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Cancer Policy Monitor: November 12, 2024

Appropriations Update

-Matt Gontarchick

Negotiations to finalize Fiscal Year (FY) 2025 appropriations remain on hold as lawmakers assess the results of the general election on November 5. The federal government is currently operating under a continuing resolution (CR) that keeps the government operating at FY 2024 spending levels through December 20.

The medical research community has been paying close attention to the appropriations process since enactment of a final FY 2024 spending measure in March 2024 that marked the first time in nearly a decade that the National Institutes of Health (NIH) did not receive a funding increase.

As a reminder, the House Appropriations Committee approved an FY 2025 spending bill in July 2024 that would provide NIH with $47.081 billion in base program funding, which is nearly the same amount allocated in FY 2024. In August, the Senate Appropriations Committee unanimously approved a bill to provide $48.9 billion in base program funding in FY 2025. However, an impasse between lawmakers on topline spending levels and adjustments to spending caps imposed earlier this year eventually led Congress to pass a CR in September 2024 that tables further negotiations on FY 2025 appropriations until after the election.

As Congress negotiates a final FY 2025 funding amount for NIH, the medical research advocacy community is united in urging Congress to “finalize the Labor, Health and Human Services, Education, and Related Agencies (Labor-HHS) spending bill by the end of the calendar year with a robust investment in NIH.” Specifically, the community is urging Congress to “provide no less than the Senate Appropriations Committee-approved level of $48.9 billion for NIH’s base budget, in addition to funding the Advanced Research Projects Agency for Health (ARPA-H) at $1.5 billion.”

If Congress agrees with this proposal that the Senate has put forward, it will result in the National Cancer Institute (NCI) receiving $7.49 billion in FY 2025, which would be an increase of $266 million over FY 2024 ($216 million for the Cancer Moonshot program and an additional $50 million increase for NCI). While the debt ceiling agreement that caps discretionary spending continues to be in place for FY 2025, we are hopeful that Congress will agree to exhibit some flexibility to allow NIH to receive this healthy increase in FY 2025. If Congress fails to reach an agreement on FY 2025 appropriations by December 20, lawmakers are likely to delay final decisions on spending into the new year. Regardless of whether lawmakers can reach an agreement by the next deadline, outcomes of the election such as control of the White House and Congress are certain to impact the direction of any spending negotiations.

As members of Congress begin to resume discussions on FY 2025 appropriations in the near future, the American Association for Cancer Research (AACR) will continue to advocate for a final federal budget that provides robust funding increases for NIH, NCI, and other research and health programs.

FDA holds Oncologic Drug Advisory Committee Meeting Discussing Utility of Biomarker for Anti-PD-1 Therapies

-Brad Davidson, PhD

Currently, anti-PD-1 therapies Keytruda and Opdivo are approved for use in the first line without respect to biomarker status for late-stage gastric, gastroesophageal junction, and esophageal cancers. On September 26, the U.S. Food and Drug Administration (FDA) convened the Oncologic Drugs Advisory Committee to discuss the use of PD-L1 expression as a predictive biomarker to select patients for anti-PD-1 drugs in these indications. The meeting centered on the benefit-risk ratio of treating patients with varying expression levels of PD-L1, suggesting FDA may restrict anti-PD1 therapies to only patients who express PD-L1 at sufficient levels.

Manufacturers of relevant drugs and the FDA highlighted data from large clinical trials, showing that anti-PD-1 therapies provided significant patient benefit in populations unselected for PD-L1 status. However, upon subgroup analysis, individuals with high PD-L1 levels benefited the most while those with low expression (scoring <1) generally saw no added benefit. Counter to this, patients and patient advocates shared anecdotal stories of individuals with low PD-L1 expression who experienced major benefit from anti-PD-1 therapies.

Further discussion highlighted key issues with PD-L1 biomarker testing. The dynamic nature of PD-L1 expression, the existence of multiple non-equivalent tests, and the presence of high interobserver variability could lead to patients being incorrectly categorized. Additionally, collecting testing samples can be difficult, potentially slowing treatment.

At the end of the proceedings, the majority of the committee voted in agreement that patients with expression <1 have unfavorable risk-benefit ratios for treatment with anti-PD-1 drugs in all indications discussed. While the committee does not make regulatory decisions, this vote signals a potential change in labeling for current anti-PD-1 therapies and in drug development for novel agents in this class. Richard Pazdur, M.D., director of the FDA Oncology Center of Excellence, noted that drug companies should collaborate to build harmonized biomarker assays and provide expanded access to these drugs should the FDA limit their usage. The full meeting can be viewed here.

REGISTER NOW: FDA-AACR Workshop: To Test or Not to Test—That Is the Question: DPD Deficiency and Weighing Potential Harms

-Rukiya Umoja, PharmD 

The FDA Oncology Center of Excellence and the American Association for Cancer Research (AACR) are hosting a hybrid workshop titled “To Test or Not to Test—That Is the Question: DPD Deficiency and Weighing Potential Harms” on January 16, 2025, at the Bethesda Marriott Pooks Hill Hotel in Bethesda, Maryland. This workshop will explore the considerations for dihydropyrimidine dehydrogenase (DPD) deficiency testing before chemotherapy with fluoropyrimidines.

