By Laura R. Bobolts, PharmD, BCOP, Senior Vice President, Clinical Strategy and Growth at OncoHealth

Key Takeaways

ASCO 2025, the largest cancer conference in the world, featured groundbreaking clinical trial results that promise to reshape the standards of care (SoC) in oncology. Because of the promising life-extending and life-sustaining impact of these emerging therapies, payers must stay informed to ensure timely access for their members with cancer.

I’ve selected five trials discussed at the conference that payers should be aware of as they involve off-label therapies already being prescribed or quickly heading for FDA approval.

SERENA-6

Background: This clinical trial was uniquely designed to study the combination of camizestrant + CDK4/6 inhibitor for the treatment of emergent ESR1 mutations ahead of disease progression during first-line aromatase inhibitor (AI) + CDK4/6 inhibitor therapy in ER+/HER2- advanced breast cancer. The new therapy could be impactful since development of an ESR1 mutation may confer resistance to an AI. A cohort of 315 patients who developed an ESR1 mutation with no disease progression while receiving first-line AI + CDK4/6i were randomized to either continue this existing treatment or switch the AI to camizestrant, an oral SERD. The primary endpoint was investigator-assessed progression-free survival (PFS).

Results: Switching the AI to camizestrant, while continuing the CDK4/6i, upon molecular progression with an ESR1m significantly reduced the risk of disease progression or death by 56% over continuing the AI. There was a 6.8 month absolute benefit in PFS.

Payer Impact: Camizestrant is still investigational, but FDA approval is anticipated by January 2026, if not sooner. Payers need to coordinate their testing policies upon approval as this represents a monumental change in NGS (next generation sequencing) frequency, performed every 2-3 months in search of an emerging ESR1 mutation. The therapy can establish a new precedent of gaining approval based on molecular progression, an ESR1 mutation biomarker appearing in the blood, not on disease progression seen on imaging. This development bears watching for payers.

ATOMIC

Background: This trial was designed to study chemotherapy alone or combined with atezolizumab (Tecentriq) as adjuvant therapy for patients with completely resected stage III dMMR colon cancer. In the experimental group, patients received six months of chemotherapy with mFOLFOX6 plus atezolizumab, followed by six-months of atezolizumab alone. The primary endpoint was disease-free survival (DFS).

Results: The addition of atezolizumab to chemotherapy led to a 50% lower risk of recurrence and a 10% overall DFS improvement at three years. Adding atezolizumab to chemo did increase the risk of side effects, including hypothyroidism, neutropenia, neuropathy, and diarrhea.

Payer Impact: This could lead to a new SoC of chemo plus one year of adjuvant atezolizumab in resected stage III dMMR colon cancer patients. This regimen is off-label today but already supported by NCCN as atezolizumab + FOLFOX or CAPEOX in dMMR or POLE/POLD1m w/ ultra-hypermutated phenotype (TMB >50 mut/Mb) stage IIC or stage III colon cancer. Payers need to note how NCCN extrapolated use to stage IIC patients on a consensus basis!

DESTINY-Breast09

Background: The results of this trial, which substitutes trastuzumab deruxtecan (T-DXd; Enhertu) + pertuzumab for the longtime SoC Cleopatra regimen of taxane + trastuzumab + pertuzumab (THP) in first-line HER2+ advanced/metastatic breast cancer, have been anticipated for many years. Eligible patients also had asymptomatic/inactive brain metastases allowed, a disease-free interval (DFI) greater than six months from their last chemo or neoadjuvant/adjuvant HER2 targeted therapy, and for HR+ patients, only one prior line of endocrine therapy for MBC. The primary endpoint was PFS by blinded independent central review (BICR).

Results: The trial results showed a median PFS of 40.7 months with T-DXd + pertuzumab versus 26.9 months with THP, the current SoC, representing a 13.8 month absolute PFS benefit. This new regimen may not be suitable for all patients due to its toxicity profile, which includes significantly higher rates of interstitial lung disease, with two fatalities occurring during the trial, and increased left ventricular ejection fraction (LVEF) dysfunction with T-DXd +pertuzumab versus THP.

