Category: Hem/Onc Updates

FDA Approves TAR-200 Monotherapy: A Novel Bladder-Sparing Strategy in BCG-Unresponsive High-Risk NMIBC

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SUMMARY: The FDA on September 9, 2025, approved Gemcitabine intravesical system (INLEXZO®) for adults with Bacillus Calmette-Guérin (BCG)-unresponsive Non-Muscle Invasive Bladder Cancer (NMIBC) with Carcinoma in Situ (CIS), with or without papillary tumors. Gemcitabine intravesical system is co-packaged with a urinary catheter and stylet, used for insertion through the urinary catheter into the bladder.

Background

According to the American Cancer Society, it is estimated that 84,870 new cases of bladder cancer will be diagnosed in 2025 and 17,420 will die of the disease. Bladder cancer is the fourth most common cancer in men but is less common in women and the average age at the time of diagnosis is 73 years. With regards to racial predisposition, Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Approximately 50% of all bladder cancers are non-invasive or in situ cancers. The current standard intervention for superficial bladder cancers-Non-Muscle Invasive Bladder Cancer (NMIBC) involves removing the bladder tumor and intravesical treatment with Bacillus Calmette-Guérin (BCG) immunotherapy, for patients with high-risk Non-Muscle Invasive Bladder Cancer, including those with Carcinoma in Situ, High Grade T1, or large-volume or recurrent Ta tumors, to reduce the risk of recurrence. Although 80% of patients have an initial complete response to BCG, more than half of patients have recurrence and progression within the first year, and develop resistance to BCG.

FDA-approved therapies for BCG-unresponsive carcinoma in situ (CIS) include systemic Pembrolizumab (KEYTRUDA®), intravesical Nadofaragene firadenovec (ADSTILADRIN®), and intravesical Nogapendekin alfa inbakicept (ANKTIVA®) plus BCG. However, these options are constrained by modest Complete Response (CR) rates, limited response durability, immune-related toxicities, procedural burden from repeated catheterizations, and the need for concurrent BCG in some regimens. Moreover, there are no approved therapies specifically indicated for BCG-unresponsive high-risk papillary disease–only NMIBC, highlighting an urgent unmet need for effective, durable, and tolerable bladder-sparing alternatives.

A Novel Intravesical Approach

TAR-200 is an innovative, miniature, pretzel-shaped intravesical drug delivery system engineered to provide continuous local release of Gemcitabine directly into the bladder. The passive, non-resorbable device is placed via catheter in a brief outpatient procedure, without anesthesia, and remains in situ for three weeks. During that time, it slowly releases 225 mg of Gemcitabine before being removed through cystoscopy. This sustained, controlled drug exposure overcomes the short dwell time limitations of conventional intravesical chemotherapy and may enhance local tumor control with reduced systemic exposure.

The SunRISe-1 Trial Design

SunRISe-1 (NCT04640623) is a global, Phase IIb, parallel-cohort study designed to evaluate TAR-200 monotherapy and TAR-200 plus Cetrelimab (an anti–PD-1 antibody) in patients with BCG-unresponsive high-risk NMIBC. Between March 2021 and April 2024, patients were enrolled at 142 sites across 14 countries.

Initially, three cohorts were planned:

  • Cohort 1: TAR-200 plus Cetrelimab
  • Cohort 2: TAR-200 monotherapy
  • Cohort 3: Cetrelimab monotherapy

Based on emerging safety and efficacy data, the protocol was amended in June 2023 to prioritize TAR-200 monotherapy for CIS populations and to expand enrollment in this arm. A fourth cohort was subsequently added to evaluate TAR-200 monotherapy in patients with high-risk papillary disease-only NMIBC, an area with no approved therapies.

Efficacy and Safety Outcomes

The FDA approval of TAR-200 (INLEXZO®) was supported by data from Cohort 2, which included 85 patients with BCG-unresponsive CIS with or without papillary tumors. Eligible patients had histologically confirmed high-grade disease following adequate BCG exposure and an ECOG performance status of 0–2. The median patient age was 71 years, 80% were male, and two-thirds presented with CIS alone. Patients received TAR-200 once every 3 weeks for 6 months, followed by maintenance dosing every 12 weeks through month 24. Tumor assessments were performed via cystoscopy and cytology every 12 weeks, with mandatory biopsies at weeks 24 and 48.

