Large NGS Trial Identifies Actionable Alterations in Most Patients With Advanced Cancers

Targeted Therapies in OncologyMay 2021
Volume 10
Issue 7
Pages: 101

Potentially clinically actionable genomic alterations were identified in a majority of patients with advanced cancers with next-generation sequencing evaluated in a prospective study.

Potentially clinically actionable genomic alterations were identified in a majority of patients with advanced cancers with next-generation sequencing (NGS), a subcohort of whom showed clinical benefits with targeted treatment directed by the NGS. The results of the prospective study were published in JAMA Oncology.1

In their assessment of the Michigan Oncology Sequencing Program (Mi-ONCOSEQ) cohort study, investigators looked at the use of NGS in 1138 patients with advanced solid tumors, which was successful in 89.2% (n=1015). Of the NGS-successful patients, 817 (80.5%) were discovered to have actionable genomic alterations for treatment, with 132 (16.2%) receiving targeted therapy based on these results. Forty-nine patients had a clinical benefit from the targeted treatment, and responses lasted 12 months or longer in 19.7% of the treated population. These results support the use of directed germline testing in all patients with advanced cancer.

“One goal for Mi-ONCOSEQ is to inform standards of practice as clinical sequencing increasingly becomes adopted as a routine standard of care,” said Arul Chinnaiyan, MD, PhD, director of the Michigan Center for Translational Pathology and senior author of the study, in an article in the Michigan Health Lab report.2 “This study helps demonstrate that the promise of individualized, precision medicine and precision oncology is becoming a reality for patients.”

Observed molecular alterations were classified into 3 tiers, depending on the potential for treatment or potential treatment resistance based on the alteration. Tier 1 alterations included those with known clinical utility, germline variants that lead to increased cancer risk, and alterations that mark more or less benefit from an FDA-approved treatment. Tier 2 alterations included alterations that would suggest benefit from investigational or off-label targeted therapy or that would suggest resistance to an FDA-approved therapy. Tier 3 alterations were those without current therapeutic implications.

According to the investigators, 817 patients (80.5%) harbored a potentially actionable tier 1 or 2 alteration, 288 patients had tier 1 alterations, and 744 had tier 2 alterations. Among these alterations, 962 (94.8%) were identified by DNA sequencing and 645 (63.5%) by RNA sequencing. In 579 cases (57.0%), all 3 modes of integrated sequencing and analysis found informative alterations for potential treatment.

Sequencing-directed therapy (SDT) was started in 132 of the 817 patients (16.2%) with potentially clinically actionable alterations, with the median time to enrollment in the treatment being 3.8 months (range, 0.2-44.0). Seventy-four patients were enrolled and treated in a clinical trial, 43 were treated with off-label therapy, and 15 were treated with on-label therapy. Forty-nine patients (37.1%) experienced clinical benefit after being matched with treatment, with the most common cancers treated being sarcoma (12 of 138 [8.7%]) and prostate adenocarcinoma (10 of 154 [6.5%]).

Treatments for patients receiving SDT included targeted CDK4/6 inhibitors (n=21), PARP inhibitors (n =16), and FGFR inhibitors (n =11). The most common treatment received was immune checkpoint inhibitors, in 29 patients. The 26 patients who were deemed to have an exceptional response to SDT had a response duration ranging from 12.1 to 39.5 months. Ten of the patients had DNA repair defects, 5 of whom had double-strand DNA repair defects, including BRCA1, BRCA2, ATM, PALB2, and BRIP1.

“Any family members who have also inherited those same mutations may be at increased risk for cancer,” added Erin F. Cobain, MD, a coauthor in the study and a clinical lecturer and oncologist at Michigan Medicine, in a statement.2 “So a lot of this testing prompted downstream genetic testing and counseling across families. That’s how sequencing can have even more far-reaching impact than just looking for therapies to directly help a current patient.”

Several factors accounted for NGS testing not being successful in some patients, including the inability to safely test, patient’s withdrawal due to entering hospice, and inadequate tumor content from the biopsy. The average age of patients who enrolled was 57 years; 53% were men. Prior to enrollment, 855 patients had received systemic therapy and an average of 47 months had elapsed between the time of the patient’s diagnosis and their enrollment in the study.

“Based on the data presented by Cobain and others, it is evident that such precision medicine strategies are especially fruitful in cancer types without clear standard-of-care options, such as carcinoma of unknown primary and other rare tumors,” investigators wrote in an editorial accompanying the study, discussing the benefits of NGS for patients with rare cancers.3

NGS remains a challenge for oncologists for several reasons, among them that the definition of clinically actionable alterations changes as new therapies emerge and that a patient’s tumors can harbor multiple mutations. According to the investigators, more novel clinical trials need to be explored to expand treatment. However, systems also must develop large-scale precision oncology studies to continue to find ways to match patients with targeted treatments.

“Our data support a recommendation for germline testing of DNA repair genes as standard practice in patients with metastatic solid tumors and comprehensive NGS profiling at diagnosis for patients with [cancer of unknown primary],” the study authors concluded.1 “With continued discovery of genomic biomarkers predictive of clinical benefit from anticancer therapies, we anticipate even broader clinical applicability of this technology.”


1. Cobain EF, Wu YM, Vats P, et al. Assessment of clinical benefit of integrative genomic profiling in advanced solid tumors. JAMA Oncol. 2021;7(4):525-533. doi:10.1001/jamaoncol.2020.7987

2. Demsky I. How useful is next-generation sequencing for patients with advanced cancer? Michigan Health Lab. March 11, 2021. Accessed March 23, 2021.

3. Yap TA, Johnson A, Meric-Bernstam F. Precision medicine in oncology—toward the integrated targeting of somatic and germline genomic aberrations. JAMA Oncol. 2021;7(4):507-509. doi:10.1001/jamaoncol.2020.7988

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