Immunotherapy with checkpoint inhibitors offers a proportion of patients a chance at long-term disease control, resembling cure in some patients. Among the many questions about immunotherapy that remain to be resolved is whether patients who discontinue therapy and develop progressive disease can benefit from retreatment.

According to a retrospective analysis of a phase I/II study presented at the European Society for Medical Oncology (ESMO) Congress 2019, retreatment is safe, and some patients with metastatic disease can achieve an objective response as well as disease control upon retreatment.¹ In patients with metastatic solid tumors who responded to durvalumab and discontinued therapy after 1 year of treatment per protocol and developed progressive disease off treatment, rechallenge with durvalumab was associated with responses (all partial) in 11.4% of patients and stable disease in 60%.

“This is the largest retrospective analysis of patients who have been rechallenged with checkpoint inhibitor therapy. These findings support the role of durvalumab in patients who experienced disease progression after planned treatment interruption. There is a benefit in some patients, and the benefit is not specific to tumor histology. We postulate that retreatment restores antitumor efficacy. Of note, there is still no answer for the optimal duration of PD-1 or PD-L1 therapy,” said lead author Siddharth Sheth, DO, MPH, of the University of North Carolina School of Medicine, Chapel Hill.

Siddharth Sheth, DO, MPH

Dr. Sheth and co-investigators set out to study the safety and efficacy of durvalumab retreatment in patients previously treated with durvalumab. Some questions they hoped to answer included the optimal duration and timing of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors as well as the optimal duration of rechallenge.

“We wanted to determine how long to treat our patients. Some patients maintain long-term response to checkpoint inhibitor therapy, even after discontinuation of treatment. We also wanted to see whether rechallenge after discontinuation and development of progressive disease could be safely done,” Dr. Sheth told listeners.

Study Details

Dr. Sheth's presentation was based on a retrospective analysis of a phase I/II study that included 1,022 adult patients with 14 different types of advanced solid tumors treated with durvalumab at 10 mg/kg every 2 weeks. For all patients who completed 1 year of therapy, treatment was discontinued; 854 patients discontinued treatment before 1 year; 168 discontinued treatment after 1 year, developed progressive disease, and were eligible to be re-treated. Of these patients, 97 were not re-treated. Dr. Sheth’s discussion focused on the 70 patients who were re-treated with durvalumab.

In the initial treatment period of 1 year, the objective response rate was 55% (5.7% complete response, and 50% partial response); 25% of patients had stable disease; six patients had progressive disease (4 were cases of pseudoprogression). While patients were off treatment, the median time without disease progression was 266 days. After rechallenge with durvalumab, 60 of 71 patients were evaluable. With retreatment, the best overall objective response was 11.4% (all partial responses); 60% had stable disease; 22.9% had progressive disease. The median time to response was 2.7 months, and the median duration of response was 16.5 months. “Responses were observed across tumor types,” Dr. Sheth said.

With initial durvalumab treatment, the disease control rate at ≥⊇24 weeks was 81.7%. With retreatment, the disease control rate at ≥ 24 weeks dropped to 47%. Progression-free survival at 12 months after retreatment was 34.2%, regardless of the tumor type. At 24 weeks after retreatment, the disease control rate among various tumor types ranged from 33% to 58.3%. The number of patients was too small to draw conclusions, but the highest rate of disease control was 58.3% in 12 patients with microsatellite-high tumors, and the lowest rate was 33.3% in patients with non–small cell lung cancer and head and neck squamous cell carcinoma.

Of 70 patients, 5 continued to respond at data cutoff; these 5 patients had either a complete or partial response on initial therapy with durvalumab. Two patients who had stable disease on initial treatment converted to partial response at retreatment.

The rate of adverse events was high in heavily pretreated patients. The rate of grade 3 or 4 adverse events was 34% at initial treatment and 44% at retreatment. No deaths were reported due to retreatment. Approximately 25% of patients had high expression of PD-L1, and these patients had higher rates of disease control. “The level of PD-L1 expression remains a predictive biomarker of response to durvalumab, even on retreatment,” Dr. Sheth said. ■

DISCLOSURE: Dr. Sheth was supported by the 2018 AACR-AstraZeneca-MedImmune Clinical Immuno-oncology Research Training Fellowship.

REFERENCE

1. Sheth S, Gao C, Mueller N, et al: Durvalumab activity in previously treated patients who stopped durvalumab without disease progression. ESMO Congress 2019. Abstract 1175O. Presented September 30, 2019.