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Oncology Accelerated Approval Withdrawals: Which Indications Need Confirmation Next?

Tara Hansen, MPH, Analyst II, Datamonitor Healthcare

The FDA Oncology Center of Excellence’s ‘industry-wide evaluation’ of accelerated approvals has already led to withdrawals of four PD-1/PD-L1 inhibitor indications, with the Oncologic Drugs Advisory Committee set to review another six in late April. Over the next two years, an additional five indications may be up for review.

Since the US Food and Drug Administration introduced the accelerated approval program in 1992, the agency has granted more than 250 approvals under this expedited pathway. The program has brought a number of important therapies to market earlier than would have been expected under the regular review process, including cancer immunotherapies.
 
However, despite the high-profile failure of several confirmatory trials for Genentech’s PD-L1 inhibitor Tecentriq (atezolizumab), Merck & Co’s PD-1 inhibitor Keytruda (pembrolizumab), and Bristol Myers Squibb’s PD-1 inhibitor Opdivo (nivolumab), none of the indications at issue for these checkpoint inhibitors were withdrawn from the market immediately after the trials failed to confirm clinical benefit. 

The Oncology Center of Excellence recently has initiated an extensive evaluation of accelerated approvals in oncology focused on indications where confirmatory trials failed to show benefit, and the Oncologic Drugs Advisory Committee will consider six of these indications for four drugs during a three-day meeting this month. 

The OCE’s comprehensive review has thus far been focused on PD-1/PD-L1 inhibitors, a class of drugs that has become ubiquitous across oncology indications over the last seven years.

A Long Overdue Reckoning...

Excluding Keytruda’s recent spate of accelerated approvals for a dosage change, there have been a total of 33 approvals for the PD-1/PD-L1 inhibitors through the expedited pathway as of 31 December 2020, affecting Keytruda, Opdivo, Tecentriq, AstraZeneca’s Imfinzi (durvalumab), and EMD Serono/Pfizer’s Bavencio (avelumab). Through the end of 2020, 10 of these indications had been converted.

Thus far, Bristol Myers Squibb and Merck & Co have converted Opdivo and Keytruda’s combined six accelerated approvals in melanoma and non-small cell lung cancer, both indications that contribute significantly to revenue, into full approvals. Opdivo is approved both as a monotherapy and as part of a combination with Bristol Myers Squibb’s CTLA-4 inhibitor Yervoy (ipilimumab). 

Keytruda’s accelerated approvals in two hematological indications – refractory classical Hodgkin’s lymphoma and refractory primary mediastinal large B-cell lymphoma (PMBCL) – have been converted to full approvals, as has the approval in recurrent or metastatic squamous cell carcinoma of the head and neck.

EMD Serono converted Bavencio’s accelerated approval for the second-line treatment of locally advanced or metastatic bladder cancer to a full approval in June 2020 based on data from the Phase III JAVELIN Bladder 100 trial. 

Of the 10 conversions to full approvals, the average time between the accelerated approval date and the conversion was 2.6 years. Notably, the average time from accelerated approval to ODAC’s scheduled review, or from approval to removal from market for those therapies that have recently been withdrawn, is markedly longer.

Regulatory Status

Average Time Since Approval

Converted (n=10)

2.6 years

Under ODAC Review (n=6)

3.3 years

Recently Withdrawn (n=4)

3.2 years

Not Yet Converted (n=13)

2.8 years

Source: Biomedtracker; FDA Postmarketing Commitment Approval Database

Bristol Myers Squibb’s voluntary December 2020 withdrawal of Opdivo’s accelerated approval for the treatment of small cell lung cancer was the first withdrawal, voluntary or required, of an accelerated approval for a PD-1/PD-L1 inhibitor. Bristol Myers Squibb’s action was followed by an additional three withdrawals: from AstraZeneca for Imfinzi in bladder cancer; from Merck & Co for Keytruda in small cell lung cancer; and from Roche for Tecentriq in bladder cancer. 

