Table 2.

Definition of therapy recommendation tiers with literature assessment criteria used for curating TOPOGRAPH with therapies listed in Australia.

Source	Criteria
Tier 1—Standard-of-care therapy using the biomarker for therapy selection and approved by TGA
Regulatory approvals	TGA-approved therapy indicated by the presence of biomarker, and reimbursed by PBS (Tier 1A)
Regulatory approvals	TGA-approved therapy indicated by the presence of biomarker, but not reimbursed by PBS (Tier 1B)
Tier 2—Standard-of-care therapy using the biomarker for therapy selection, but not approved by TGA
Regulatory approvals	Therapy indicated by this biomarker, not approved by TGA, but approved by other international jurisdiction(s), e.g., FDA or EMA, in the indication, with strong supporting literature.
Clinical guidelines	Therapy indicated by this biomarker, as endorsed by established clinical guidelines e.g., eviQ (Australia) or NCCN (Category 1 or Category 2 A with strong supporting literature).
Phase 3 trials	Therapy with positive efficacy results in ≥1 studies with prospective biomarker selection.
Phase 2 trials	Therapy with exceptional efficacy results in ≥1 studies with prospective biomarker selection.
Phase 2 basket trials	Therapy with exceptional efficacy results in ≥1 studies with prospective histotype subgroups.
Tier 3—Therapy with strong clinical evidence of antitumour activity in the presence of the biomarker.
Phase 3 trials	Therapy with positive antitumour activity demonstrated in a pre-specified exploratory biomarker subgroup analysis in a phase 3 study; inconclusive or conflicting subgroup efficacy data in phase 3 trials.
Phase 2 trials	Therapy with positive antitumour activity demonstrated in ≥1 prospectively and biomarker-selected phase 2 trials, defined as meeting its primary endpoint and included in preplanned biomarker subgroups
Phase 2 basket trials	Therapy with positive antitumour activity demonstrated in ≥1 prospectively and positive prospective phase 2 trials, including preplanned histotype-specific subgroups
Phase 1 trials	Therapy with positive antitumour activity demonstrated in ≥1 well-sized, prospectively biomarker-selected phase 1 studies that demonstrates exceptional activity
Tier 4—Therapy with strong preclinical or early clinical evidence of antitumour activity in the presence of the biomarker
Phase 2 trials (including basket trials)	Therapy showing probable antitumour activity in an exploratory biomarker subgroup in phase 2 or phase 3 clinical trial(s).
Phase 1 trials	Therapy showing probable antitumour activity in dose expansion phase of a phase 1 clinical trial with prospectively defined biomarker subgroups
Retrospective studies, real-world data registry, or reviews	Therapy showing probable antitumour activity identified from a well-sized patient registry, retrospective cohort study, or literature reviews.
Case report/case series	Therapy showing probable antitumour activity as identified by efficacy or objective response in ≥1 case reports or series, regardless of prospective or retrospective selection by biomarker.
Clinical trial registries	Therapy studied in a clinical trial where the biomarker is selected as an inclusion criteria (any phase).
Preclinical research	Therapy with strong preclinical rationale cell-line or animal studies suggestive of antitumour activities.
Tier R1—Standard-of-care therapy not recommended in the presence of the biomarker, as listed in regulatory approval documents or clinical guideline
Regulatory approval	Therapy where the biomarker is explicitly listed as a contraindication (to a therapy that may otherwise be prescribed for the indication) in regulatory approval documents, suggesting a lack of efficacy in this biomarker subgroup.
Clinical Guidelines	Therapy where the biomarker is explicitly listed as a contraindication (to a therapy that may otherwise be prescribed for the indication) in an established clinical guideline, suggesting a lack of efficacy in this biomarker subgroup.
Tier R2—Therapy predictive of lack of antitumour activity in the presence of the biomarker based on compelling clinical or preclinical evidence
Phase 2/3 clinical trials	Therapy where the biomarker or histology subgroup (basket trial) in ≥ 1 clinical trials showed below expected response for antitumour activity
Retrospective studies, real-world data registry, or reviews	Therapy where a well-sized biomarker subgroup is identified from the sources with a below expected response of antitumour activity
Case report/case series	Therapy where published case reports or case series showing below-than-expected response of antitumour activity
Clinical trial registries	Therapy examined in a clinical trial (any phase) where the biomarker is listed as an exclusion criteria suggestive of resistance, lack of antitumour activities or efficacy.
Preclinical research	Therapy examined in well-structured drug sensitivity studies, or exploratory analysis of tumour progression, suggest a plausible mechanism where the biomarker is associated with lack of response to therapy, including both intrinsic and acquired mechanisms.

Note: Special sub-tiers 3B/4B (not listed in this table) is designated to indicate a therapy that has evidence of tier (1–3) and tier 4, respectively, in another cancer type. The 3B-tier definition is line with the specification OncoKB definition of level of evidence.

Ph1 phase 1, Ph2 phase 2, Ph3 phase 3, PBS Pharmaceutical Benefit Schedule, TGA Therapeutic Goods Administration of Australia.