Similar to complementary diagnostic tests for detecting
BRCA mutations, tests for detecting
EGFR mutations required both analytical and clinical validation. Roche’s cobas
® EGFR Mutation Test v1 was an RT-PCR test for the detection of exon 19 deletions or exon 21 L858R missense mutations in non-small cell lung cancer (NSCLC), for which erlotinib is indicated
[119]. The EURTAC study was a phase 3 trial that screened 1044 patients using a clinical trial assay with a combination of methods for comparing erlotinib vs. cisplatin chemotherapy
[120]. The FDA then approved the tissue-based cobas
® EGFR Mutation Test v1 test based on retrospective testing of 487 samples, which had 432 results that could be compared to the clinical trial assay
[119][121]. When compared, the cobas
® EGFR Mutation Test v1 had an overall percent agreement of 96.3% (416/432)
[121]. While retrospective analysis of the progression-free survival from the EURTAC study was not completed, the cobas
® EGFR Mutation Test v1 was used to enroll 217 patients for treatment with erlotinib vs. gemcitabine/cisplatin showing a significant increase in PFS using erlotinib in
EGFR mutation-positive patients
[122]. The ASPIRATION and FAST-ACT2 studies also supported the effectiveness of erlotinib in patients with
EGFR mutations detected by the cobas
® EGFR Mutation Test v1
[123][124]. In another bridging study, Roche retrospectively tested samples from the ENSURE, ASPIRATION, and FAST-ACT2 studies with the cobas
® EGFR Plasma Test v2
[125][126]. In a pooled analysis of the 897 paired samples available, an imperfect concordance with a positive predictive agreement (PPA) of 72.1% (339/470) and negative predictive agreement (NPA) of 97.9 (418/427) was recorded
[126]. However, a negative plasma test would lead to patients using a solid tissue biopsy to determine the
EGFR status, so a positive predictive value (PPV) of 97.6% was enough to approve the first liquid biopsy test for detecting exon 19 deletion and exon 21 L858R mutation in 2016 - the cobas
® EGFR Plasma Test v2.
[127]. With osimertinib, cobas
EGFR Mutation Test v1 was used in the inclusion criteria for the AURA2 phase 2 clinical trial
[128]. Then, in a bridging study, the cobas
EGFR Plasma Test v2 test detected a T790M gatekeeper mutation with a PPA of 56.8% and a NPA of 80.2%
[129]. Osimertinib was also established as a first-line treatment option for patients with exon 19 deletion and L858R mutation, where both plasma and tissue are now used
[130][131][132]. Plasma or tissue was also approved as a companion diagnostic for gefitinib, but no trials are cited in the approval
[133].
4.3.3. Other
The Guardant360 CDx has also been approved for the detection of
KRAS G12C mutations to indicate usage of sotorasib based on concordance studies comparing samples from the CodeBreaK100 study originally analyzed with the Therascreen
KRAS RGQ PCR Kit
[134][135][136]. With 189 patients compared, the PPA was 70.7% (82/116) and the NPA was 100% (73/73). Importantly, the Guardant360 CDx had no false positives and an overall response rate in the positive patient population of 38%
[134][137]. The newest approval from the FDA of the Agilent Resolution ctDx FIRST assay was also for the detection of the
KRAS G12C mutation for use with adagrasib, another
KRAS inhibitor
[138].