Therapeutic tiering for targeted therapies when no genomic alteration is specifically mentioned in the professional guidelines

[wesleygoar]

Submitter Name

Laura Corson

Submitter Affiliation

Oncology Consultant for Somatic ClinGen

Submitter Github Handle

No response

Additional Submitter Details

No response

Project Details

"When a genomic alteration is found in most cases of a specific diagnosis, the trial is run on the diagnosis without requiring an assay for the biomarker. The drug is then FDA-approved for the diagnosis with no mention of the biomarker despite ample evidence that the genomic alteration confers sensitivity to the specific FDA-approved targeted therapy. Technically these drug-biomarker-diagnosis combinations don't meet the criteria specified by AMP/ASCO/CAP for Tier IA. Should they be Tier IB? Can a committee be formed to officially designate them as Tier IB. As there may be evidence of that the genomic alteration confers sensitivity in another diagnosis and one may want to consider it Tier IIC for another cancer type, the Tier I designation is needed.

A handful of examples Include:
(1) The SMO inhibitors sonidegib/vismodegib for basal cell carcinoma, the majority of which are driven by mutations in PTCH1. Of note: these SMO inhibitors have also shown clinical benefit in SHH medulloblastoma and NCCN guidelines recommend vismodegib for ""SHH activated"" medulloblastoma, however the activation needs to be upstream of SMO but PTCH1 is not specifically mentioned.
(2) The EZH2 inhibitor tazemetostat for epithelioid sarcoma, the majority of which are driven by SMARCB1 loss. (Of note: other diagnoses driven by SMARCB1 loss (e.g. poorly differentiated chordoma) have also shown sensitivity although studies were not large enough to gain FDA-approval. Should we consider these IIC with clinical evidence?)
(3) The KIT/PDGFRA inhibitor avapritinib for systemic mastocytosis, the majority of which are driven by KIT p.D816V. (Of note: other diagnoses with KIT p.D816V (e.g. AML) have also shown sensitivity.)
(4) The EPAS1 (HIF2A) inhibitor belzutifan for renal cell carcinoma, with VHL LoF being the driver >90% of clear cell RCC cases. Other tumor types with VHL loss have also shown clinical benefit.
(5) The PDGFR/KIT/ABL inhibitor imatinib for dermatofibrosarcoma protuberans, the majority of which are driven by PDGFB (or in rare cases PDGFD) fusions.
(6) The CSF1R/FLT3/KIT inhibitor pexidartinib for tenosynovial giant cell tumor, the majority of which are driven by CSF fusions."

Required Knowledge

Familiarity with mechanism of action of targeted therapies

[malachig]

A preliminary survey of interest (where every participant was allowed to vote twice) resulted in 10 votes for this topic.