The upcoming ODAC meeting on 27–29 April will discuss one indication for Opdivo (hepatocellular carcinoma), two indications for Tecentriq (triple-negative breast cancer and urothelial carcinoma), and three indications for Keytruda (urothelial carcinoma, gastric cancer, and hepatocellular carcinoma). Given the recent withdrawals and these six additional indications under ODAC review, the landscape has already changed significantly since the OCE’s review was initiated.

Accelerated Approvals by Current Status

Source: Biomedtracker; FDA Postmarketing Commitment Approval Database

Excepting the indications currently under ODAC review, there are three PD-1/PD-L1 inhibitors with accelerated approvals granted as of 31 December 2020 with indications that have not yet been converted: Keytruda, Opdivo, and Bavencio.

… But What Comes Next?

The FDA typically requires postmarketing studies or clinical trials to demonstrate and confirm clinical benefit for drugs approved under the accelerated approval pathway. There are an additional five indications – two for Opdivo and three for Keytruda – with projected postmarketing requirement completion dates before the end of 2023. 

Bavencio’s only accelerated approval indication that has not yet been converted is for the treatment of metastatic Merkel cell carcinoma, and the projected postmarketing requirement completion date is December 2026.

Opdivo

The postmarketing requirement for Opdivo’s approval as an adjuvant treatment for patients with 
high-risk, invasive urothelial carcinoma requires Bristol Myers Squibb to submit a final report with datasets from the Phase III CA209274 trial examining the effect of Opdivo on disease-free survival.

Positive data from the Phase III CA209274 trial evaluating Opdivo after surgery in patients with 
high-risk, muscle-invasive urothelial carcinoma were announced in September 2020. In the study, Opdivo demonstrated a statistically significant improvement in disease-free survival over placebo, both in the intent-to-treat population and in patients with tumors that express PD-L1. Based on these data, it seems unlikely that Opdivo’s label in this indication will be withdrawn in the future. 

However, not all postmarketing requirements include references to specific trials.

In the case of Opdivo’s approval in patients with microsatellite instability high (MSI-H) or mismatch repair deficient metastatic (DMMR) colorectal cancer who have progressed following treatment with fluoropyrimidine, oxaliplatin, and irinotecan, the FDA only required a final report from “trials conducted to verify and describe the clinical benefit of nivolumab.” 

The dataset must include data from at least 150 patients who were enrolled in trials sponsored by Bristol Myers Squibb, and the patients must have been followed for at least 12 months from the onset of response.

Keytruda

Keytruda’s tumor-agnostic approval for patients with MSI-H or mismatch repair deficient solid tumors has a similarly ambiguous postmarketing requirement. The FDA said the final datasets need to include “at least 124 patients with colorectal cancer enrolled in Merck-initiated trials; at least 300 patients with non-colorectal cancer, including a sufficient number of patients with prostate cancer, thyroid cancer, small cell lung cancer; and ovarian cancer; and 25 children,” according to the agency’s postmarketing commitments database. 

With a projected completion date in March 2023, Merck & Co still has almost two years to collect the necessary data. Furthermore, confirmatory trials have already been initiated in Keytruda’s other two upcoming indications – cervical cancer and endometrial carcinoma. 

The Phase III KEYNOTE-826 study is the confirmatory trial to support Keytruda’s accelerated approval as a treatment for recurrent or metastatic cervical cancer patients with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS >1). It is expected to be completed in late November 2022. The postmarketing requirement requires Merck & Co to submit analyses and datasets with a final report for PFS and OS from the trial, which is testing Keytruda against standard-of-care chemotherapy. 

Merck & Co recently reported positive data from the Phase III KEYNOTE-775 trial of Keytruda and Lenvima in patients with advanced endometrial carcinoma following one prior platinum-based regimen in any setting. In this trial, the combination of Keytruda and Lenvima demonstrated a statistically significant and clinically meaningful improvement in the primary endpoints of PFS and OS as well as the secondary endpoint of ORR versus chemotherapy against the comparator arm, the treatment of physician’s choice of doxorubicin or paclitaxel. 

