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Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
Although epidermal growth factor receptor–mutant lung cancers generally don’t benefit from checkpoint inhibitors, there may be some subtypes that do respond, results of a large, multi-institution analysis suggest.
Compared with wild-type lung cancer cases, tumors with epidermal growth factor receptor (EGFR) exon 19 deletion did indeed have worse outcomes after progressive death-1/progressive death–ligand 1 (PD-1/PD-L1) blockade; however, tumors harboring EGFR L858R mutations had comparable response rates and overall survival.
These findings don’t change clinical practice, but do serve as a “foundation” for more research into which patients with EGFR-mutant disease might benefit from immunotherapy, according to Katherine Hastings, PhD, of Yale University, New Haven, Conn., and associates.
“We unequivocally support the guidance that EGFR TKIs should be the preferred first-line treatment option for patients with EGFR-mutant lung cancer,” Dr. Hastings and coauthors wrote in Annals of Oncology.
To date, clinical investigations of immune checkpoint inhibitors in patients with EGFR-mutant lung cancers have largely been discouraging, the authors wrote. However, there have been some exceptions, including a phase 2 study where third-line durvalumab showed activity in some patients with EGFR-positive, PD-L1-expressing advanced non–small cell lung cancer (NSCLC).
Accordingly, the investigators sought to determine whether specific molecular features made a difference. They looked at a total of 171 EGFR-mutant lung cancers that had been treated with PD-1/PD-L1 inhibitors, alone or in combination with a cytotoxic T-lymphocyte antigen 4 inhibitor.
In their analysis, they drilled down on the most common EGFR tyrosine kinase inhibitor–sensitizing alleles: EGFR exon 19 deletions, which represented 76 cases, and EGFR L858R, which represented 44 cases. For comparison, they looked at a cohort of 212 patients with EGFR wild-type NSCLC who had also been treated with immune checkpoint inhibitors.
EGFR exon 19 deletion cases had a significantly lower overall response rate versus EGFR wild-type tumors, at 7% versus 22%, respectively (P = .002), the investigators found. Likewise, overall survival was significantly reduced, with a hazard ratio of 0.69 (95% confidence interval, 0.493-0.965; P = .03).
By contrast, EGFR L858R tumors had similar response rates versus EGFR wild type, at 16% and 22%, respectively (P = .42); overall survival also was similar, with a hazard ratio of 0.917 (95% CI, 0.597-1.409; P = .69).
Of note, progression-free survival was reduced in both EGFR L858R and EGFR exon 19 deletion cases as compared with EGFR wild-type cases, though the investigators wrote that discrepancy might be related to variations in scanning intervals between different institutions that contributed cases to the study.
“Overall, these data suggest that patients with EGFR exon 19–mutant tumors, in particular, have a significantly reduced benefit upon treatment with immune checkpoint inhibitors,” the authors noted.
In a separate but related analysis of 383 patients with EGFR-mutant lung cancer, tumor mutation burden was lower in EGFR exon 19 deletion cases as compared with the EGFR L858R cases. That finding lined up with the immunotherapy response data, the investigators wrote, though it’s unclear what might be driving the differences in tumor burden between these two groups.
There were no differences in response to immune checkpoint blockade based on whether or not tumors harbored the EGFR T790M mutation, the investigators added. Similarly, PD-L1 expression did not impact response.
The study authors reported disclosures related to Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Calithera Biosciences, Daiichi, Eli Lilly, Merck, Mirati Therapeutics, Novartis, Pfizer, Roche, and Takeda, among others.
SOURCE: Hastings K et al. Ann Oncol. 2019 May 14. doi: 10.1093/annonc/mdz141.
FROM ANNALS OF ONCOLOGY