Multidrug Combo Testing Feasible in NSCLC

A phase II trial has demonstrated that testing multiple immunotherapy-based combinations simultaneously, with biomarker-driven treatment matching where possible, is a viable approach in patients with non–small cell lung cancer (NSCLC)—providing an example of how novel trial designs can improve the efficiency of drug testing. Preliminary findings were presented at the International Association for the Study of Lung Cancer's 2020 World Conference on Lung Cancer, held virtually January 28–31, 2021.

The ongoing HUDSON study was launched in 2017 to address an unmet need: Although anti–PD-1/PD-L1 agents have improved outcomes in NSCLC, “a significant number of patients experience primary or acquired resistance to immune checkpoint inhibitors, even combined with chemotherapy,” said Benjamin Besse, MD, PhD, of Institut Gustave Roussy in Villejuif, France, who presented the results.

HUDSON enrolled 262 patients with advanced or metastatic NSCLC lacking actionable mutations such as in EGFR, whose disease worsened after platinum chemotherapy and an anti–PD-1/PD-L1 agent. After molecular screening, the investigators pinpointed biomarkers that enabled them to match 85 patients to one of four AstraZeneca drug combinations. These contained the PD-L1 inhibitor durvalumab (Imfinzi) as backbone, paired respectively with the PARP inhibitor olaparib (Lynparza) for homologous recombination repair deficiency or STK11 mutations; the ATR inhibitor ceralasertib for ATM mutations; oleclumab, which targets CD73; or danvatirsen, targeting STAT3.

To date, another 177 patients with no treatment-matchable biomarkers have also received therapy; they were stratified by whether their disease progression at the time of enrollment was due to primary or acquired resistance to anti–PD-1/PD-L1 agents. These patients were then randomly assigned to receive one of the study's four combinations.

Of these combinations, “preliminary signals of efficacy were observed in patients that received ceralasertib and durvalumab,” Besse concluded—an effect that was “potentially more pronounced” in the cohort of 18 ATM-selected patients, with an overall response rate (ORR) of 11.1% and a median progression-free survival (PFS) of 7.4 months. The ORR and median PFS were 10.5% and 4.2 months in 20 nonmatched patients with primary resistance, and 8.3% and 5 months in 24 patients with acquired resistance. In the biomarker-matched group, patients with STK11 mutations, who received olaparib plus durvalumab, had the poorest outcomes, with an ORR of 4.8% and a median PFS of 1.4 months.

HUDSON is “regularly amended to add new arms according to the science,” Besse said. Currently, the investigators are evaluating durvalumab alongside AstraZeneca/Daiichi Sankyo's HER2-targeted antibody–drug conjugate trastuzumab deruxtecan (Enhertu), as well as paired with AstraZeneca's angiogenesis inhibitor cediranib (Recentin).

“I think that the HUDSON trial is an example of where we need to move in terms of clinical trial infrastructure and design,” said Justin Gainor, MD, of Massachusetts General Hospital in Boston, who is not involved. “Identifying therapies for patients who have progressed after prior PD-1 blockade and chemotherapy is a critical unmet need in lung cancer,” he added, yet it's not feasible to run a separate trial testing every combination—necessitating novel study designs that can efficiently identify promising possibilities. As HUDSON continues, Gainor hopes to gain more insight into the efficacy and side effects of the various combinations; he is also eager for additional biomarker analyses.

Gainor also praised HUDSON for stratifying patients based on type of immunotherapy resistance. “I think this is where the field needs to move—trying to better define resistance to PD-1 pathway blockade,” he said. “The underlying mechanisms of primary versus acquired resistance may be fundamentally different, and by separating out those two patient populations we may be able to identify signals better moving forward.” –Catherine Caruso