At the data cutoff (March 31, 2025), the overall CR rate was 82.4%, representing the highest single-agent response rate reported in this disease setting. The median Duration of Response (DOR) reached 25.8 months, with estimated 12-month CR and DOR rates of 57.4% and 65.7%, respectively. Median follow-up among responders was 9.2 months.

Treatment was well tolerated, with most adverse events localized and manageable. The most frequent treatment-related events (≥10%) were pollakiuria (35%), dysuria (29%), urinary urgency (15%), and urinary tract infection (15%), consistent with localized bladder irritation rather than systemic toxicity.

Clinical Implications

The results from SunRISe-1 mark a pivotal advance in the management of BCG-unresponsive NMIBC. TAR-200 monotherapy demonstrated durable, high-level intravesical activity without the need for re-induction or systemic immune checkpoint inhibition. Its favorable risk-benefit profile, coupled with the logistical simplicity of outpatient placement, positions TAR-200 as a transformative bladder-sparing therapy for patients ineligible or unwilling to undergo cystectomy.

Unlike conventional intravesical treatments requiring patients to retain fluid instillations for 1–2 hours before voiding, TAR-200 provides continuous, controlled Gemcitabine release over weeks, fundamentally shifting the procedural and pharmacologic paradigm of NMIBC care in the urology clinic.

Conclusion

SunRISe-1 establishes TAR-200 monotherapy (INLEXZO®) as the first intravesical drug-releasing system with proven efficacy and safety in localized bladder cancer. With an 82% CR rate and durable responses extending beyond two years, TAR-200 represents a significant step forward in meeting the long-standing need for effective, tolerable, and durable bladder-sparing therapy in patients with BCG-unresponsive high-risk NMIBC.

TAR-200 for Bacillus Calmette-Guérin–Unresponsive High-Risk Non–Muscle-Invasive Bladder Cancer: Results From the Phase IIb SunRISe-1 Study. Daneshmand S, Van der Heijden MS, Jacob JM, et al. Journal of Clinical Oncology. https://doi.org/10.1200/JCO-25-01651

Maintaining Physician Preference in CLL Care and Its Impact on Outcomes

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Written by: M. Yair Levy, MD
Sponsored by: BeOne Medicines

Chronic lymphocytic leukemia (CLL) is a heterogeneous disease that has seen a remarkable treatment evolution over the past decade. Approximately one-third of CLL patients will not require treatment, with clinical observation remaining the standard for asymptomatic patients.1 For CLL patients requiring treatment, historical regimens have been limited to cytotoxic chemotherapy, administered alone or in combination with anti-CD20 immunotherapy.2 In 2016, two classes of targeted therapies entered the CLL marketplace. Most notably among these are inhibitors of the anti-apoptotic protein B-cell lymphoma 2 (Bcl2), and the B-cell proliferative regulator Bruton’s tyrosine kinase (BTK).2 Introduction of first-generation covalent BTK inhibitors (cBTKis) was followed by second-generation, as well as non-covalent BTKis.2 The rapid expansion of targeted therapies over the last decade has profoundly impacted the clinical management of CLL.

The multitude of therapeutic options in today’s CLL treatment landscape, which often includes several drugs in a single class, provides oncologists the unprecedented opportunity to weigh the entire clinical picture for each patient, and personalize their treatment strategy accordingly. Clinicians leverage decades of medical training to gauge pharmacokinetic and pharmacodynamic differences between therapies, weighing drug-specific efficacy, tolerability and safety for each patient. There is also concurrent influence from reputable medical bodies, such as NCCN guidelines and FDA approved treatments. Most importantly, every CLL patient and their disease are unique. It is imperative to protect physicians’ decision-making freedom to the degree that it permits individualized treatment approaches and the prescription of specific therapies, without undue external influence.

Step therapy is a growing utilization management strategy among health plan Pharmacy Benefit Managers (PBMs) that threatens physician autonomy. As its colloquial name “fail-first” implies, step therapy is a cost-saving approach that requires a patient to have tried, and failed, alternative drug(s), before the PBM will cover the originally prescribed drug.3 Step therapies transfer the onus of decision-making from the treating physician to a commercial entity, robbing the clinician of their ability to personalize care and maximize patient outcomes. This leads to worsening provider burnout, depersonalization, and exacerbates oncology physician shortages. Step therapies also place additional burden on clinical support staff and negatively impact CLL patient outcomes.

