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Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.
Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.
“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”
Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).
The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.
CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.
Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
ORR and PFS
The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).
With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).
The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.
There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).
There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.
She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
Adverse events
As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.
“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.
Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.
A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
Data inspire cautious optimism
The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.
Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.
“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”
There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.
She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”
Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.
“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”
CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.
SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.
Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.
Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.
“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”
Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).
The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.
CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.
Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
ORR and PFS
The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).
With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).
The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.
There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).
There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.
She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
Adverse events
As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.
“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.
Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.
A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
Data inspire cautious optimism
The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.
Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.
“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”
There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.
She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”
Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.
“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”
CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.
SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.
Patients who received tiragolumab, an anti-TIGIT antibody, in combination with atezolizumab, a PD-L1 inhibitor, had superior overall response rates (ORR) and progression-free survival (PFS), when compared with results of patients who received placebo with atezolizumab.
Melissa L. Johnson, MD, of the Sarah Cannon Research Institute in Nashville, Tenn., presented these results as part of the American Society of Clinical Oncology virtual scientific program.
Dr. Johnson explained that TIGIT is an immunomodulatory receptor present on activated T cells and natural killer cells in multiple cancers, including NSCLC.
“TIGIT inhibits T cells and natural killer cells by binding to its ligand PVR on tumor cells and antigen-presenting cells,” she said. “TIGIT expression strongly correlates with PD-1 expression, sometimes on the same tumor-infiltrating T cells in lung cancer. So the hypothesis of this trial was that anti-TIGIT antibodies, which prevent TIGIT from binding to its ligand, could restore the antitumor response and could complement the activity of anti–PD-L1/PD-1 antibodies.”
Dr. Johnson noted that combination anti–TIGIT/PD-L1 antibody treatment synergistically improved tumor control and prolonged survival over either antibody alone in preclinical models (Cancer Cell. 2014 Dec 8;26[6]:923-937). In addition, tiragolumab has been evaluated in a phase 1 study, both as monotherapy and in combination with atezolizumab, in multiple solid tumors (NCT02794571).
The phase 2 CITYSCAPE study (NCT03563716) was initiated to confirm the efficacy and safety of tiragolumab plus atezolizumab versus placebo plus atezolizumab for the first-line treatment of NSCLC, Dr. Johnson said.
CITYSCAPE enrolled 135 patients with chemotherapy-naive, PD-L1–positive, locally advanced or metastatic NSCLC. Patients did not have EGFR or ALK alterations.
Half of patients (n = 68) were randomized to receive tiragolumab at 600 mg plus atezolizumab at 1,200 mg, both given on day 1 of every 3-week cycle. The other half of patients (n = 67) were randomized to receive atezolizumab at the same dose and schedule plus placebo.
ORR and PFS
The study’s primary analysis was conducted in June 2019 at a median follow-up of 5.9 months. At that time, the ORR and PFS data showed an early benefit with tiragolumab. The ORR was 31% in the tiragolumab arm and 16% in the placebo arm. The median PFS was 5.42 months and 3.58 months, respectively (hazard ratio, 0.57).
With an additional 6 months of follow-up, the tiragolumab benefit persisted, Dr. Johnson said. The updated ORR in the intent-to-treat population was 37% in the tiragolumab arm and 21% in the placebo arm. The median PFS was 5.6 months and 3.9 months, respectively (HR, 0.58).
The tiragolumab combination showed “clinically meaningful” improvements in ORR and PFS, Dr. Johnson said. She also noted “a greater magnitude of improvement” was seen in patients with a PD-L1 tumor proportion score of 50% or greater.
There were 29 patients in each treatment arm with a PD-L1 tumor proportion score of 50% or greater. Among these patients, the ORR was 66% in the tiragolumab arm and 24% in the placebo arm. The median PFS was not reached and 4.1 months, respectively (HR, 0.30).
There were no significant differences in ORR or PFS among patients with PD-L1 tumor proportion scores below 50%, Dr. Johnson noted.
She added that duration of response and overall survival data are not yet mature and will be presented at a future conference.
Adverse events
As reported in the primary analysis, tiragolumab plus atezolizumab had a tolerable safety profile, Dr. Johnson said.
“Despite a near doubling of the median treatment duration [at the updated analysis], there were similar numbers of any-cause adverse events, grade 3-5 adverse events, and serious adverse events,” she said.
Overall, adverse events occurred in 99% of patients in the tiragolumab arm and 96% of those in the placebo arm. Rates of grade 3-5 adverse events were 48% and 44%, respectively. Rates of serious adverse events were 37% and 35%, respectively.
A higher frequency of adverse events in the tiragolumab arm was related to an increase in immune-related events, including infusion reactions, pruritus, rash, arthralgia, and nephritis. This makes sense because the patients in that group were receiving two active immunotherapies, Dr. Johnson said.
Data inspire cautious optimism
The safety and activity of tiragolumab plus atezolizumab are “to be confirmed in an ongoing phase 3 study called SKYSCRAPER-01 [NCT04294810],” Dr. Johnson said.
Invited discussant Grace K. Dy, MD, of Roswell Park Comprehensive Cancer Center in Buffalo, N.Y., said the ORRs in CITYSCAPE have “generated a lot of buzz,” but she urged caution pending phase 3 results.
“While we are all excited by the data and want to see a winner, we should be careful, as speed can also crash and burn,” she said. “We have plenty of examples of promising studies that collapsed in later phase trials.”
There is room, however, for cautious optimism that the combination is a promising advance “as long as no prognostic or confounding variable is determined later on to be nonrandomly distributed between the groups to account for the difference seen,” Dr. Dy said.
She also noted that “the distribution of favorable or unfavorable mutations between the groups is unknown, and understanding this will be relevant.”
Preclinical data suggest the presence of DNM1 expression is crucial for maximizing the effect of TIGIT blockade, and tumor MHC class 1 expression appears to be reduced alongside reductions in DNM1 expression in the intratumoral natural kill cells in lung cancer specimens, Dr. Dy explained.
“Assessment of these biomarkers will be instructive,” she said. “More recent data also appear to implicate a paradoxical role of soluble CD155 or PVR ligand in actually inhibiting DNM1, so the effect of systemic TIGIT blockade may be mitigated if there is rebound increase of counterbalancing signals by increased secretion of soluble CD155, and we look forward to more data in the future regarding this.”
CITYSCAPE was sponsored by Genentech. Dr. Johnson disclosed relationships with Genentech and numerous other companies. Dr. Dy disclosed relationships with AstraZeneca, GlaxoSmithKline, Takeda, Amgen, Bristol-Myers Squibb, Regeneron, and Tesaro.
SOURCE: Rodriguez-Abreu D et al. ASCO 2020, Abstract 9503.
FROM ASCO 2020