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ATLANTA -- Pembrolizumab (Keytruda) led to long-term responses in advanced small cell lung cancer (SCLC), a second-generation TRK-targeted agent showed promise in patients relapsing on first-generation TRK-directed agents, and umbralisib could fill an unmet need in marginal zone lymphoma (MZL).

These three studies were selected among the thousands of new studies presented here at the American Association for Cancer Research annual meeting.

Pembrolizumab in Third- and Later-Line SCLC

In a pooled analysis of 83 evaluable SCLC patients from two early KEYNOTE trials, 16 patients achieved an objective response (19.3%) with pembrolizumab, which included two complete responders, reported Hyun Cheol Chung, MD, PhD, of Yonsei University College of Medicine in Seoul.

At the time of the analysis, the median duration of response had not yet been reached, but nine patients had responses lasting 18 months and beyond. Most responses (14 of the 16 patients) were observed in patients with PD-L1-positive disease.

Patients in the phase Ib KEYNOTE-028 and phase II KEYNOTE-158 trials had received at least two prior lines of therapy. Median progression-free survival (PFS) among all evaluable SCLC patients was 2 months and overall survival was 7.7 months. Rates of overall survival at 1 and 2 years were 34% and 21%, respectively, which compared favorably to in the third- and later-line setting, said Chung.

Among 131 patients evaluable for safety in the two trials, grade 3 or higher treatment-related adverse events (AEs) occurred in 10% of patients, which included three deaths -- intestinal ischemia, pneumonia, and encephalopathy. Immune-related AEs occurred in 21% of patients.

TRK-Directed Agents Take Next Step

In another study, 10 of 29 evaluable patients with various types of TRK-related solid cancers whose disease progressed on a previous TRK-directed agent achieved a complete or partial response with LOXO-195, a second-generation TRK inhibitor, according to a presentation from David Hyman, MD, of Memorial Sloan Kettering Cancer Center in New York City.

Last year, the FDA approved larotrectinib (Vitrakvi) for pediatric and adult patients with metastatic or unresectable solid tumors that harbor a neurotrophic receptor tyrosine kinase (NTRK) gene fusion. However, most of these tumors eventually become resistant to larotrectinib through mutations in NTRK, said Hyman. Nine of 20 patients who had NTRK-related resistance to larotrectinib responded to the second-generation agent.

For their analysis, the researchers included 31 LOXO-195-treated patients from a phase I trial (n=20) or the FDA's expanded access program (n=11).

The side effect profile was consistent with other TRK inhibitors, with common treatment-emergent AEs including dizziness or ataxia (65%), nausea and vomiting (50%), anemia (30%), myalgia (20%), abdominal pain (20%), fatigue (20%), and lymphopenia (20%).

Umbralisib in MZL

In relapsed/refractory MZL, 55% of patients in the phase II UNITY-NHL trial achieved responses with umbralisib, an investigational drug that targets PI3K-delta, including four complete responders, reported Nathan Fowler, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Responses were seen in patients with extranodal, nodal, and splenic disease. The clinical benefit rate was 84% among the 38 patients evaluable for response, said Fowler, and the rate of PFS at 1 year was 71%. Median duration of response was not yet reached. Patients had 2 median prior lines of treatment, with 18% having received rituximab alone and 68% exposed to chemoimmunotherapy.

Importantly, the agent appeared to have a tolerable safety profile, a distinction from the earlier PI3K-targeting agent idelalisib (Zydelig). Common AEs included diarrhea (45%), nausea (29%), fatigue (26%), headache (26%), cough (24%), and decreased appetite (21%). Common grade 3/4 events were neutropenia in 8% of patients, and febrile neutropenia and diarrhea in 5% of patients each. There were no reports of colitis or pneumonitis.