PUL01.02 AcceleRET Lung: A Phase 3 Study of First-Line Pralsetinib in Patients with RET-Fusion+ Advanced/Metastatic NSCLC

Abstract

prospective, multi-center, observational, case-control studies with longitudinal follow-up. Plasma cfDNA was subjected to a targeted methylation sequencing assay using high-efficiency methylation chemistry to enrich for methylation targets, and a machine-learning classifier determined cancer status and predicted TOO. Observed methylation fragments characteristic of cancer and TOO (cancer "signals") were combined across targeted regions and assigned a relative probability of cancer and of a specific TOO. Test performance was also assessed in a subgroup of participants with clinical suspicion of cancer but without pathologic diagnosis or treatment at the time of enrollment. Results: Performance is reported at 99.3% specificity (95% confidence interval [CI], 98.3-99.8%) (ie, a combined false positive rate across all cancers of <1%-a level required for population-level screening). Across all cancers, stage I-III sensitivity was 43.9% (95% CI, 39.4-48.5%). Combined cancer detection sensitivity (95% CI) was 18% (13-25%) in stage I (n¼185), 43% (35-51%) in stage II (n¼166), 81% (73-87%) in stage III (n¼134), and 93% (87-96%) in stage IV (n¼148). TOO was predicted for 96% of all cancers detected; of these, TOO was correct in 93% of cases. Among participants enrolled with suspicion of cancer and subsequently confirmed to have cancer (n¼75), cancer detection across all stages was 46.7% (35/75; 95% CI, 35.1-58.6%) and TOO prediction accuracy was 97.1% (34/ 35; 95% CI, 85.1-99.9%). None of the non-cancer participants in the subgroup (n¼15) had a cancer signal (ie, specificity was 100%). Conclusion: Detection of multiple cancers across stages using methylation signatures in plasma cfDNA was achieved with a single, fixed, low, false positive rate, and simultaneously provided accurate TOO prediction. This targeted methylation assay is undergoing validation in preparation for prospective clinical investigation as a cancer detection diagnostic.

Pralsetinib (Gavreto)

“…Patients will be enrolled in approximately 97 sites in across the Americas (including Canada), Asia, Europe, and Oceania. [32][33][34] • Aged 18 years and older • Pathologically confirmed, definitively diagnosed, locally advanced (not able to be treated with surgery or radiotherapy) or metastatic NSCLC that has not been treated with systemic anticancer therapy for metastatic disease RET gene fusion in tumour and/or blood from laboratory…”

“…AcceleRET-Lung, 32 Besse et al� (2021), 33 The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date� For clinical studies with more than a primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures� b The date on which the last participant in a clinical study was examined or received an intervention or treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit)� Source: AcceleRET-Lung, 32 Besse et al� (2021), 33 and Popat et al� (2022)� 34 This study is currently recruiting participants, with a planned enrolment of approximately 226 patients.…”

“…AcceleRET-Lung, 32 Besse et al� (2021), 33 The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date� For clinical studies with more than a primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures� b The date on which the last participant in a clinical study was examined or received an intervention or treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit)� Source: AcceleRET-Lung, 32 Besse et al� (2021), 33 and Popat et al� (2022)� 34 This study is currently recruiting participants, with a planned enrolment of approximately 226 patients. The estimated primary completion date (on which the last participant in a clinical study will be examined or receive an intervention to collect final data for the primary outcome measure) and study completion date (on which the last participant in a clinical study will be examined or receive an intervention or treatment to collect final data for the primary outcome measures, secondary outcome measures, and AEs) are September 30, 2023, and December 31, 2024, respectively.…”

“…For nonsquamous histology, the treatment regimen will be carboplatin or cisplatin plus pemetrexed (with vitamin supplementation) with or without pembrolizumab followed by optional pemetrexed (with vitamin supplementation) maintenance with or without pembrolizumab; for squamous histology, the treatment regimen will be either carboplatin or cisplatin plus gemcitabine, or carboplatin with paclitaxel plus nab-paclitaxel and pembrolizumab followed by maintenance pembrolizumab. [32][33][34] Stratification factors include intended use of pembrolizumab, history of brain metastases, and ECOG PS. Key eligibility criteria include no prior systemic treatment for advanced and/ or metastatic NSCLC; RET fusion-positive tumour by local or central assessment; no additional actionable oncogenic drivers; no prior selective RET inhibitor; and measurable disease as defined by RECIST 1.1.…”

“…Crossing over to receive pralsetinib upon disease progression will be permitted for patients randomized to the SOC arm. [32][33][34] The primary end point is PFS (defined by RECIST 1.1) assessed by a BICR, whereas the secondary end points include ORR, OS, DOR, disease control rate, clinical benefit rate, time to intracranial progression, intracranial ORR, safety and tolerability, and quality of life evaluations. Identification of potential biomarkers of antineoplastic activity and resistance is an exploratory end point.…”