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In 2020, Yongchang Zhang, MD, of the Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine/Central South University in Changsha, China, and colleagues with ROS1-rearranged non-small cell lung cancer (NSCLC) who acquired ROS1 G2032K-mediated resistance to lorlatinib (Lorbrena), but responded to immunochemotherapy.

That experience led the team to conclude that "ROS1 G2032 K is a novel mutation that mediates resistance to lorlatinib," and that "with the lack of targeted therapeutic options after lorlatinib resistance, checkpoint inhibitor [ICI] plus chemotherapy may be considered as a treatment option in patients with ROS1-rearranged NSCLC."

The researchers built on that patient data with a multisite, retrospective study of 23 patients who received ICIs -- durvalumab (Imfinzi) or pembrolizumab (Keytruda) -- plus chemotherapy. Once again, these patients had ROS1-rearranged NSCLC.

The authors have now reported in that three patients who received chemoradiotherapy followed by ICI-chemotherapy scored a partial response (PR) and had a progression-free survival (PFS) of 17.9 months. And among half a dozen patients who got first-line ICI-chemotherapy, all but one achieved PR with a median PFS 24.3 months. Among 14 previously treated patients who received later-line ICI-chemotherapy, the objective response rate (ORR) was 28.6% and median PFS was 5.8 months.

Zhang's group pointed out that "previous studies have shown the efficacy of ROS1-TKIs, entrectinib [Rozlytrek] or lorlatinib, in addressing brain metastases of patients with ROS1-rearranged NSCLC; however, there are no data on the outcomes with immunotherapy in this population."

The study addressed that issue by showing that for the 10 patients who had brain metastasis before receiving ICI-chemotherapy, four had intracranial PRs and five had intracranial stable disease, for an intracranial ORR of 40% and an intracranial disease control rate of 90%.

"Our data provide real-world clinical evidence that supports the use of ICIs as an alternative treatment option in ROS1-rearranged lung cancer regardless of brain metastatic status," Zhang and co-authors concluded.

In related news, Jessica Jiyeong Lin, MD, of Massachusetts General Hospital Cancer Center in Boston, shared findings from the phase I/II in a presentation at ASCO's 2023 annual meeting.

What was the impetus for the TRIDENT-1 trial?

Lin: is a next-generation ROS1 and TRK tyrosine kinase inhibitor [TKI] currently under evaluation in the global pivotal phase I/II TRIDENT-1 trial. Here, we report the first efficacy and safety data for repotrectinib in TKI-naïve and pretreated patients with ROS1-fusion lung cancer by the status of baseline CNS [central nervous system] metastasis. In TRIDENT-1, patients with advanced ROS1-positive lung cancer were grouped into four cohorts by treatment history and received repotrectinib therapy.

Patients with treated or untreated asymptomatic CNS metastasis were eligible to enroll.

What were some of the main findings?

Lin: Each cohort included patients with CNS metastases at baseline, of which a subset had measurable CNS mets, and patients without CNS metastasis at baseline. Among TKI-naïve patients, systemic ORR was 89% in patients with CNS metastases at baseline and 75% in those without CNS metastases at baseline.

At 12 months, 93% and 84% of responders, respectively were continuing to respond. In the one prior ROS1 inhibitor and no prior chemo cohort, systemic ORR was 33% in patients with CNS metastases and 41% in those without CNS mets ... among TKI-naïve patients, seven of eight had an intracranial response for an intracranial response rate of 88%.

Among 12 patients pretreated with one TKI and no chemo, the intracranial response rate was 42%. At the time of data cutoff, there were no intracranial PFS events among patients with measurable baseline brain mets in the TKI-naïve cohort ... among 12 patients with measurable baseline brain mets, in the one prior TKI and no chemotherapy cohort, the intracranial PFS ranged from 1.6 to 12.8 months.

Of note, among those patients who did not have CNS metastases at baseline, only one of the 53 TKI-naive patients and eight of 58 patients across the three TKI-pretreated cohorts developed a new brain lesion.

What about the safety findings?

Lin: Safety was generally consistent in patients with ROS1-positive lung cancer with or without CNS metastasis. Grade 3 or higher treatment-related adverse events [AEs] occurred in 23% of patients. Few treatment-related AEs led to treatment discontinuation, and there were no treatment-related deaths. Rates of nervous system AEs, including dizziness, were similar in patients with or without CNS metastasis.

What's the take-home message?

Lin: Repotrectinib demonstrated durable clinical activity in patients with TKI-naïve or pretreated ROS1-fusion positive NSCLC with or without baseline CNS metastases. Systemic efficacy was seen in patients regardless of the status of baseline CNS mets. And across both TKI-naïve and pretreated cohorts, intracranial responses were observed.

These findings suggest that repotrectinib could represent a potential new treatment option for patients with ROS1-fusion positive advanced NSCLC, including those with CNS metastases.

Read the study here.