In the Journals

Broad-based genomic sequencing fails to improve advanced NSCLC survival

Photo of Carolyn Presley 2018
Carolyn J. Presley

Patients with advanced non-small cell lung cancer who underwent broad-based genomic sequencing in a community oncology setting did not appear to have better survival than patients who underwent routine testing for ALK and EGFR, according to findings from a retrospective cohort study.

“Lung cancer is the one cancer where precision medicine should be helpful in seeing a survival difference. Right now, we are doing the test, but we aren’t seeing a survival difference, probably because we aren’t getting patients the drugs they need for the mutations we are finding,” Carolyn J. Presley, MD, MHS, assistant professor in the division of thoracic oncology/geriatric oncology at The Ohio State University Comprehensive Cancer Center, told HemOnc Today. “We need to be able to track genetic testing results better between clinicians, we need more trials for new targeted cancer drugs, and we need to make cancer drugs affordable for our patients.”

Broad-based genomic sequencing assesses multiple genes to identify mutations in tumors among patients with advanced NSCLC.

However, the procedure can be costly. There also is a lack of evidence to suggest routine use of broad-based genomic sequencing can improve survival among patients with advanced NSCLC treated in the community.

Because more research is needed to determine if broad-based genomic sequencing is more beneficial than routine EGFR/ALK testing, Presley and colleagues evaluated data from 5,688 patients with advanced NSCLC (median age, 67 years; 63.6% white) from the Flatiron Health Database who underwent broad-based genomic sequencing (n = 875) or routine testing for alterations in EGFR or ALK (n = 4,813) in a community oncology clinic.

Patients had stage IIIB/IV or unresectable nonsquamous NSCLC and had received at least one line of antineoplastic treatment.

One-year mortality from initiation of first-line treatment served as the primary outcome for the instrumental variable analysis. OS — defined as the time from the start of first-line treatment to the date of death, last follow-up, or data cut-off date of July 31, 2016 — served as the primary outcome for the propensity score-matched survival analysis.

Secondary outcomes included frequency of specific genetic alterations and treatments received.

Among patients who underwent broad-based genomic sequencing — which included any multigene panel sequencing assay examining more than 30 genes — 778 patients (88.9%) had a genetic mutation identified, the most common of which were TP53 (55.1% of mutations detected), followed by KRAS (34.2%), EGFR (21.9%), CDKN2A (15.7%) and STK11 (12.2%).

In total, 4.5% received targeted treatment based on sequencing results, 9.8% received routine EGFR- or ALK-targeted treatment, and 85.1% received no targeted treatment.

Patients receiving broad-based genomic sequencing appeared more likely to receive immunotherapy (4% vs. 1.7%) or clinical trial regimens (0.6% vs. 0.4%; P < .001 for both) than routine-tested patients.

Results showed a 1-year unadjusted mortality rate of 49.2% among patients who underwent broad-based genomic sequencing compared with 35.9% among patients who underwent routine testing.

Results of the instrumental variable analysis did not show a significant association between broad-based genomic sequencing and 1-year mortality; the predicted probability of mortality at 1 year was 41.1% among the broad-based genomic sequencing group compared with 44.4% among the routine testing group (difference = 3.6%; 95% CI, 18.4 to 11.1).

The results were surprising, according to Presley.

“There has been a great deal of interest in precision medicine, and many are calling for all patients with cancer to have broad-based genomic sequencing with hundreds of genes,” Presley said. “So, we were surprised that it wasn’t demonstrating improved survival.”

The propensity score-matched survival analysis showed similar findings (42.0% vs. 45.1%), for an HR of 0.92 (95% CI, 0.73-1.11). The unmatched cohort demonstrated an HR of 0.69 (95% CI, 0.62-0.77).

Improved access to clinical trials and targeted treatments should occur alongside of increased use of broad-based genomic sequencing in the community setting, according to the researchers.

