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Pink Sheet – Accelerated Approval: US FDA Panel To Reconsider Six Indications For Checkpoint Inhibitors

Pink Sheet – Accelerated Approval: US FDA Panel To Reconsider Six Indications For Checkpoint Inhibitors

Executive Summary

Oncologic Drugs Advisory Committee will meet for three days in April to consider whether indications for Tecentriq, Keytruda and Opdivo should remain on label despite failure to confirm clinical benefit; review is part of the Oncology Center of Excellence’s ‘industry-wide evaluation’ of accelerated approvals, which has led to withdrawals of four other PD-1/L-1 inhibitor claims.

The US Food and Drug Administration’s extensive use of accelerated approval for checkpoint inhibitors will be on the line next month when an advisory committee weighs the future of six indications under the expedited pathway for three cancer immunotherapies that have failed to confirm clinical benefit.

The Oncologic Drugs Advisory Committee will meet 27-29 April to discuss whether to keep on label or withdraw: two indications for Genentech, Inc.’s PD-L1 inhibitor Tecentriq (atezolizumab); three for Merck & Co., Inc.’s PD-1 inhibitor Keytruda (pembrolizumab); and one for Bristol Myers Squibb Company’s PD-1 inhibitor Opdivo (nivolumab). The indications at issue – which include breast, urothelial, gastric and hepatocellular cancers – have been the subject of confirmatory trials that failed to verify clinical benefit.

The meeting, which was announced in a Federal Register notice, was requested by the Oncology Center of Excellence as part of its “industry-wide evaluation of accelerated approvals in oncology in which confirmatory trials did not confirm clinical benefit,” the FDA said in a press release.

ODAC will consider the current landscape of available therapies relative to the accelerated approval indications that are being re-examined, whether these indications should remain on label and if additional trials should be required.

Story continues after table…

Accelerated Approval Indications Going To ODAC

Drug/Sponsor

Indication

Accelerated Approval Date

Tecentriq (atezolizumab), Genentech

In combination with paclitaxel protein-bound for treatment of adult patients with unresectable locally advanced or metastatic triple-negative breast cancer whose tumors express PD-L1

March 2019

Locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy

April 2017

Keytruda (pembrolizumab), Merck & Co

Locally advanced or metastatic urothelial carcinoma not eligible for cisplatin-containing chemotherapy

May 2017

Recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, with disease progression on or after two or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, HER2/neu-targeted therapy

September 2017

Hepatocellular carcinoma that has been previously treated with sorafenib

November 2018

Opdivo (nivolumab), Bristol-Myers Squibb

Hepatocellular carcinoma that has been previously treated with sorafenib

September 2017

Four Indications Down…

The ODAC meeting announcement provides the most public detail to date about OCE’s initiative to clean-up the labels of the PD-1/L-1 class, where accelerated approvals have been frequent and, in some cases, followed shortly thereafter by disclosure of negative confirmatory trial results.

“When confirmatory trials do not confirm clinical benefit, a re-evaluation must be performed to determine if the approval should be withdrawn.” – FDA’s Richard Pazdur

The OCE initiative came to public light with the recent withdrawals of Opdivo’s indication for third-line metastatic small cell lung cancer, and a second-line urothelial cancer claim for AstraZeneca PLC’s PD-L1 inhibitor Imfinzi (durvalumab). (Also see “Accelerated Approval: US FDA Review Of Expedited Program Could Bring More Withdrawals” – Pink Sheet, 23 Feb, 2021.)

Two additional accelerated approval indication withdrawals have since been announced by sponsors: Keytruda’s third-line metastatic SCLC indication and Tecentriq’s second-line urothelial cancer indication.

Story continues after table…

Accelerated Approval Indications Recently Withdrawn

Drug/Sponsor

Indication

Accelerated Approval Date/Withdrawal Announcement

Opdivo (nivolumab), Bristol-Myers’ Squibb

Metastatic small cell lung cancer (SCLC) with progression after platinum-based chemotherapy and at least one other line of therapy

August 2018/December 2020

Imfinzi (durvalumab), AstraZeneca

Locally advanced or metastatic urothelial carcinoma with disease progression: during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

May 2017/February 2021

Keytruda (pembrolizumab), Merck & Co.

Metastatic SCLC with disease progression on or after platinum-based chemotherapy and at least one other prior line of therapy

June 2019/March 2021

Tecentriq (atezolizumab), Genentech

Locally advanced or metastatic urothelial carcinoma with disease progression: during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy

May 2016/March 2021

 

“Since the inception of the accelerated approval program, including these four withdrawals, only 6% of accelerated approvals for oncology indications have been withdrawn,” the FDA said in announcing the ODAC meeting.

