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An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.
“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).
Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.
“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.
Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.
“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
Data confirm KRAS as a therapeutic target
Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.
Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.
“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
KRYSTAL-1 study design and safety
KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.
Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.
The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).
Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).
Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
Greater effect seen with co-mutation
KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.
A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.
“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.
Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.
“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.
A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.
Data could support drug combination
The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.
“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”
The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.
An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.
“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).
Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.
“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.
Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.
“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
Data confirm KRAS as a therapeutic target
Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.
Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.
“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
KRYSTAL-1 study design and safety
KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.
Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.
The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).
Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).
Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
Greater effect seen with co-mutation
KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.
A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.
“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.
Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.
“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.
A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.
Data could support drug combination
The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.
“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”
The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.
An objective response rate was seen in 45% of patients, with a further 51% achieving stable disease, for a disease control rate of 96%.
“The vast majority of patients had significant tumor shrinkage,” said study investigator Gregory J. Riely, MD, PhD, when presenting the results at the European Lung Cancer Virtual Congress 2021 (Abstract 990_PR).
Dr. Riely, vice chair of clinical research in the department of medicine at Memorial Sloan Kettering Cancer Center in New York, noted that just 6 of the 70 patients in this phase 1/2 trial showed evidence of measurable tumor growth.
“This new way of targeting an oncogene may very well represent an evolutionary step forward in the management of lung cancer patients, akin to when we first had EGFR inhibitors,” Alastair Greystoke, MBChB, PhD, said in his discussion of the trial.
Dr. Greystoke, a clinical senior lecturer and honorary consultant in medical oncology at Newcastle (England) University, observed that the availability of KRAS-targeting agents could have a large potential impact on clinical practice. They could add another 14% of patients with NSCLC to the list of those who are eligible for molecularly-targeted therapy.
“It may be that soon, almost half our patients with lung adenocarcinoma will have a potential targetable abnormality,” Dr. Greystoke said.
Data confirm KRAS as a therapeutic target
Adagrasib is now the second drug to show promise as an inhibitor of KRAS G12C. In a phase 2 trial, the KRAS inhibitor sotorasib produced a response rate of 37%, a median response duration of 10 months, and a median progression-free survival of 6.8 months in patients with NSCLC.
Data on response duration and progression-free survival are not yet available for adagrasib. However, the duration of response extended past 11 months in four of the six patients who achieved a partial response to adagrasib in the phase 1/1b portion of the KRYSTAL-1 trial.
“What we’ve seen from this data, and data with other agents, is that responses are very heterogeneous,” Dr. Greystoke observed. “A small number of patients do not respond at all. In some patients, responses are short-lived, whilst in other patients, responses are long and still ongoing.”
KRYSTAL-1 study design and safety
KRYSTAL-1 is an ongoing phase 1/2 study designed to assess the safety and clinical activity of adagrasib in patients with advanced solid tumors that have a KRAS G12C mutation, including NSCLC.
Dr. Riely reported data on 79 patients with advanced or metastatic NSCLC who had progressed despite being treated with chemotherapy and immunotherapy. Of these, 18 patients had participated in the phase 1/1b dose-escalation and dose-expansion phase of the study, and 61 had participated in the phase 2 portion. Adagrasib was given at a twice-daily dose of 600 mg.
The patients’ median age was 65 years, 85% were White, and 57% were women. Almost all (95%) were current or former smokers, which is unsurprising since the KRAS G12C mutation is rarely seen in never-smokers. Almost all patients had nonsquamous histology (96%) and had received PD-1 or PD-L1 inhibitors (92%).
Treatment-related adverse events of any grade occurred in 85% of patients, and 30% of patients had grade 3-4 events. The most frequent treatment-related grade 3-4 adverse events were fatigue (6%), increased ALT or AST (each 5%), QT prolongation (3%), anemia (2%), nausea (2%), and vomiting (2%).
Two grade 5 adverse events were recorded – a case of pneumonitis in a patient with recurrent pneumonitis and one case of cardiac failure. Adverse events led to discontinuation in 4.5% of patients.
Greater effect seen with co-mutation
KRAS is commonly co-mutated, so the investigators performed an exploratory analysis to see if the presence of other mutations – STK11, KEAP1, and TP53 – might affect the results of adagrasib.
A greater objective response rate was seen in patients with the STK11 mutation than in those without it (64% and 33%, respectively). STK11 is associated with poorer responses to immune checkpoint inhibitors.
“We hypothesized that adagrasib treatment recruits T cells into the tumor and that T-cell infiltration may reverse STK11-mediated immune suppression,” Dr. Riely said. This theory seemed to be borne out with further analyses, though Dr. Greystoke raised doubts. There was no sign of STK11 mutations having any effect on response rates with adagrasib in preclinical studies.
Patients with KEAP1 as a co-mutation had a lower response rate than that of those without it (36% and 48%, respectively), which is in keeping with what might be expected. KEAP1 is known to be associated to a poor response to chemotherapy and immunotherapy.
“I think this data is very provocative but needs to be confirmed in larger cohorts,” Dr. Greystoke said. It could mean that adagrasib has the potential to turn a “cold tumor, hot,” enabling the use of immunotherapies.
A new cohort has been included in the KRYSTAL-1 study to further evaluate how having both the KRAS G12C and STK11 mutations may affect treatment with adagrasib.
Data could support drug combination
The adagrasib data lend support to the combination of KRAS G12C inhibitors with other molecularly-targeted treatments for NSCLC, Dr. Greystoke said, such as with tyrosine kinase inhibitors or immunotherapies. He noted that high steady-state levels of adagrasib were detected in the blood, and these levels were well above those needed for potential efficacy.
“This gives us confidence that if we do need to drop the dose below the recommended phase 2 dose to allow potential combinations with a small-molecule inhibitor due to overlapping toxicity or overlapping pharmacokinetics, that it is safe to do and shouldn’t [have an] impact on efficacy,” Dr. Greystoke said. “Overall, all this information will help us drive forward the next round of clinical trials of probably a combination of treatments.”
The KRYSTAL-1 study is supported by Mirati Therapeutics, Inc. Dr. Riely disclosed relationships with Mirati Therapeutics, Merck, Novartis, Pfizer, Takeda, and Roche. Dr. Greystoke was not involved in the study but disclosed relationships with Amgen, AstraZeneca, Boehringer-Ingelheim, Bristol-Myers Squibb, Merck, Novartis, Pfizer, Lilly, Takeda, and Roche.
FROM ELCC 2021