“This is the only way we will start to see a survival difference alongside our advances in sequencing techniques,” Presley said. “Right now, we are seeing broad-based genetic testing being done and patients aren’t getting the drugs they need for a variety of reasons. There is now the ‘right to try,’ but what about the ‘right to afford’ your medications?” she said, adding that cost has remains an issue for oral targeted treatments for cancer.

“These drugs just are not affordable and impair our ability to treat our patients,” she said.

The study by Presley and colleagues provides critical insights into how broad-based genomic sequencing can be used in the community oncology setting, were most patients in the U.S. are treated, Paul A. Bunn Jr., MD, distinguished professor in the division of medical oncology, and Dara L. Aisner, MD, PhD, director of the Colorado Molecular Correlates Laboratory, both from University of Colorado Anschutz Medical Campus, wrote in a related editorial.

However, various limitations of the study — the 2011 to 2016 study timeframe, the high incremental value of a 30-gene cutoff, the low rate of treatment among patients with identified mutations, among others — call into question the authors’ conclusion.

“The limitations of this investigation suggest that the authors’ conclusion that broad testing is not warranted should be tempered to ensure that patients receive the right therapy for the right alteration at the right time,” Bunn Jr. and Aisner wrote. – by Melinda Stevens

For more information:

Carolyn J. Presley, MD, can be reached at The Ohio State University, Medical Oncology, B424 Starling Loving Hall, 320W10th Ave., Columbus, OH 43214; email: carolyn.presley@osumc.edu.

Disclosures: Presley reports grants from the Yale Lung SPORE Career Development Award, the Robert Wood Johnson/Veterans Affairs Clinical Scholars Program and from The Ohio State University K12 Training Grant for clinical faculty Investigators. Please see the study for all other authors’ relevant financial disclosures. Bunn reports consultant fees from AstraZeneca, Bristol-Myers Squibb, Genentech, Lilly, Merck, Merck-Serono, Novartis, Pfizer and Takeda. Aisner reports consultant income from AbbVie, Bristol-Myers Squibb and Genentech.

Photo of Carolyn Presley 2018
Carolyn J. Presley

Patients with advanced non-small cell lung cancer who underwent broad-based genomic sequencing in a community oncology setting did not appear to have better survival than patients who underwent routine testing for ALK and EGFR, according to findings from a retrospective cohort study.

“Lung cancer is the one cancer where precision medicine should be helpful in seeing a survival difference. Right now, we are doing the test, but we aren’t seeing a survival difference, probably because we aren’t getting patients the drugs they need for the mutations we are finding,” Carolyn J. Presley, MD, MHS, assistant professor in the division of thoracic oncology/geriatric oncology at The Ohio State University Comprehensive Cancer Center, told HemOnc Today. “We need to be able to track genetic testing results better between clinicians, we need more trials for new targeted cancer drugs, and we need to make cancer drugs affordable for our patients.”

Broad-based genomic sequencing assesses multiple genes to identify mutations in tumors among patients with advanced NSCLC.

However, the procedure can be costly. There also is a lack of evidence to suggest routine use of broad-based genomic sequencing can improve survival among patients with advanced NSCLC treated in the community.

Because more research is needed to determine if broad-based genomic sequencing is more beneficial than routine EGFR/ALK testing, Presley and colleagues evaluated data from 5,688 patients with advanced NSCLC (median age, 67 years; 63.6% white) from the Flatiron Health Database who underwent broad-based genomic sequencing (n = 875) or routine testing for alterations in EGFR or ALK (n = 4,813) in a community oncology clinic.

Patients had stage IIIB/IV or unresectable nonsquamous NSCLC and had received at least one line of antineoplastic treatment.

One-year mortality from initiation of first-line treatment served as the primary outcome for the instrumental variable analysis. OS — defined as the time from the start of first-line treatment to the date of death, last follow-up, or data cut-off date of July 31, 2016 — served as the primary outcome for the propensity score-matched survival analysis.

