CHICAGO — Targeted high-dose radiation therapy led to a fivefold improvement in progression-free survival (PFS) for patients with oligoprogressive lung cancer, according to a study reported here.
Median PFS increased from 9 weeks with standard treatment to 44 weeks among patients randomized to stereotactic body radiotherapy (SBRT). In contrast, SBRT did not improve PFS in patients with advanced breast cancer and oligoprogression.
New lesions accounted for most of the progressive disease in the breast cancer cohort, whereas the lung cancer cohort had a mix of new lesions and progression of existing lesions, a disparity that requires further study, reported C. Jillian Tsai, MD, PhD, of Memorial Sloan Kettering Cancer Center in New York City, at the American Society for Radiation Oncology (ASTRO) meeting.
“In this preplanned interim analysis, we observed a significant difference of using SBRT in improving progression-free survival in a lung cohort, with a median progression-free survival of 44 months,” said Tsai. “That is longer than with many third and fourth-line systemic therapies published to date. There is no benefit of SBRT in the breast cohort … and the mechanisms of the difference are being investigated right now.”
Complexities of Oligoprogression
In contrast to oligometastatic disease, which represents a relatively stable disease state, oligoprogression refers to a “very dynamic and very volatile” disease state, said Tsai. The condition arises from a background of mixed response to systemic therapy, and results in a state of “constantly progressing” disease.
No standard of care exists for oligoprogressive disease, she continued. Clinicians may choose to switch therapies, continue with the same therapy if the progression is limited, or add a different drug or mode of treatment. Median PFS associated with second-line therapies in advanced lung cancer ranges from 1 to 10 months. Progression after second-line therapy has no standard treatment. A similar situation exists for metastatic breast cancer, and in the absence of a standard for second-line and beyond, the median PFS ranges from 2.3 to 5.6 months.
Tsai reported interim results from the ongoing Consolidative Use of Radiotherapy to Block (CURB) Oligoprogression study. The trial is one of three (including one in Canada and one in England) evaluating SBRT to treat oligoprogression. CURB is limited to patients with advanced non-small cell lung cancer (NSCLC) or metastatic breast cancer.
For the NSCLC cohort, eligible patients had tumors with no driver mutations or with targetable mutations that had progressed on first-line targeted therapy. The breast cancer cohort enrolled patients with triple-negative disease or high-risk hormone receptor-positive metastatic breast cancer that had progressed on first-line systemic therapy. Eligible patients in both cohorts can have as many as five progressive lesions, as defined by various clinical or radiographic criteria.
Patients in both cohorts are randomized to standard-of-care (SOC) systemic therapy or to SBRT plus SOC therapy. The primary endpoint is PFS.
Tsai presented data for 106 patients, 59 with NSCLC and 47 with breast cancer. The patients had a median age of 67-70, a median of two oligoprogressive lesions, a median of five total metastatic lesions, and a median of two prior systemic therapies.
Tale of Two Diseases
The primary analysis of both cohorts combined showed a median PFS of 31 weeks for the SBRT group versus 11 weeks who received only SOC therapy (P=0.002). Further analysis showed that the benefits of SBRT were driven almost entirely by the NSCLC cohort, which had a 35-week absolute improvement (P=0.001). Patients in the breast cancer cohort had a median PFS of 18 weeks with SBRT and 19 weeks without (P=0.478).
In a multivariable analysis of the NSCLC cohort, treatment with SBRT was the strongest predictor of a PFS benefit (HR 0.34, 95% CI 0.18-0.74). Patients who had a greater number of oligoprogressive lesions and those who had received more prior systemic therapies appeared to do worse with SBRT.
SBRT was associated with a higher incidence of grade ≥2 adverse events (AEs), irrespective of cause (61% vs 40%). However, SBRT-related AEs were infrequent, consisting of one case each of pneumonitis, diarrhea, and gastrointestinal reflux.
Post-treatment progression occurred in 78 patients, 40 in the NSCLC group and 38 in the breast group. Emergence of new lesions accounted for almost all of the progression events in the breast cancer cohort (n=34 of 38), whereas progression events in the NSCLC group consisted of 18 new lesions, additional progression of 18 existing lesions, and unknown source in four cases. The difference in new lesions was statistically significant (P<0.001). The disparity requires further study to look for an explanation, but the difference could account for the lack of SBRT benefit in the breast cancer group, said Tsai.
A quarter-century of research has shown that oligometastasis comprises a spectrum of disease in terms of number of metastases, organs involved, and rate of progression, said ASTRO invited discussant Steven Chmura, MD, PhD, of the University of Chicago. Subsets of patients are potentially curable with metastasis-directed therapy in addition to systemic therapy.
The results clearly suggest a PFS benefit for NSCLC, as well as a lack of signal for breast cancer, he continued. A phase III trial in NSCLC appears warranted. However, a reasonable argument could be made that the SOC arm was set up to fail by allowing so many prior lines of therapy and by not mandating a switch in therapy. Chmura concluded by encouraging colleagues to enroll patients in ongoing and future trials to help resolve the questions surrounding management of oligoprogressive disease.
The CURB trial is sponsored by Memorial Sloan Kettering Cancer Center.
Tsai disclosed relationships with Varian Medical and Galera therapeutics.
Chmura disclosed relationships with Astellas Pharma, RefleXion Medical Systems, Bristol Myers Squibb, Merck, AstraZeneca, and Varian Medical.