The final reports will likely be necessary to fulfill the postmarketing requirements, and the trial is expected to be completed in March 2023. Given the data seen thus far though, the path to a full approval for this combination seems relatively straightforward.

Accelerated approvals for PD-1/PD-L1 inhibitors that have not yet converted, and projected postmarketing requirements completion dates

Drug/Sponsor

Indication

Accelerated Approval Date

Confirmatory Trial

Trial Initiation Date

Projected Postmarketing Commitment Completion Date

Bavencio (avelumab), EMD Serono/Pfizer

For the treatment of adults and pediatric patients 12 years and older with metastatic Merkel cell carcinoma

March 2017

Phase II JAVELIN Merkel 200 (Part B)*

June 2014

December 2026

Keytruda (pembrolizumab), Merck & Co

In combination with chemotherapy, for the treatment of patients with locally recurrent, unresectable or metastatic triple-negative breast cancer whose tumors express PD-L1 (combined positive score (CPS) ≥10) as determined by an FDA-approved test

November 2020

Phase III KEYNOTE-355*

July 2016

December 2026

For the treatment of adult and pediatric patients with unresectable or metastatic tumor mutational burden-high (TMB-H) (≥10 mutations/megabase (mut/mb)) solid tumors, as determined by an FDA-approved test, that have progressed following prior treatment and who have no satisfactory alternative treatment options

June 2020

N/A

-

December 2025

In combination with lenvatinib, indicated for the treatment of patients with advanced endometrial carcinoma that is not microsatellite instability-high (MSI-H) or mismatch repair deficient (DMMR), who have disease progression following prior systemic therapy and are not candidates for curative surgery or radiation

September 2019

Phase III KEYNOTE-775*

June 2018

March 2023

For the treatment of adult and pediatric patients with recurrent locally advanced or metastatic Merkel cell carcinoma

December 2018

Phase III KEYNOTE-913**

February 2019

December 2032

For the treatment of patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy whose tumors express PD-L1 (CPS >1) as determined by an FDA-approved test

June 2018

Phase III KEYNOTE-826*

October 2018

May 2023

For the treatment of adults and pediatric patients with unresectable or metastatic, microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (DMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or metastatic, microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (DMMR) colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

May 2017

N/A

-

March 2023

Opdivo (nivolumab), Bristol-Myers Squibb

In combination with Yervoy, for the treatment of patients with hepatocellular carcinoma (HCC) who have been previously treated with Nexavar

March 2020

Phase III CheckMate 9DW**

September 2019

July 2024

In combination with Yervoy for the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (DMMR), metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

July 2018

Phase III CheckMate 8HW**

July 2019

July 2024

For the treatment of adults and pediatric patients 12 years and older with microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (DMMR), metastatic colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan

July 2017

Phase III CheckMate 8HW**

July 2019

September 2021

For the treatment of adult patients with classical Hodgkin lymphoma that has relapsed or progressed after:
•Autologous hematopoietic stem cell transplantation (HSCT) and brentuximab vedotin, or
•3 or more lines of systemic therapy that includes autologous HSCT

April 2017

Phase III CheckMate 812**

May 2017

December 2026

For the treatment of locally advanced or metastatic urothelial carcinoma patients who:
•Have disease progression during or following platinum-containing chemotherapy
•Have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

February 2017

Phase III CA209274*

February 2016

February 2022

For the treatment of classical Hodgkin lymphoma that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and post-transplantation brentuximab vedotin

May 2016

Phase III CheckMate 812**

May 2017

December 2026

*Mentioned in postmarketing commitment or confirmed via company communication.

**Analyst assumption based on company trial descriptions, postmarketing commitment requirements and ongoing trials.

Source: Biomedtracker; Trialtrove®; FDA Postmarketing Commitment Approval Database

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