New Gains in Frontline Non-Small Cell Lung Cancer

AACR sceneEach spring, those of us who watch the oncology space turn our attention to two big U.S. meetings for the latest research news: the American Association of Cancer Research (AACR) annual scientific meeting, held in April, and the American Society of Clinical Oncology (ASCO), which will take place in June. AACR previously focused primarily on preclinical research. However, this year the big news from the meeting highlighted some significant clinical data in the area of frontline non-small cell lung cancer (NSCLC) treatment.

 

Merck gained the majority of the spotlight with the presentation of data from its KEYNOTE-189 clinical trial of Keytruda (pembrolizumab) plus chemotherapy (Alimta and platinum therapy), which some thought leaders hailed as “clinical practice-changing” for patients with NSCLC.  Results of the trial showed the combination therapy to reduce the rate of death by half compared to chemotherapy alone. While the greatest benefit was seen amongst patients who exhibited high PD-L1 expression, a significant survival benefit was seen for all patients, regardless of their PD-L1 expression level.  The final overall survival rate has not yet been reached in this trial; median progression-free survival was 8.8 months for the patients receiving Keytruda plus chemotherapy versus 4.9 months for those receiving chemotherapy alone. As the Keytruda-chemotherapy combination is already approved by the U.S. Food and Drug Administration, this data is expected to encourage oncologists to more widely adopt the combination therapy as a new standard of care in NSCLC.

 

Bristol-Myers Squibb also presented good results from its Checkmate-227 trial, which combines two of the company’s immuno-oncology products: PD-1 inhibitor Opdivo (nivolumab) and CTLA-4 inhibitor Yervoy (ipilimumab).  When it began, the trial looked only at PD-L1 expression, but prior to initial analysis, BMS amended the trial to include an analysis of tumor mutational burden (TMB). TMB is a promising biomarker for PD-1 / PD-L1 therapies, and the data from Checkmate-227 has been highly anticipated.  BMS measured TMB using the FoundationOne CDx assay, and found that in TMB-high (defined as 10 mutation/mega base) patients, the Opdivo/Yervoy combination had a 45.3% response rate versus 26.9% in the chemotherapy arm. Moreover, the responses to the combination were quite durable; with 43% alive and progression free at one year, versus 13% for the chemotherapy group. Moreover, the benefit was seen regardless of patients’ PD-L1 expression levels or tumor histology (squamous versus nonsquamous).  

 

Frontline NSCLC was also the focus of Roche’s presentation of new data from the IMpower150 trial of Tecentriq (atezolizumab), Avastin and chemotherapy in patients with nonsquamous disease. Roche had previously announced a median PFS of 8.3 months versus 6.8 months for the control group, but new results from the trial highlighted especially good outcomes for two subgroups of patients treated with the three-drug combination. Patients who were positive for EGFR/ALK+ had a median PFS of 9.7 months versus 6.1 for control patients, while in patients with liver metastases, the median PFS was 8.2 months versus 5.4 for controls, with a hazard ratio of 0.4.  Patients without liver metastases experienced the higher hazard ratio of 0.64. The positive results were seen in both low and high PD-L1 expressors, with high PD-L1 expressors enjoying an enhanced benefit.

 

How will these different therapeutic approaches actually compete in the marketplace under “real-world” conditions?  How will TMB fit with PD-L1 testing for frontline treatment decisions? Will a three-drug combination be too logistically complex and costly, or will it find a useful place in the therapeutic arsenal against NSCLC? And what will be the next cancer indication to report outstanding results from combination therapies, whether they are IO combinations or combinations of IO drugs and other anticancer approaches? We’ll be keeping an eye out at ASCO and elsewhere to find out.