TMB as New Biomarker in NSCLC -- Ready for Clinic?

Alexander M. Castellino, PhD

April 17, 2018

CHICAGO — A new biomarker has emerged in lung cancer. Patients with newly diagnosed advanced non–small cell lung cancer (NSCLC) who were found to have a high tumor mutational burden (TMB), defined as having more than 10 mutations per megabase, fared better with immunotherapy than with standard-of-care chemotherapy (CT).

Dr Matthew Hellmann

These patients were at a significantly 42% reduced risk for disease progression if they received the immunotherapy combination of nivolumab (Opdivo, Bristol-Myers Squibb) and ipilimumab (Yervoy, Bristol-Myers Squibb) compared with patients who received standard-of-care CT, according to data from the phase 3 CheckMate-0227 study.

The new results were presented here at the American Association for Cancer Research (AACR) 2018 Annual Meeting, and the study was simultaneously published online in the New England Journal of Medicine.

"These practice-changing data establish the combination of nivolumab and ipilimumab as a first-line treatment option for patients with high-TMB NSCLC," said principal investigator Matthew Hellmann, MD, assistant attending at Memorial Sloan Kettering Cancer Center in New York City.

This study also establishes TMB as an important and reliable biomarker in lung cancer, he said, and he suggested that TMB should now be measured in this patient population.

However, a pathologist who discussed the study at the meeting disagreed and said that TMB as a biomarker is not yet ready for routine clinical use.

Study Details

CheckMate-227 was conducted in 1739 patients with stage IV or recurrent NSCLC who had not received prior chemotherapy and whose tumors did not harbor ALK or EGFR mutations.

In the initial study design, patients were assigned in a 2:1 ratio on the basis of their having high-PD-L1 expression or low PD-L1 expression. Across each of these arms, patients received either a combination of nivolumab and reduced-dose ipilimumab, or nivolumab monotherapy, or histology-based chemotherapy (control arm).

However, after tumor mutational burden emerged as a biomarker in CheckMate 12 and CheckMate 032, the study protocol was amended to evaluate progression-free survival (PFS) regardless of PD-L1 status as a coprimary endpoint.

The coprimary endpoints after the amendment were overall survival (OS) for patients who received the combination of nivolumab and ipilimumab compared with CT in PD-L1 selected tumors and PFS for the combination compared with CT in patients with a high TMB.

TMB was determined using the validated FoundationOne CD assay (Foundation Medicine, Inc).

Results in Patients With High TMB

"The first endpoint presented here examined PFS among patients with high TMB, which is an emerging biomarker that is independent of PD-L1 expression and characterizes about 45% of patients with NSCLC," Hellmann said.

Of 299 patients with high TMB, 139 received the immunotherapy combination, and 160 received CT.

After a median follow-up of 11.5 months, PFS in this patient population was significantly longer for those who received the combination of nivolumab and ipilimumab compared with patients who received CT (hazard ratio, 0.58; P = .0002).

One-year PFS more than tripled for patients who received the combination: 43%, vs 13% for CT. Median PFS was 7.2 for the patients who received the nivolumab and ipilimumab combination, vs 5.4 months for the patients who received CT.

Preliminary data for OS trended in favor of nivolumab and ipilimumab; median OS was 23 months, vs 16.7 months for the CT arm. One-year OS also favored the nivolumab and ipilimumab combination: 67% vs 58%.

The objective response rate (ORR) was 45.3% for patients with NSCLC with a high TMB who received the combination of nivolumab and ipilimumab compared with 26.9% for patients who received CT.

Median duration of response was not reached for patients who received the combination; it was 5.4 months for patients who received CT. The 1-year duration of response rate was almost triple for patients who received the combination: 68%, vs 25% for patients who received CT.

Hellmann also shared PFS and ORR data for patients based on PD-L1 expression; these clinical benefits were similar for patients with either a high or low level of PD-L1 expression, indicating that PD-L1 and TMB are independent markers, Hellmann noted.

Hellmann also showed data that provided evidence for incremental benefit for each immunotherapy agent added. One-year PFS for patients who received only CT was 16%; for patients who received nivolumab alone, 1-year PFS was 29%; it was 42% for patients who received nivolumab and ipilimumab — a stepwise increment of 13%.

