Table 2.
FDA approved cytotoxic drugs and targeted agents for treating patients with PDAC
| Reference | Cytotoxics | Stage | FDA Approval |
|---|---|---|---|
| Burris et al.22 | Gemcitabine | Metastatic: first line | 1996 |
| Neoptolemos et al.31,32 | 5-fluoruracil/folinic acid | Adjuvant—post-surgery | NA:α 2004 |
| Moore et al.23 | Gemcitabine + *erlotinib | Metastatic: first line | 2005 |
| Conroy et al.24 | FOLFIRINOX | Metastatic: first line | 2010 |
| Von Hoff et al.25 | Gemcitabine + nab-paclitaxel | Metastatic: first line | 2013 |
| Wang-Gillam et al.26 | 5FU + nal-irinotecan | Metastatic: second line, post-gemcitabine | 2015 |
| Neoptolemos et al.27 | Gemcitabine + capecitabine | Adjuvant—post-surgery | 2016 |
| Conroy et al.28 | Modified FOLFIRINOX | Adjuvant—post-surgery | 2018 |
| Wainberg et al.29 | 5FU + nal-irinotecan + oxaliplatin | Locally advanced or metastatic: first line | 2022 |
| Reference | Targeted Agents | Pathogenic Gene Target, Prevalence | FDA Approval |
| Le et al.51 | Pembrolizumab | **Lymphocyte programmed cell death protein 1 (PD-1) receptor, tumors with microsatellite instability (MSI-Hi) or deficient mismatch repair (dMMR), 1%–3% | 2017 |
| Marabelle et al.52 | Pembrolizumab | ¶ PD-1 receptor, high tumor mutation burden (TMB ≥10 mutations/megabase), <1% | 2020 |
| Drilon et al.53 | Larotrectinib | † Inhibitor of tropomyosin receptor kinases (TRKs), tumor NTRK1/2/3 fusions, <1% | 2018 |
| Doebele et al.54 | Entrectinib | † TRK inhibitor, tumor NTRK1/2/3 fusions, <1% | 2019 |
| Golan et al.55 | Olaparib | PARP inhibitor, germline BRCA1/2, maintenance, 1%–5% | 2019 |
| FDA56 | Dostarlimab-gxly | ‡ PD-1 receptor, deficient mismatch repair (dMMR) tumors, 1%–2% | 2021 |
| Salama et al.57 | Dabrafenib + trametinib | ƒ BRAF/CRAF + MEK1/MEK2 inhibitors, BRAFv600E tumors, <1% | 2022 |
| Schram et al.65 | Zenocutuzumab | **Neuregulin ligand (NRG1) binding to HER2: HER3 heterodimers, tumor NRG1 fusions, <1% | 2022 |
| Reference | Emerging Targeted Agents | Pathogenic Gene Target, Prevalence | |
| Reiss et al.58 | Rucaparib | # PARP inhibitor. Germline or somatic BRCA1/2, or PALB2, 1%–5% | |
| Singhi et al.59 | Critzotinib | ALK, 0.16% all cases, 1.6% in patients < 50-years old | |
| Velthaus et al.60 | Lorlatinib | ROS1, 1% | |
| Strikler et al.61 | Sotorasib | Binds to KRASG12C—GDP in inactive state, KRASp.G12C tumors, 1%–2% | |
| Bekaii-Sabb et al.64 | Adagrasib | Binds to KRASG12C—GDP in inactive state, KRASp.G12C tumors, 1%–2% | |
| Heining et al.62 | Afatinib | Pan-EGFR tyrosine kinase inhibitor in KRAS wild-type tumors with NRG1 gene fusions, <1% | |
NA = not applicable as 5 fluoruracil/folinic acid were generic agents not requiring FD approval, but adjuvant chemotherapy first established as proof of principle.
Erlotinib is a small molecule tyrosine kinase inhibitor against EGFR, but the survival difference in combination with gemcitabine is a matter of only a few weeks but with considerable toxicity, so hardly used.
This applies to agnostic solid tumors (with defined mutations but of unknown tumor type) that have progressed following prior treatment and who have no satisfactory alternative treatment options.
High TMB (agnostic) as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options.
Either metastatic or where surgical resection is likely to result in severe morbidity (agnostic), and who have no satisfactory alternative treatments, or whose cancer has progressed following treatment.
Recurrent or advanced solid tumors (agnostic), as determined by an FDA-approved dMMR test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options.
Unresectable or metastatic solid tumors (agnostic), who have progressed following prior treatment and have no satisfactory alternative treatment options.
Advanced pancreatic cancer who had received >16 weeks of platinum-based chemotherapy without evidence of resistance.