Secondary outcomes included frequency of specific genetic alterations and treatments received.

Among patients who underwent broad-based genomic sequencing — which included any multigene panel sequencing assay examining more than 30 genes — 778 patients (88.9%) had a genetic mutation identified, the most common of which were TP53 (55.1% of mutations detected), followed by KRAS (34.2%), EGFR (21.9%), CDKN2A (15.7%) and STK11 (12.2%).

In total, 4.5% received targeted treatment based on sequencing results, 9.8% received routine EGFR- or ALK-targeted treatment, and 85.1% received no targeted treatment.

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Patients receiving broad-based genomic sequencing appeared more likely to receive immunotherapy (4% vs. 1.7%) or clinical trial regimens (0.6% vs. 0.4%; P < .001 for both) than routine-tested patients.

Results showed a 1-year unadjusted mortality rate of 49.2% among patients who underwent broad-based genomic sequencing compared with 35.9% among patients who underwent routine testing.

Results of the instrumental variable analysis did not show a significant association between broad-based genomic sequencing and 1-year mortality; the predicted probability of mortality at 1 year was 41.1% among the broad-based genomic sequencing group compared with 44.4% among the routine testing group (difference = 3.6%; 95% CI, 18.4 to 11.1).

The results were surprising, according to Presley.

“There has been a great deal of interest in precision medicine, and many are calling for all patients with cancer to have broad-based genomic sequencing with hundreds of genes,” Presley said. “So, we were surprised that it wasn’t demonstrating improved survival.”

The propensity score-matched survival analysis showed similar findings (42.0% vs. 45.1%), for an HR of 0.92 (95% CI, 0.73-1.11). The unmatched cohort demonstrated an HR of 0.69 (95% CI, 0.62-0.77).

Improved access to clinical trials and targeted treatments should occur alongside of increased use of broad-based genomic sequencing in the community setting, according to the researchers.

“This is the only way we will start to see a survival difference alongside our advances in sequencing techniques,” Presley said. “Right now, we are seeing broad-based genetic testing being done and patients aren’t getting the drugs they need for a variety of reasons. There is now the ‘right to try,’ but what about the ‘right to afford’ your medications?” she said, adding that cost has remains an issue for oral targeted treatments for cancer.

“These drugs just are not affordable and impair our ability to treat our patients,” she said.

The study by Presley and colleagues provides critical insights into how broad-based genomic sequencing can be used in the community oncology setting, were most patients in the U.S. are treated, Paul A. Bunn Jr., MD, distinguished professor in the division of medical oncology, and Dara L. Aisner, MD, PhD, director of the Colorado Molecular Correlates Laboratory, both from University of Colorado Anschutz Medical Campus, wrote in a related editorial.

However, various limitations of the study — the 2011 to 2016 study timeframe, the high incremental value of a 30-gene cutoff, the low rate of treatment among patients with identified mutations, among others — call into question the authors’ conclusion.

“The limitations of this investigation suggest that the authors’ conclusion that broad testing is not warranted should be tempered to ensure that patients receive the right therapy for the right alteration at the right time,” Bunn Jr. and Aisner wrote. – by Melinda Stevens

For more information:

Carolyn J. Presley, MD, can be reached at The Ohio State University, Medical Oncology, B424 Starling Loving Hall, 320W10th Ave., Columbus, OH 43214; email: carolyn.presley@osumc.edu.

Disclosures: Presley reports grants from the Yale Lung SPORE Career Development Award, the Robert Wood Johnson/Veterans Affairs Clinical Scholars Program and from The Ohio State University K12 Training Grant for clinical faculty Investigators. Please see the study for all other authors’ relevant financial disclosures. Bunn reports consultant fees from AstraZeneca, Bristol-Myers Squibb, Genentech, Lilly, Merck, Merck-Serono, Novartis, Pfizer and Takeda. Aisner reports consultant income from AbbVie, Bristol-Myers Squibb and Genentech.