The safety profile for the combination of nivolumab and ipilimumab was similar to that seen in other studies, Hellmann noted. Treatment-related grade 3 or 4 toxicities were reported in 31% of patients who received the combination, vs 36% of patients who received CT.

"The results show that in TMB-high NSCLC patients, nivolumab plus ipilimumab provides improved benefit compared to chemotherapy, increases benefit compared to anti-PD-1 monotherapy, yields durable responses, spares the use of chemotherapy in the first-line setting, and could preserve an effective option in the second line of therapy, if needed," Hellmann said in an AACR news release.

He indicated that OS data were still maturing and will add further insight into the clinical benefit of nivolumab plus ipilimumab as a first-line option for NSCLC patients with high TMB.

Hellmann concluded that CheckMate 227 introduced two new standards of care — it establishes nivolumab and ipilimumab in the first-line setting of metastatic NSCLC with high TMB, and it "validates TMB as an important and independent biomarker to be routinely tested in treatment-naive, advanced NSCLC."

Questions for Clinical Practice

Alice T. Shaw, MD, PhD, cochair of the AACR Annual Meeting Clinical Trials Committee and director of the Center for Thoracic Cancers at Massachusetts General Hospital Cancer Center, Boston, who moderated a press conference, asked Hellmann about TMB testing: if it is widely available, if all TMB tests are the same, and if there are other ways of achieving this end through so-called liquid biopsies.

Hellmann responded that TMB is not a new test and that the readout data are available with next-generation sequencing through tests such as FoundationOne and the MSKImpact (Memorial Sloan Kettering Cancer Center).

"The trial represents a new piece of the pie and allows us to match patients to appropriate therapy," he said. "TMB is another marker that brings a new benefit to patients," he added.

When asked whether these data will drive testing for TMB, he said yes.

Naiyer A. Rizvi, MD, director of thoracic oncology and director of immunotherapeutics for the Division of Hematology and Oncology at Columbia University Medical Center, New York City, provided additional insights into TMB testing during a discussion of CheckMate 227.

He noted that TMB can be assessed using whole-exome sequencing or FoundationOne. Whole-exome sequencing examines coding regions of 21,522 genes and defines TMB on the basis of 200 missense mutations in the tumor exome. FoundationOne has a targeted gene panel of 324 cancer-related genes and defines TMB as the number of somatic mutations per megabase of genome examined.

Rizvi said that TMB testing was feasible, and added that FoundationOne results may be available within 2 to 3 days.

Rizvi suggested this approach should be applied across all tumors. However, he noted that although TMB was prospectively defined in CheckMate 227, selection was not prospective. "A prospective confirmatory study is recommended," he added.

However, pathologist David L. Rimm, MD, PhD, from Yale University School of Medicine in New Haven, Connecticut, was emphatic that TMB was not yet ready for use in patient care.

In discussing CheckMate 568, which provided the basis for the use of TMB as a predictive biomarker, Rimm noted that TMB is a complementary biomarker to PD-L1. However, TMB testing is not standardized. It is associated with PFS, but not OS; and the actual costs are five to 10 times as much as those for immunohistochemistry and requires 10 times more tissue.

"TMB is provocative and warrants further study, standardization, and prospective testing," Rimm said.

"TMB is NOT ready for use in patient care," he concluded.

CheckMate-227 was supported by Bristol-Myers Squibb (BMS) and Ono Pharmaceutical. Dr Hellmann is a paid consultant for BMS, Genentech/Roche, AstraZeneca, Merck, Janssen, Novartis, Mirati Therapeutics, and Shattuck labs. Dr Rizvi is a paid consultant for Bristol-Myers Squibb, Merck, Astra-Zeneca, Pfizer, Novartis, Roche, Gritstone Oncology, and ARMO Biosciences. Dr Rimm consults with Ultivue, Perkin Elmer, Cell Signalling Technologies, Merck, AstraZeneca, Aligent, BMS, Bethyl Labs, Biocept, Cepheid, Navigate/Novartis, Gilead Sciences, and OptraScan.

American Association for Cancer Research (AACR) 2018 Annual Meeting. Abstract CT077, presented April 16, 2018.

N Engl J Med. Published online April 16, 2018. Full text

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