian suggested that these patients might not be HRD-negative at all, since the tests on which their HRD status was based “are imperfect”.
Understanding the extent to which HRD-positives are actually responsible for any benefit is key to estimating the possible breadth of any label here. And of course nothing is yet known about OS, a secondary Duo-O endpoint that is still immature.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
Whether Imfinzi is active here goes to the heart of why Duo-O’s positive hit is unexpected. Immunotherapy has tended not to work in ovarian cancer: witness the failures of Roche’s Imagyn-050, Merck KGaA/Pfizer’s Javelin Ovarian 100 and Merck & Co’s Keynote-100 trials.
Next to test the theory will be Merck & Co’s Keylynk-001 trial, which tests Keytruda followed by Lynparza in the maintenance phase, and like Duo-O enrolled only Brca-negative patients. The Athena-Combo trial of Opdivo and Rubraca was to have read out in the first quarter, but its sponsor, Clovis, has gone out of business.
Astrazeneca appears to have teased out a positive result for Imfinzi in ovarian cancer – a setting that so far has proved intractable for anti-PD-(L)1 drugs. The data, toplined positive in April, concern the Duo-O study of an Avastin/Imfinzi/Lynparza triplet, and have just been presented at an Asco late-breaker.
The result is notable for having apparently succeeded where other PD-(L)1/Parp inhibitor combinations have failed, and one reason for this might be Astra’s exclusion of Brca-positive patients, who would normally be expected to do well on Avastin/Lynparza alone. Still, questions will remain about Imfinzi's contribution, the breadth of the effect, and the robustness of a progression-free survival endpoint.
Debate continues about the validity of PFS in ovarian cancer, and there have been cases where a clinical benefit on PFS has been followed by a clearly negative result in terms of overall survival. This has, for instance, seen use of GSK’s Parp inhibitor, Zejula, narrowed in ovarian cancer maintenance.
Complexities
Duo-O had a complex three-arm design, and included two settings. Active cohorts comprised chemo/Avastin/Imfinzi first line followed by Avastin/Imfinzi with or without Lynparza in the maintenance setting; this was compared against a control cohort of chemo/Avastin followed by Avastin maintenance.
A further crucial twist is that the trial enrolled Brca-negative patients only, and its PFS endpoint was split between two co-primaries: an effect in all-comers, and in Brca-negatives who were nevertheless positive for some other type of HRD mutation.
The good news is that the Avastin/Imfinzi/Lynparza maintenance triplet met both co-primaries, with p<0.0001. The bad that Avastin/Imfinzi had no advantage over control at all.
The survival curves reveal another nuance. It might have been assumed that HRD-positive patients are driving the all-comers benefit, but in fact in HRD-negatives, some 60% of the Duo-O Brca-negative population, the triplet also beat control.
PD-(L)1 + Parp inhibition in ovarian cancer | |||||
---|---|---|---|---|---|
Trial | Setting | Active treatment | Comparator | Note | Brca restriction? |
Roche | |||||
WO39409* | ≥2L | Tecentriq + Rubraca | Uncontrolled | Ended 2020 after Covid-related protocol amendment, no data reported | None in ovarian cancer cohort |
Merck KGaA/Pfizer | |||||
Javelin Ovarian Parp 100 | 1L & maintenance | Chemo + Bavencio, then Bavencio + Talzenna | Chemo +/- Avastin, then Talzenna or Avastin | Discontinued after failure of Javelin Ovarian 100 trial | None evident |
Merck & Co and/or Astrazeneca | |||||
Duo-O | 1L & maintenance | Chemo + Avastin + Imfinzi, then Avastin + Imfinzi +/- Lynparza | Chemo + Avastin, then Avastin | Maintenance triplet positive for PFS in HRD+ves, all-comers & HRD-ves | Must be Brca-ve (including other HRD+ves) |
Keylynk-001 | 1L & maintenance | Chemo + Keytruda, then Lynparza | Chemo +/- Keytruda, then placebo | PFS in PD-L1+ves & all-comers are co-primaries**; ends Oct 2023 | Must be Brca-ve |
Bristol Myers Squibb/Pharma& (ex Clovis) | |||||
Athena-Combo | 1L maintenance | Opdivo + Rubraca | Opdivo or Rubraca or placebo | PFS primary, data were due Q1 2023*** | None evident |
Note: *not phase 3; **earlier PFS & OS were co-primaries; ***forecast made by Clovis, which later entered bankruptcy and sold Rubraca to Pharma& for $70m. Source: company statements & clinicaltrials.gov. |
That Parp inhibition should work in patients with no HRD mutation seems counterintuitive. Presenting Duo-O at a pre-Asco press briefing, Memorial Sloan Kettering’s Dr Carol Aghajanian suggested that these patients might not be HRD-negative at all, since the tests on which their HRD status was based “are imperfect”.
Understanding the extent to which HRD-positives are actually responsible for any benefit is key to estimating the possible breadth of any label here. And of course nothing is yet known about OS, a secondary Duo-O endpoint that is still immature.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
Whether Imfinzi is active here goes to the heart of why Duo-O’s positive hit is unexpected. Immunotherapy has tended not to work in ovarian cancer: witness the failures of Roche’s Imagyn-050, Merck KGaA/Pfizer’s Javelin Ovarian 100 and Merck & Co’s Keynote-100 trials.