Registration is now open for virtual and in-person attendance.

Fluoropyrimidine drugs, such as 5-Fluorouracil (5-FU) and capecitabine (Xeloda), are commonly used to treat various solid tumors. The DPD enzyme is crucial for metabolizing these drugs into non-toxic compounds, and individuals with DPD deficiency are at a higher risk of experiencing severe adverse effects. Consequently, there has been ongoing discussion about whether DPD deficiency testing should be incorporated as a standard part of clinical practice guidelines in the United States.

This workshop will bring together experts from academia, industry, FDA, and patient advocacy organizations to examine the existing information and evidence surrounding DPD deficiency testing, consider the clinical implications of requiring testing, and discuss the regulatory considerations for modifying FDA product labeling to require testing.

For additional information, please visit the workshop website. 

Wasserman Schultz, DeGette Lead Letter Urging FDA to Progress on Reviews of Illegal E-Cigarettes

-Blake William Rostine

On October 16, 2024, Representatives Debbie Wasserman Schultz (D-FL) and Diana DeGette (D-CO) formally called on the FDA to finalize the review of e-cigarette products currently awaiting Premarket Tobacco Product Applications (PMTAs) review. In an official letter to the FDA, the representatives expressed concern about the high level of youth e-cigarette users and their decision to allow menthol-flavored e-cigarettes to be on the market.

With nearly 500,000 e-cigarette PMTAs currently under review, the FDA has expressed that a current lack of resources and a large influx of PMTAs has delayed their process. To address the backlog, the FDA has suggested increased fund allocations, including user-fees from e-cigarette companies. However, members of Congress have expressed concern about giving the institution more resources, stating that they have not shown themselves to efficiently use their current funds.

Addressed to FDA Commissioner Dr. Robert Califf and Director for the Center for Tobacco Products Dr. Brian King, the letter urged the FDA to “continue to work closely with the [Department of Justice] and other participating agencies” to use more aggressive penalizations for e-cigarette manufacturers, including product seizures, civil monetary policies, and criminal prosecutions to remove illegal products from the market and deter youth e-cigarette use.

Sixty-three Democratic members of the House of Representatives joined Reps. Wasserman Schultz and DeGette in the signing of this letter. The full letter is available online.

ONCOLOGY APPROVAL RECAP

Between September 21 and October 25, the FDA approved two new oncology drugs and two new indications for previously approved oncology drugs, and traditionally approved one drug previously approved through accelerated pathways:

  • Osimertinib was approved for adults with locally advanced, unresectable (stage 3) non-small cell lung cancer (NSCLC) with EGFR exon 19 deletions or exon 21 L858R mutation as detected by an FDA approved test whose disease has not progressed during or following concurrent or sequential platinum-based chemoradiation therapy. This is the fifth indication for Osimertinib in NSCLC. This application received priority review and breakthrough designation. Review was conducted under FDA’s Project Orbis for concurrent review of oncology products through collaboration with international partners in Australia, Canada, and Switzerland.
  • Selpercatinib was granted traditional approval for patients greater than two years of age with advanced or metastatic medullary thyroid cancer (MTC) with a RET mutation confirmed by an FDA test. This drug initially received accelerated approval for this disease in patients greater than 12 years old in 2020 and pediatric patients of 2 years of age or older in May 2024. This application was granted priority review, breakthrough therapy, and orphan drug designations.
  • Nivolumab was approved with platinum-doublet chemotherapy in the neoadjuvant setting followed by single-agent adjuvant nivolumab for adults with resectable NSCLC without known EGFR mutations or ALK rearrangements. This is the fifth indication of nivolumab in NSCLC alone, but its first in the perioperative setting. Future perioperative approvals may come under increased scrutiny in the wake of multiple FDA initiatives seeking to reform perioperative trials, including an FDA-AACR workshop and Oncologic Drug Advisory Committee meeting. Review was conducted under FDA’s Project Orbis for concurrent review of oncology products through collaboration with international partners in Australia, Brazil, Canada, and Israel.
  • Inavolisib was approved in combination with palbociclib and fulvestrant for adults with PIK3CA mutated, hormone receptor-positive, and HER2 negative locally advanced or metastatic breast cancer following recurrence on or after completion of adjuvant endocrine therapy. This is the first FDA approval of inavolisib in any setting. Review was performed under FDA’s Project Orbis for concurrent consideration through collaboration with international partners in Australia, Canada, and Switzerland. This application received priority review and breakthrough designations.
  • Zolbetuximab-clzb was approved in combination with fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative and CLDN18.2 positive gastric or gastroesophageal junction adenocarcinoma. This is the first approval of zolbetuximab-clzb in any setting, and it is now the only FDA-approved oncology drug targeting claudin 18.2. The review process was bolstered by use of the Real-Time Oncology Review pilot program and priority review, fast track, and orphan drug designations.