Payer Impact: While the new regimen of T-DXd + pertuzumab might become the new SoC for some, overall survival data is immature, the optimal sequencing of subsequent therapy is unknown, and quality of life may be reduced as there is no chemotherapy-free maintenance period. Off-label use is not yet widely supported by Medicare regulations. The trial is not yet published in full text and is not yet NCCN-supported, but payers may consider approving this therapy on a case-by-case basis. This therapy could quickly become a SoC for high risk patients where the benefits may outweigh the risks (ex: visceral crisis, brain metastases, PIK3Cam). Payers need to note that patients who were HR+ were allowed the addition of endocrine therapy, but not a CDK4/6i, to T-DXd and pertuzumab.

MATTERHORN

Background: This trial evaluated the addition of durvalumab (Imfinzi) to perioperative 5-fluorouracil, leucovorin, oxaliplatin, and docetaxel chemotherapy (D-FLOT) in resectable stage II-IVA gastric/gastroesophageal junction (GEJ) adenocarcinoma patients. The primary endpoint was event-free survival (EFS).

Results: The proposed regimen, D-FLOT, represents the first positive perioperative trial outcome in gastric cancer using an immune checkpoint inhibitor.

The addition of durvalumab to perioperative FLOT significantly reduced the risk of disease recurrence, progression, or death by 29%. Results showed a clear separation of the curve and a significant benefit.

Payer Impact: Immediately following ASCO, requests for this new regimen, D-FLOT, were coming in from the payer side. Adding durvalumab to FLOT is a practice-changing regimen because of the increased survival benefit without recurrence, progression, or treatment-related complications. Payers need to be mindful that PD-L1 positivity is not required with D-FLOT, while it is required with immune checkpoint inhibitor use in metastatic disease. Also, durvalumab is administered for a maximum of 14 cycles, dosed every 4 weeks—4 cycles with perioperative chemotherapy, followed by 10 cycles of durvalumab alone. Off-label use may be supported by Medicare as the study is published in the New England Journal of Medicine.

IMforte

Background: This maintenance trial studied the impact of adding lurbinectedin (Zepzelca) to first-line atezolizumab maintenance following chemo/atezolizumab for extensive stage small cell lung cancer (ES-SCLC). Patients who showed no disease progression after first-line treatment were randomized to either receive lurbinectedin + atezolizumab or atezolizumab alone maintenance. Primary endpoints were overall survival (OS) and independent review facilitated PFS.

Results: The addition of lurbinectedin to atezolizumab maintenance reduced the risk of disease progression or death by 46%. They also showed a 2.6 month added overall survivor benefit with lurbinectedin + atezolizumab, which may seem small, but with this aggressive form of cancer, this level of benefit is a win. Side effects were higher with more neutropenia, anemia, and thrombocytopenia.

Payer Impact: Lurbinectedin has a PDUFA date for consideration of FDA approval by October 7, 2025, for use as 1st line maintenance therapy in combination with atezolizumab for ES-SCLC patients whose disease has not progressed after 1st line induction with atezolizumab, carboplatin, and etoposide. Payers may have challenges with this treatment if providers fail to conduct imaging following induction chemotherapy, a requirement to ensure no disease progression before moving onto lurbinectedin and atezolizumab maintenance. Payers should also ensure patients have G-CSF primary prophylaxis covered, as G-CSF was required in the trial to reduce the duration of severe neutropenia. The study is published in The Lancet, which may secure off-label coverage in Medicare members.

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These five studies were just a few of the many presentations at ASCO 2025. The conference showcased the latest in cancer research with clinical trials and treatment innovation from the thousands of experts who explored the meeting’s theme, “Driving Knowledge to Action: Building a Better Future”. Sharing this important knowledge will go a long way to help prepare payers for the ongoing changes in cancer therapies that will follow.