Stay Up
to Date
Stay Up
to Date
Breaking News,
Updates, & More
Breaking News,
Updates, & More
Click Here to
Subscribe
Click Here to
Subscribe

High Tumor Mutation Burden Predictive Biomarker for Survival in Metastatic Non–Small-Cell Lung Cancer

TON - June 2019, Vol 12, No 3 - Lung Cancer
Phoebe Starr

Atlanta, GA—Immune checkpoint inhibitors represent a tremendous advance in the treatment of several types of cancers. Although approximately 20% to 25% of patients will have durable responses with these agents, it has been challenging to find biomarkers to identify who these patients are.

PD-L1 expression is a suboptimal biomarker, and researchers are looking at other potential biomarkers. Results of a retrospective exploratory analysis of the MYSTIC study suggest that high tumor mutation burden (TMB) can identify patients with non–small-cell lung cancer (NSCLC) who will have a survival ­benefit with the checkpoint inhibitor durvalumab (Imfinzi) and the investigational CTLA-4 antibody tremelimumab.

Moreover, high TMB is independent of PD-L1 expression, said lead investigator Solange Peters, MD, PhD, Chair, Thoracic Malignancies, Oncology Department, Centre Hospitalier Universitaire Vaudois, Switzerland, who discussed the results at the 2019 American Association for Cancer Research meeting. Furthermore, the analysis showed that blood TMB is as reliable as tissue TMB, overcoming one of the main disadvantages of inadequate tissue samples from patients with lung cancer and other tumors.

“TMB was predictive of an overall survival benefit with first-line durvalu­mab and durvalumab plus tremelimu­mab in metastatic NSCLC. In tissue TMB greater than or equal to 10, overall survival was improved with durvalumab, with or without tremelimumab, versus chemotherapy, but the small data set limits interpretation,” said Dr Peters. “Low TMB identified patients who did better on chemotherapy,” she added.

MYSTIC Study Details

MYSTIC was a phase 3 clinical trial that randomized 1118 patients with stage IV NSCLC to 1 of 3 treatment arms for first-line therapy—durvalumab alone; durvalumab plus tremelimumab; and platinum-based chemotherapy. Patients were enrolled regardless of level of PD-L1 expression.

The primary end point was not met. In the overall analysis of the MYSTIC study, no significant difference was found in overall survival (OS) between the 2 treatment arms. The OS results according to tissue TMB and blood TMB were exploratory end points.

Patients with the cutoff of tissue TMB ≥10 mutations/megabase (mut/Mb) of DNA had a median OS of 18.6 months with durvalumab, 16.6 months with durvalumab plus tremelimumab, and 11.9 months with chemotherapy. The difference between the 2 durvalumab arms did not reach statistical significance. Patients with a lower TMB (ie, <10 mut/Mb) did better with chemotherapy alone.

A separate analysis showed that using a higher threshold of TMB—≥20 mut/Mb—was associated with improved survival for durvalumab plus tremelim­u­mab versus chemotherapy.

“We observed markedly improved overall survival and greater clinical benefit with durvalumab plus tremelimumab versus chemotherapy, indicating the potential contribution of tremelimumab in this setting,” Dr Peters noted.

“The results of the exploratory analysis support prospective study of blood TMB as a predictive marker for immunotherapy,” she said, but noted that raising the threshold for a cut point restricts the therapy to fewer patients. “This should be studied in as many clinical trials as possible.”

TMB a Predictive Biomarker for Immunotherapy Benefit

“TMB is a predictive biomarker for a survival benefit from immunotherapy that is independent of PD-L1 expression. However, TMB had not previously been studied to show a survival benefit for immune checkpoint inhibitor versus chemotherapy,” Dr Peters told the audience.

Tissue TMB is measured by next-­generation sequencing from Foundation Medicine. “Blood TMB was evaluated for the first time in MYSTIC, using a Guardant sequencing platform that comprises a 500-gene panel. In a subset of patients with matched tissue and blood samples, blood TMB showed good correlation with tissue TMB,” Dr Peters told the audience. “Blood TMB is easier, less invasive, and faster,” she added.

The investigators used several thresholds for blood TMB, including >16 mut/Mb. “We found better survival compared to chemotherapy in all patients defined as high TMB, irrespective of threshold chosen,” Dr Peters said.

Using blood TMB ≥20 mut/Mb as a threshold, OS was superior with high TMB and a significant benefit with durvalumab plus tremelimumab versus chemotherapy was seen using this higher threshold.

In patients with high blood TMB >20 mut/Mb, the 2-year OS was 48% with the combination of durvalumab plus tremelimumab, 33.8% with durvalumab alone, and 19% for chemotherapy.

“In patients with blood TMB <20 mut/Mb, no significant survival difference was observed for immunotherapy, and chemotherapy is still a good option,” she said.

“PD-L1 and blood TMB are independent biomarkers for survival. They do not correlate. You look at different patients when you use these biomarkers,” Dr Peters said.

No difference was observed in safety outcomes when patients with high TMB were compared with the overall study population.

Related Items
Osimertinib plus Savolitinib Promising for Non–Small-Cell Lung Cancer with MET-Driven Resistance
Phoebe Starr
TON - June 2019, Vol 12, No 3 published on June 17, 2019 in Lung Cancer
Gilteritinib a New Standard of Care for Relapsed or Refractory AML with FLT3 Mutation
Phoebe Starr
TON - June 2019, Vol 12, No 3 published on June 17, 2019 in Leukemia
Infigratinib a Novel, Potent Selective TKI Targeting FGFR Fusions in Different Tumor Types
Phoebe Starr
TON - June 2019, Vol 12, No 3 published on June 17, 2019 in Emerging Therapies
Umbralisib Shows Encouraging Results in Relapsed or Refractory Marginal-Zone Lymphoma
Phoebe Starr
TON - June 2019, Vol 12, No 3 published on June 17, 2019 in Lymphoma
Lorbrena (Lorlatinib) Approved for the Treatment of Metastatic Non–Small-Cell Lung Cancer with ALK Mutation
Loretta Fala, Medical Writer
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals, Lung Cancer
Vizimpro (Dacomitinib) Approved for First-Line Treatment of Metastatic Non–Small-Cell Lung Cancer with EGFR Mutation
Loretta Fala, Medical Writer
2019 Fourth Annual Oncology Guide to New FDA Approvals published on June 5, 2019 in FDA Approvals, Lung Cancer
Explosive Development of BCMA CAR T-Cell Therapies for Multiple Myeloma
Phoebe Starr
TON - April 2019, Vol 12, No 2 published on April 22, 2019 in Immunotherapy
April 16, 2019 – FDA Approvals, News & Updates
Yvette Florio Lane
Web Exclusives published on April 16, 2019 in FDA Approvals, In the News, Lung Cancer
FDA Approves Tecentriq plus Chemotherapy for First-Line Treatment of Extensive-Stage Small-Cell Lung Cancer
Yvette Florio Lane
Web Exclusives published on March 22, 2019 in FDA Approvals, In the News, Lung Cancer
5 mg Tamoxifen as Effective as 20 mg Daily in Early Localized Breast Cancer
Phoebe Starr
TON - February 2019, Vol 12, No 1 published on March 1, 2019 in Breast Cancer
Last modified: June 18, 2019

©2019 Green Hill Healthcare Communications, LLC, an affiliate of The Lynx Group. All rights reserved.
1249 South River Road - Suite 202, Cranbury, NJ 08512