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Patients with advanced, mutated lung cancer had "clinically meaningful" continuation of treatment beyond progression following local therapy, primarily radiation therapy (RT), a small retrospective analysis showed.

The median time to progression after local therapy was 6.8 months, while the median time to next systemic therapy was 10 months in 61 patients with ALK/ROS1/RET-rearranged lung cancers. Patients also appeared to benefit from a second local therapy.

Earlier use of local therapy was associated with greater benefit, reported Andreas Rimner, MD, of Memorial Sloan Kettering Cancer Center in New York City, and coauthors, in . Time to progression and next therapy decreased with third local therapy versus the first and second local treatments.

"The persistent pattern of solitary or oligo-PD [progressive disease] following local therapy suggests that this approach can be repeated," the researchers wrote. "While subsequent courses of local therapy appear to be associated with lesser overall benefit in prolonging TTP [time to progression] and next therapy there appear to be unique clinical situations where this approach continues to provide clinically meaningful benefit, particularly in light of the favorable toxicity profile for local therapy observed here."

"We recommend strong consideration of local therapy for oligoprogression on ALK, ROS1, or RET TKI [tyrosine kinase inhibition] when feasible to address all progression, particularly in the setting of a first or second use of local therapy for a given patient," they concluded.

The findings build on that local therapy prolongs survival and time to next therapy among patients with EGFR-mutant lung cancer treated with TKIs. The data also compare favorably with showing that continuing crizotinib (Xalkori) in ALK-fusion lung cancer beyond progression without local treatment resulted in a median treatment duration of 4.5 months, the authors noted.

Background

The development of selective TKIs has transformed treatment of ALK/ROS1/RET-rearranged lung cancer, but universal emergence of acquired resistance in advanced disease limits treatment durability. Widespread progression may lead to use of a different systemic therapy, whereas more limited progression might be amenable to local therapy and continuation of the TKI, Rimner and coauthors noted.

Oligoprogression, typically defined as up to five sites of progression with any additional disease sites remaining in control, occurs in up to half of oncogene-driven adenocarcinomas treated with TKIs. Solitary sites of progression account for about 20% of TKI progression. The pattern of localized resistance or pharmacokinetic failure raises the possibility that local therapy might prolong the clinical benefit of ongoing TKI treatment, the authors continued.

Two phase II trials showed about a threefold improvement in progression-free survival (PFS, and ) with ablative therapies and surgery as compared with maintenance chemotherapy or targeted therapy alone. A comparing standard-of-care systemic therapy with or without RT for oligoprogressive lung and other types of cancer showed a doubling of PFS and a 13-month improvement in overall survival.

Although the additive effects of local therapy have been demonstrated in EGFR-mutant lung cancer, local therapy had not been investigated in ALK/ROS1/RET-rearranged lung cancer. Rimner and colleagues evaluated the efficacy of local therapy on oligoprogressive lung cancer treated from 2012 to 2020 with ALK/ROS1/RET inhibitors. The primary outcomes were time from local therapy to progression, next therapy, and death.

Key Findings

The analysis included 61 patients with ALK (n=37), ROS1 (n=12), or RET (n=12) fusions. Local therapy comprised RT in 92% of cases, surgery in 13%, and percutaneous thermal ablation in 8%. Local therapy addressed all progressing sites in 85% of cases. Patients continued existing TKI therapy in addition to the local therapy.

The 6.8 months of median PFS after local therapy compared favorably with PFS of 4.3 to 7.1 months in small published cohorts of ALK-fusion positive patients who received RT for central nervous system (CNS) and extra-CNS oligoprogression, the authors noted. The results also were similar to those reported in EGFR-mutant lung cancer treated with local therapy, "suggesting that the paradigm of local therapy for oligoprogression may achieve comparable results across drivers."

The 34-month median overall survival from local therapy also compared favorably with previously reported small series, they added.

Patients who received three or more local therapies had a shorter PFS and time to next therapy than those who received a first or second local therapy. Patients with more progressing sites at the time of local therapy also had a shorter time to subsequent systemic therapy.

The study demonstrated that local therapy can allow patients with ALK/ROS1/RET-driven non-small cell lung cancers to be maintained on their current systemic therapy with TKIs and delay initiating a new systemic therapy, said Salma Jabbour, MD, of the Rutgers Cancer Institute of New Jersey in New Brunswick and a clinical expert for the American Society for Radiation Oncology.

"This extension of the duration of the current TKI systemic therapy can preserve additional lines of systemic therapy and possibly prolong survival rates," Jabbour, who was not involved in the study, told 乌鸦传媒 via email. "These important findings suggest that most patients had a benefit to TKI therapy after progression with a median of about 7 months until another progression. This approach using local therapy for progression can help to target resistant clones with a different mechanistic approach than the TKI therapy."

"One unique aspect is that this cohort of patients with mutationally driven cancers specifically with ALK/ROS/RET mutations and oligoprogression has not been studied as much as patients with EGFR mutations, a more common driver mutation in NSCLC."

Due to the retrospective nature of the study, selection bias was one possible limitation of the study.

"We do not know which patients were not offered local therapy due to more widespread disease or if this approach using local therapy could help patients with a larger number of metastases," Jabbour added.

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