… Six More To Go?

The decision to convene an ODAC on the six indications suggests that removal of these claims from labeling is either a closer call for the FDA than were the initial four, or sponsors have disagreed with the agency’s view either that additional studies should be conducted or the indications withdrawn.

“We are committed to ensuring the integrity of the accelerated approval program, which is designed to bring safe and effective drugs to patients with unmet medical needs as quickly as possible,” OCE director Richard Pazdur said in an FDA press release. “When confirmatory trials do not confirm clinical benefit, a re-evaluation must be performed to determine if the approval should be withdrawn.”

The ODAC meeting provides an opportunity for the agency’s external oncology experts and cancer patients to share input and perspective with the FDA, Pazdur said. “After this advisory meeting, our staff will consider the committee’s comments and will make final decisions regarding continuing approval of each indication.”

Genentech said checkpoint inhibitors, like Tecentriq, continue to demonstrate benefits across multiple cancer types and have been transformative for many patients. “We remain committed to following the science to better understand cancer, including which patients may benefit most from immunotherapy treatment,” the company said. “We look forward to continued collaboration with the FDA and discussions with the advisory committees.”

Keytruda “addresses a significant unmet medical need for many of these patients with advanced bladder, liver and gastric cancers, and we look forward to the dialogue with the ODAC and to working with the FDA in its review of the accelerated approval of these three indications,” Merck said.

BMS said that despite an evolution in the hepatoceullar treatment landscape in recent years Opdivo continues to address an unmet need, and the company appreciates the opportunity to discuss this in more depth with the advisory committee.

‘Long Overdue’ Re-examination

The FDA’s accelerated approval pathway allows drugs to reach market on the basis of a surrogate or intermediate clinical endpoint that is reasonably likely to predict clinical benefit, giving patients earlier access to treatments for serious diseases than they might otherwise have had if trials relied solely upon clinical outcomes.

However, drugs and indications that have come to market under the program have seen their share of confirmatory trials that either were not conducted in a timely fashion or failed to verify clinical benefit. The FDA cannot unilaterally take an accelerated approval drug off the market, and pursuing such a withdrawal is a timely, burdensome process, particularly if the sponsor objects to the drug or indication’s removal.

Prior to the four recent PD-1/L-1 indication withdrawals, 10 accelerated approval drugs or indications  had been withdrawn for failure to complete a postmarketing trial or to confirm clinical benefit, according to a Pink Sheet analysis. (Also see “Accelerated Approval Withdrawals Through The Years” – Pink Sheet, 25 Apr, 2019.) Only one of those, the breast cancer claim for Genentech’s Avastin (bevacizumab), came after a public hearing requested by the sponsor under the accelerated approval regulations.

More recently, the Center for Drug Evaluation and Research has proposed withdrawal of accelerated approval for AMAG Pharmaceuticals Inc.’s preterm birth prevention drug Makena, but the sponsor has opposed the withdrawal and requested a public hearing.

The ability of accelerated approval drugs or indications to remain on market sometimes for years after failed confirmatory trials has led to harsh criticism of the pathway from some academics and consumer groups.

In general, the FDA has staunchly defended its use of the program as enabling quicker access to promising drugs for patients in need. The oncology review office also has moved aggressively to ensure that confirmatory trials are actively recruiting or fully enrolled at the time of accelerated approval to minimize the interval between FDA clearance and receipt of data aimed at confirming clinical benefit. (Also see “Accelerated Approval: US FDA Defends Size Of Premarket Safety Databases, Confirmatory Endpoints” – Pink Sheet, 5 Mar, 2018.)

“I think it’s long overdue that these kinds of reviews are taken and I think that ultimately they will only improve consumer confidence and trust in the accelerated approval program that it’s operating as it was originally intended,” Aaron Kesselheim, professor of medicine at Harvard Medical School and a faculty member in the Division of Pharmacoepidemiology and Pharmacoeconomics at Brigham and Women’s Hospital, said in an interview.

Kesselheim has authored several papers critical of the agency’s use of the accelerated approval program. He has proposed that FDA assess penalties on manufacturers who fail to start confirmatory trials shortly after approval. (Also see “NEJM Takes Aim At Expensive Accelerated Approval Drugs Amid Congressional Drug Pricing Debate” – Pink Sheet, 24 May, 2017.)

