"Hitting the Target" Should Be Focus of Next-Generation Agents in Lung Cancer
The future generation of agents in lung cancer should be evaluated in improved predictive biomarker-driven trials to identify patients who are most likely to benefit or have detriment for both TKIs and checkpoint inhibitors.
David R. Gandara, MD
The future generation of agents in lung cancer should be evaluated in improved predictive biomarker-driven trials to identify patients who are most likely to benefit or have detriment for both TKIs and checkpoint inhibitors, explained David R. Gandara, MD, in a presentation during the 20th Annual International Lung Cancer Congress.
“If we can design drugs that have a target, and we can effectively hit the target with that drug, then this personalized or precision medicine approach will be more effective,” said Gandara, director of the Thoracic Oncology Program, professor of medicine, and senior adviser to the director at the University of California Davis Comprehensive Cancer Center, and 2017 Giant of Cancer Care® in Lung Cancer. “Hopefully, we will target all these classes of agents and we will benefit patients more—and we will do it a cost-effective manner.”
In his presentation, Gandara spoke to three requisites to move from empiric-based therapy to this heavier personalized approach: tissue- or blood-based tumor profiling, predictive biomarkers for targeted agents, and trial designs that define the activity of a drug against its target.
One such forward-designed trial is the Lung Cancer Master Protocol (Lung-MAP), a biomarker-driven, umbrella-design study in which patients are assigned to substudies based on their genomic profile. More than 200 molecular abnormalities are analyzed before enrolling patients on substudies with targeted therapies that match their genomic analysis.
Since its inception in 2014, Lung-MAP has registered nearly 2000 patients and is offered at more than 650 medical centers and community hospitals in the United States. In January 2019, Lung-MAP expanded to include patients with all types of non—small cell lung cancers (NSCLC).
“If you have a drug or a combination of drugs in the patients who are considered immune-refractory, we have a place for you—whether it’s de novo refractory, whether it’s an acquired resistance, regardless of the primary endpoint, or of the histologic subtype,” said Gandara, adding that the various Lung-MAP substudies all have regulatory intent.
Unmet Need
As of January 2019, there are more than 2250 clinical trials requiring more than 380,000 patients—and almost none of them, he said, are biomarker-driven studies. Gandara called it “recruitment fatigue,” as the median patient recruitment rate for PD-1/PD-L1 combination trials has significantly decreased in recent years.
Therefore, the clinical trial paradigm needs to evolve for targeted and immunotherapies, and move away from all-comer phase III designs, which are failing to optimize the benefit of such agents in select populations.
“It needs to [happen] at a regulatory fashion,” said Gandara. “If the biomarker is placed into a trial at an exploratory retrospective subset fashion, it will not help with the regulatory approval of that agent.”
With the increasing number of FDA-approved anticancer agents, less than 10% of them have a therapeutic target that have been translated into a predictive biomarker, he explained, and less than 10% of approved drugs have an available companion diagnostic that complements its approval. Having more companion diagnostics, he said, would likely improve the therapeutic ratio of such agents.
“There are now 8 guideline-recommended oncogenes and it’s growing every 6 months or so from [National Comprehensive Cancer Network] guidelines, IASLC, and ESMO. If we have a target and we have a drug that is effective against that target, we can have higher response rates, generally over 50%, and there is more coming,” said Gandara, citing targets such as RET, EGFR, NTRK, ALK, and MET exon 14 skipping mutations, among others.
Biomarker-Driven Data
KRAS is another target prevalent in lung cancer, with KRASG12C found in approximately 13% of cases. Recent phase I data that were presented at the 2019 ASCO Annual Meeting demonstrated activity with the highly specific, irreversible KRASG12C inhibitor AMG 510. Results showed that the first-in-class agent achieved a 50% response rate in patients with KRASG12C-positive advanced NSCLC.2 Among the 10 evaluable patients with NSCLC, 5 patients had a partial response (PR), with 4 confirmed PRs.
“I think this is going to be a breakthrough,” Gandara said. “Obviously a lot more data are needed, but it is highly encouraging.”
Tumor heterogeneity and the uptick in exploratory immunotherapy combinations are also grounds for better biomarker-driven studies, said Gandara, who added, “Combination of biomarkers will provide largely non-redundant information and additional predictive value.”
For example, findings from the phase III OAK trial showed that patients with previously treated, advanced NSCLC had an improvement in median overall survival (OS) with atezolizumab (Tecentriq) compared with docetaxel, regardless of PD-L1 expression. In an analysis of the biomarker-evaluable population in OAK, data showed that there was limited overlap between blood tumor mutational burden (bTMB) ≥16 and high PD-L1 expression (P = .62).3
In the small sample size from OAK (n = 229), 30 tumors had bTMB ≥16 as well as PD-L1 expression on tumor cells (TC) of 3 or tumor-infiltrating immune cells (IC) of 3. Patients with both these biomarkers showed superior progression-free survival (PFS) when treated with atezolizumab (HR, 0.38; 95% CI, 0.17-0.85) compared with those who had just bTMB ≥16 (HR, 0.64; 95% CI, 0.46-0.91) or PD-L1 TC3 or IC3 alone (HR, 0.62; 95% CI, 0.41-0.93).
OS was also improved in the subgroup with both markers (HR, 0.23; 95% CI, 0.09-0.58) versus bTMB ≥16 (HR, 0.64; 95% CI, 0.44-0.93) or PD-L1 TC3 or IC3 alone (HR, 0.44; 95% CI, 0.27-0.71).
References
- LUNG-MAP Precision Medicine Trial Expands To Include More Patients. Lung Cancer Master Protocol. Published January 29, 2019. https://bit.ly/2HD4GLf. Accessed January 29, 2019.
- Fakih M, O'Neil B, Price TJ, et al. Phase 1 study evaluating the safety, tolerability, pharmacokinetics (PK), and efficacy of AMG 510, a novel small molecule KRASG12C inhibitor, in advanced solid tumors. J Clin Oncol. 2019;37 (suppl; abstr 3003).
- Gandara DR, Paul SM, Kowanetz M, et al. Blood-based tumor mutational burden as a predictor of clinical benefit in non-small-cell lung cancer patients treated with atezolizumab. Nature Med. 2018;24:1441-1448. doi: 10.1038/s41591-018-0134-3.