Next to test the theory will be Merck & Co’s Keylynk-001 trial, which tests Keytruda followed by Lynparza in the maintenance phase, and like Duo-O enrolled only Brca-negative patients. The Athena-Combo trial of Opdivo and Rubraca was to have read out in the first quarter, but its sponsor, Clovis, has gone out of business.
Astrazeneca appears to have teased out a positive result for Imfinzi in ovarian cancer – a setting that so far has proved intractable for anti-PD-(L)1 drugs. The data, toplined positive in April, concern the Duo-O study of an Avastin/Imfinzi/Lynparza triplet, and have just been presented at an Asco late-breaker.
The result is notable for having apparently succeeded where other PD-(L)1/Parp inhibitor combinations have failed, and one reason for this might be Astra’s exclusion of Brca-positive patients, who would normally be expected to do well on Avastin/Lynparza alone. Still, questions will remain about Imfinzi's contribution, the breadth of the effect, and the robustness of a progression-free survival endpoint.
Debate continues about the validity of PFS in ovarian cancer, and there have been cases where a clinical benefit on PFS has been followed by a clearly negative result in terms of overall survival. This has, for instance, seen use of GSK’s Parp inhibitor, Zejula, narrowed in ovarian cancer maintenance.
Complexities
Duo-O had a complex three-arm design, and included two settings. Active cohorts comprised chemo/Avastin/Imfinzi first line followed by Avastin/Imfinzi with or without Lynparza in the maintenance setting; this was compared against a control cohort of chemo/Avastin followed by Avastin maintenance.
A further crucial twist is that the trial enrolled Brca-negative patients only, and its PFS endpoint was split between two co-primaries: an effect in all-comers, and in Brca-negatives who were nevertheless positive for some other type of HRD mutation.
The good news is that the Avastin/Imfinzi/Lynparza maintenance triplet met both co-primaries, with p<0.0001. The bad that Avastin/Imfinzi had no advantage over control at all.
The survival curves reveal another nuance. It might have been assumed that HRD-positive patients are driving the all-comers benefit, but in fact in HRD-negatives, some 60% of the Duo-O Brca-negative population, the triplet also beat control.
PD-(L)1 + Parp inhibition in ovarian cancer | |||||
---|---|---|---|---|---|
Trial | Setting | Active treatment | Comparator | Note | Brca restriction? |
Roche | |||||
WO39409* | ≥2L | Tecentriq + Rubraca | Uncontrolled | Ended 2020 after Covid-related protocol amendment, no data reported | None in ovarian cancer cohort |
Merck KGaA/Pfizer | |||||
Javelin Ovarian Parp 100 | 1L & maintenance | Chemo + Bavencio, then Bavencio + Talzenna | Chemo +/- Avastin, then Talzenna or Avastin | Discontinued after failure of Javelin Ovarian 100 trial | None evident |
Merck & Co and/or Astrazeneca | |||||
Duo-O | 1L & maintenance | Chemo + Avastin + Imfinzi, then Avastin + Imfinzi +/- Lynparza | Chemo + Avastin, then Avastin | Maintenance triplet positive for PFS in HRD+ves, all-comers & HRD-ves | Must be Brca-ve (including other HRD+ves) |
Keylynk-001 | 1L & maintenance | Chemo + Keytruda, then Lynparza | Chemo +/- Keytruda, then placebo | PFS in PD-L1+ves & all-comers are co-primaries**; ends Oct 2023 | Must be Brca-ve |
Bristol Myers Squibb/Pharma& (ex Clovis) | |||||
Athena-Combo | 1L maintenance | Opdivo + Rubraca | Opdivo or Rubraca or placebo | PFS primary, data were due Q1 2023*** | None evident |
Note: *not phase 3; **earlier PFS & OS were co-primaries; ***forecast made by Clovis, which later entered bankruptcy and sold Rubraca to Pharma& for $70m. Source: company statements & clinicaltrials.gov. |
That Parp inhibition should work in patients with no HRD mutation seems counterintuitive. Presenting Duo-O at a pre-Asco press briefing, Memorial Sloan Kettering’s Dr Carol Aghajanian suggested that these patients might not be HRD-negative at all, since the tests on which their HRD status was based “are imperfect”.
Understanding the extent to which HRD-positives are actually responsible for any benefit is key to estimating the possible breadth of any label here. And of course nothing is yet known about OS, a secondary Duo-O endpoint that is still immature.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
A separate question is how much benefit Imfinzi brings; notably only the addition of Lynparza to the maintenance stage yielded a positive result. “If we had to do it again of course we would have a fourth arm that had Avastin and Lynparza maintenance,” said Aghajanian.
Whether Imfinzi is active here goes to the heart of why Duo-O’s positive hit is unexpected. Immunotherapy has tended not to work in ovarian cancer: witness the failures of Roche’s Imagyn-050, Merck KGaA/Pfizer’s Javelin Ovarian 100 and Merck & Co’s Keynote-100 trials.
Next to test the theory will be Merck & Co’s Keylynk-001 trial, which tests Keytruda followed by Lynparza in the maintenance phase, and like Duo-O enrolled only Brca-negative patients. The Athena-Combo trial of Opdivo and Rubraca was to have read out in the first quarter, but its sponsor, Clovis, has gone out of business.