Table 2.
Cancer drug indications that initially received accelerated approval but failed to improve primary endpoint in confirmatory trials
| Drug | Indication | Endpoint leading to accelerated approval | Post-approval trial results | Outcome as of May 2021 | Status in current NCCN guidelines* |
|---|---|---|---|---|---|
| Gemtuzumab | AML | RR | OS, DFS, RR all not improved; concerning safety signals | Voluntarily withdrawn; subsequently approved with lower dose and new schedule in different population | NA |
| Gefitinib | NSCLC | RR | 3 confirmatory trials failed to confirm benefit: one closed early, one non-inferiority study, one failed to improve primary endpoint of OS | Voluntarily withdrawn; subsequently approved in different population (EGFR mutations positive only) | NA |
| Tositumomab | Follicular lymphoma | RR | Confirmatory trial not completed; other trial suggested no survival benefit | Voluntarily withdrawn | NA |
| Bevacizumab | HER2 negative breast | PFS | Three trials with no improvement in OS; PFS improved | Revoked by FDA over objection of manufacturer | Yes: category 2A |
| Fludarabine | B cell CLL | RR | Confirmatory trial not completed | Voluntarily withdrawn | NA |
| Bevacizumab | Glioblastoma | RR | OS (primary endpoint) and quality of life not improved; PFS improved | Converted to regular approval | Category 2A |
| Nivolumab | Melanoma after ipilimumab or BRAF inhibitor | RR | OS and PFS both not improved | Converted to regular approval on basis of results from other trials | Category 2A |
| Pembrolizumab | PDL1 + gastric or gastro-oesophageal cancer | RR | OS and PFS not improved in 2 trials | Voluntarily withdrawn; ODAC voted 6-2 in favour of withdrawal | Category 2A |
| Atezolizumab | Urothelial, second line | RR | OS and PFS both not improved | Voluntarily withdrawn | Removed |
| Atezolizumab | Urothelial, first line | RR | OS not improved; PFS improved | Pending; ODAC voted 10-1 against withdrawal | Category 2A |
| Pembrolizumab | Urothelial, first line | RR | OS not improved; PFS not improved | Pending; ODAC voted 5-3 against withdrawal | Category 2A |
| Olaratumab | Soft tissue sarcoma | OS from phase II trial | OS not improved; PFS detrimental | Voluntarily withdrawn | Removed |
| Atezolizumab | PDL1+ TNBC | PFS | OS and PFS both not improved | Pending; ODAC voted 7-2 against withdrawal | Category 1 |
| Durvalumab | Urothelial | RR | OS not improved; PFS detrimental | Voluntarily withdrawn | Removed |
| Nivolumab | Hepatocellular cancer | RR | OS not improved; PFS not improved | Voluntarily withdrawn; ODAC voted 5-4 in favour of withdrawal | Category 2A |
| Nivolumab | SCLC | RR | OS not improved in 2 confirmatory trials; PFS improved in one and detrimental in another | Voluntarily withdrawn | Category 3 |
| Pembrolizumab | Hepatocellular cancer | RR | OS and PFS both not improved | Pending; ODAC voted 8-0 against withdrawal | Category 2B |
| Pembrolizumab | SCLC | RR | OS not improved; PFS improved | Voluntarily withdrawn | Category 3 |
AML=acute myeloid leukaemia; CLL=chronic lymphocytic leukaemia; EGFR=epidermal growth factor receptor; FDA=US Food and Drug Administration; NA=not applicable; ODAC=Oncology Drug Advisory Committee; OS=overall survival; PFS=progression-free survival; RR=response rate; SCLC=small cell lung cancer; TNBC=triple negative breast cancer.
*
As of 12 May 2021.