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Oncology Accelerated Approval Surrogates

what surrogate endpoints has the fda accepted for accelerated approval of oncology drugs, and which were later withdrawn?

Read 263 sources·6 steps

I've put the full analysis in the document panel (oncology_accelerated_approval_surrogates.md). Here's the essence.

FDA grants accelerated approval on an endpoint "reasonably likely to predict clinical benefit," with a confirmatory trial required to verify it. Across the oncology review record a handful of surrogates recur — and a few of those approvals didn't survive confirmation ¹¹³.

The surrogates FDA has accepted, and where they led:

Objective response rate (ORR), large and durable, is the most common basis — a substantial, lasting tumor response in refractory or metastatic disease, with duration of response as necessary support ¹¹³²⁶.

But the surrogate can mislead. Gefitinib (Iressa) won accelerated approval on a ~15% single-arm ORR ⁹; confirmatory studies including ISEL then showed no survival benefit, the indication was narrowed, and it was effectively withdrawn — before returning in 2015 for EGFR-mutated disease ³².

Gemtuzumab ozogamicin (Mylotarg) was approved on ~30% ORR in AML; confirmatory trial SWOG S0106 was stopped early (no benefit, more induction deaths) and it was voluntarily withdrawn in 2010, later re-approved in 2017 at a revised dose ²⁵²⁸.

Progression-free survival (PFS) is accepted when the effect is large in a randomized study with no survival harm, used where response rate has not correlated with overall survival ¹³.

Pathologic complete response (pCR) is accepted only in neoadjuvant high-risk early breast cancer, and only contingent on later DFS/EFS/OS confirmation ⁷.

A reviewer caveat: an original NDA/BLA review documents the AA decision and its surrogate, but confirmatory readouts and withdrawals land years later. Pembrolizumab, for example, is documented here as AA-on-durable-ORR, but the withdrawal itself sits outside the original review ²⁶.

The full surrogate framework, the per-drug detail, and the Drugs@FDA sources are in the document panel. If you want, I can pull the 2021 ODAC checkpoint-inhibitor withdrawal record next.

Sources read(263)

[1]Drugs@FDAp.10Capecitabine (Xeloda) review — response rate as an AA surrogate (NDA 020896)

[7]Drugs@FDAp.16Pertuzumab (Perjeta) medical review — pCR in neoadjuvant breast cancer (BLA 125409)

[9]Drugs@FDAp.30Gefitinib (Iressa) statistical review — 15% ORR single-arm AA (NDA 021399)

[13]Drugs@FDAp.19Panitumumab (Vectibix) medical review — ORR/PFS (BLA 125147)

[25]Drugs@FDAp.129Gemtuzumab ozogamicin (Mylotarg) medical review — SWOG S0106 & 2010 withdrawal (BLA 761060)

[26]Drugs@FDAp.218Pembrolizumab (Keytruda) review — durable-ORR accelerated approval (BLA 125514)

[28]Drugs@FDAp.5Gemtuzumab ozogamicin (Mylotarg) summary review (BLA 761060)

Open this answer, with every source, in Rhizome

Surrogate endpoints in oncology accelerated approval, and drugs withdrawn after confirmatory trials

Methodology

I searched Drugs@FDA review documents (medical, statistical, cross-discipline, and multidiscipline reviews plus approval and administrative correspondence) for the surrogate endpoints FDA has accepted as the basis for accelerated approval (AA) in oncology, and for accelerated approvals later withdrawn after confirmatory failure. I first ran broad synthesis queries on the surrogate-endpoint framework and withdrawn-drug discovery, then drilled named products individually against their original review packages to verify the AA basis and surrogate used. An important scope limitation: an original NDA/BLA review PDF documents the AA decision and its surrogate endpoint, but confirmatory-trial readouts and formal withdrawals occur years later and generally are not in that original review. So the retrieved documents firmly establish the surrogate endpoints and the AA basis, but they only capture the actual withdrawal event for the two older cases where a later re-approval review recounted the history.

Part 1 — Surrogate endpoints FDA has accepted for oncology accelerated approval

FDA grants accelerated approval on an endpoint "reasonably likely to predict clinical benefit," with a confirmatory trial required to verify benefit. The surrogates documented in the reviews:

Surrogate endpoint	How FDA frames it	Example
Objective response rate (ORR), large and durable	A substantial, durable tumor response in refractory or metastatic disease with limited options is reasonably likely to predict benefit; durability is emphasized as necessary support ¹¹³	Capecitabine (Xeloda) response rate ¹; gefitinib NSCLC, 15% ORR single-arm ⁹; pembrolizumab durable ORR ²⁶
Progression-free survival (PFS)	Accepted when the effect is large in a randomized study with no evidence of survival harm; used where ORR has not correlated with OS ¹³	Panitumumab (Vectibix), ORR/PFS ¹³
Pathologic complete response (pCR)	Accepted only in neoadjuvant high-risk early breast cancer; AA contingent on later DFS/EFS/OS confirmation ⁷	Pertuzumab (Perjeta), neoadjuvant breast cancer ⁷

Disease-free survival (DFS) and overall survival (OS) appear in the reviews as confirmatory / direct clinical-benefit endpoints, not as AA surrogates ⁷. Minimal residual disease (MRD) was not documented as an AA basis in the retrieved sources.

Part 2 — Accelerated approvals withdrawn after confirmatory trials (fully documented)

These two cases have the withdrawal explicitly documented, because a later re-approval review recounted the history.

Drug	AA indication	Surrogate	Confirmatory outcome and withdrawal
Gefitinib (Iressa)	Locally advanced/metastatic NSCLC after platinum and docetaxel failure (2003 AA)	~15% ORR in a single-arm trial ⁹	Post-marketing confirmatory studies failed to confirm benefit; the ISEL trial showed no overall-survival improvement. Indication narrowed and effectively withdrawn, then re-approved in 2015 for EGFR-mutated NSCLC ³²
Gemtuzumab ozogamicin (Mylotarg)	CD33-positive AML in first relapse, older patients not candidates for cytotoxic chemotherapy (2000 AA)	~30% ORR ²⁵	Confirmatory trial SWOG S0106 stopped early: no improvement in remission and more induction deaths; sponsor voluntarily withdrew in 2010. Re-approved in 2017 with a different dose/schedule ²⁵²⁸

Part 3 — AA confirmed on a surrogate, but withdrawal not verifiable from retrieved sources

For the checkpoint inhibitors, the retrieved reviews confirm the accelerated approval and the surrogate endpoint (durable ORR), but the original review PDFs do not contain the later confirmatory readout or a withdrawal decision — so any withdrawal is flagged as not documented here.

Drug	AA indication (as documented)	Surrogate	Withdrawal status in retrieved sources
Pembrolizumab (Keytruda)	Recurrent/metastatic HNSCC after platinum; metastatic Merkel cell carcinoma	Durable ORR ²⁶	Not documented in retrieved reviews ²⁶

Bottom line

The recurring pattern: FDA accepts a large, durable response (ORR) or a large PFS effect as the surrogate, grants accelerated approval, and requires a confirmatory trial. When that trial fails — Mylotarg's SWOG S0106, Iressa's ISEL — the approval is withdrawn, sometimes to return later in a better-defined population. The surrogate buys speed; the confirmatory trial is where the benefit is proven or the approval is lost.

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