“The inherent quid pro quo is faster access to the market and patients in exchange for rigorous research done after approval and a re-examination of the approved indication in a timely fashion. That’s the whole package. You can’t just have one half without the other.” – Harvard’s Aaron Kesselheim

He also coauthored a study that found only about half of the confirmatory trials for drugs receiving accelerated approval during a five-year period were completed within three years after approval, and many relied on surrogate measures rather than clinical endpoints. (Also see “JAMA Study Continues Wave Of Accelerated Approval Criticism Amid Expansion Of Pathway” – Pink Sheet, 28 Aug, 2017.)

“The accelerated approval pathway is a potentially very important pathway because it provides substantial flexibility in the standards for drug approval on the basis of extremely tenuous surrogate measures in cases where there’s unmet medical need,” Kesselheim said. However, under the program as conceived, “there’s supposed to be an actual rigorous trial that tests a clinically meaningful endpoint that occurs after the drug’s accelerated approval. And if that trial fails or demonstrates important safety issues, then that accelerated approval is supposed to be removed.”

Although the OCE’s re-evaluation of accelerated approval is limited to cancer drugs, Kesselheim said the continued availability of drugs and indications cleared under this pathway should be the focus of greater agency scrutiny, regardless of therapeutic area.

“The inherent quid pro quo is faster access to the market and patients in exchange for rigorous research done after approval and a re-examination of the approved indication in a timely fashion,” Kesselheim said. “That’s the whole package. You can’t just have one half without the other.”

Diana Zuckerman, president of the National Center for Health Research, said the ODAC meeting on accelerated approvals “is very welcome although long overdue.”

However, Zuckerman said it is not clear why the advisory committee meeting “is focused on specific indications for cancer drugs rather than reviewing the policies that rushed so many approvals in record time followed by years of delays in withdrawals or rescinding approval when it became clear that the treatments don’t work.”

“In some cases, the science is moving so quickly that the treatment landscape can change, so it’s important to periodically examine the status of drugs that received accelerated approvals in a complete and current context.” – Friends of Cancer Research’s Jeff Allen

Although the accelerated approval process may be characterized as “working” if approvals are eventually reversed, the delays are indefensible, Zuckerman said. “FDA needs to improve its standards for approval for cancer treatments as well as more urgently reversing bad decisions when the data support that.”

Friends of Cancer Research president and CEO Jeff Allen said the ODAC meeting “is a positive opportunity to openly discuss the available evidence regarding subsequent safety and benefit of products that have gone through accelerated approval.”

“In some cases, the science is moving so quickly that the treatment landscape can change, so it’s important to periodically examine the status of drugs that received accelerated approvals in a complete and current context,” Allen said. “I really think this can help further strengthen the program in the long run.”

At Pazdur’s request, FOCR has convened a multi-stakeholder working group to take a fresh look at the accelerated approval pathway. The group has suggested reframing approval around a benefit/risk construct, rather than a surrogate endpoint, and requiring sponsors to reapply for continued approval rather than putting the onus on the FDA to try to get a drug off the market for failure to confirm clinical benefit. (Also see “Accelerated Approvals Could Be Improved By Focusing On Benefit/Risk, Making Withdrawal Easier” – Pink Sheet, 9 Feb, 2021.)

Urothelial Cancer A Focus

Urothelial cancer seems to be a particular focus of the FDA’s re-evaluation of accelerated approval indications for the checkpoint inhibitors.

Of the 10 indications already withdrawn or going before ODAC, two are for prior platinum-treated metastatic urothelial carcinoma (Imfinzi, Tecentriq), and two are for first-line, cisplatin-ineligible urothelial carcinoma (Tecentriq, Keytruda).

Keytruda and Pfizer Inc.’s PD-L1 inhibitor Bavencio (avelumab) hold regular approval in second-line urothelial cancer following disease progression with platinum-based therapy.

In June 2018, the FDA restricted the cisplatin-ineligible urothelial cancer claims for Tecentriq and Keytruda to those patients who express the PD-L1 biomarker. This action followed study findings of lower survival associated with use of Keytruda or Tecentriq as monotherapy compared with platinum chemotherapy in previously untreated metastatic urothelial cancer patients with low expression of the PD-L1 biomarker. (Also see “US FDA Fine-Tunes Tecentriq, Keytruda First-Line Bladder Cancer Accelerated Approval Indications” – Pink Sheet, 21 Jun, 2018.)

ODAC will take up the cisplatin-ineligible urothelial cancer claims for both Tecentriq and Keytruda in one day, on 28 April.

 

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