PBM-mandated BTKi coverage is a common scenario that exemplifies how step therapy negatively impacts CLL patient outcomes. In my clinical experience, PBMs have required frontline use of the first-generation BTKi ibrutinib. Ibrutinib is an efficacious drug that has revolutionized CLL treatment, but it is poorly tolerated, as compared with 2nd generation BTKis, which directly contributes to decreased treatment compliance and impacts patient outcomes. Ibrutinib also carries the risk of adverse cardiologic events, including atrial arrythmias, ventricular arrhythmias and sudden death.4 As a provider who has lost a patient due to this adverse event, it’s imperative that safety risks of specific drugs are weighed by an experienced clinician on a case-to-case basis. Furthermore, there is an urgent need for step therapy reform that considers clinical data in determining drug coverage. In the case of BTKi coverage, there is clinical evidence demonstrating a lower risk of adverse cardiologic events with use of second-generation BTKi agents.4 As cancer patient advocates, oncologists must continue to push back against step therapies that infringe on patient safety and well-being, and may adversely affect outcomes.

As oncology drugs continue to enter the ever-changing healthcare marketplace, it’s increasingly critical that physicians communicate the importance of preserving autonomy to PBMs and other decision-making parties. There is potential for other drug pricing provisions, such as those included in the 2022 Inflation Reduction Act (IRA),5 to impact CLL patient outcomes in a manner similar to that which is seen with PBM-mediated step therapy. Under the IRA, the government may select certain medications for which it will cap the cost of for Medicare recipients.5 While designed to reduce patient financial burden, provisions of the IRA, such as the ability to target costs of small molecules (like BTKis) years before other drug types, may have harmful effects on oncology treatment.5 This risks physicians being forced to utilize certain medications for which cost setting has been established, similar to step therapy, and has already been shown to disincentivize the development of small molecule drugs since the IRA was enacted.5 Given that CLL primarily affects elderly populations,2 drug pricing provisions affecting Medicare could impact CLL prescribing patterns, and there is precedent to surmise that commercial payers may adopt similar strategies of government-sponsored programs.

In diseases like CLL where therapeutic nuances matter, restricting access to preferred agents can have profound consequences. While the extra hours spent justifying what seems like every clinical decision, completing paperwork, appealing denials, and engaging in peer-to-peer calls may feel like “death by a thousand paper cuts”, oncologists have the responsibility as patient advocates to do no harm. We must continue to advocate for policies that prioritize patient outcomes over cost-driven algorithms, and ensure that clinical decision-making remains in the hands of those best equipped to make it: the treating physicians.

References:

  1. Shadman M. Diagnosis and Treatment of Chronic Lymphocytic Leukemia: A Review. JAMA. 2023;329(11):918-932. doi:10.1001/jama.2023.1946.
  2. Sekeres S, Lamkin EN, Bravo E Jr, Cool A, Taylor J. Resistance Mutations in CLL: Genetic Mechanisms Shaping the Future of Targeted Therapy. Genes (Basel). 2025;16(9):1064. Published 2025 Sep 10. doi:10.3390/genes16091064.
  3. Royce TJ, Schenkel C, Kirkwood K, Levit L, Levit K, Kircher S. Impact of Pharmacy Benefit Managers on Oncology Practices and Patients. JCO Oncol Pract. 2020;16(5):276-284. doi:10.1200/JOP.19.00606.
  4. Moslehi JJ, Furman RR, Tam CS, et al. Cardiovascular events reported in patients with B-cell malignancies treated with zanubrutinib. Blood Adv. 2024;8(10):2478-2490. doi:10.1182/bloodadvances.2023011641.
  5. The Inflation Reduction Act and Medicare Drug Price “Negotiation”. Pharmaceutical Research and Manufacturers of America (PhRMA) website. https://phrma.org/policy-issues/government-price-setting/inflation-reduction-act. Accessed October 1, 2025.

Polygenic Risk Scores Predict Future Breast Cancer Events After In Situ Disease

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Preinvasive breast lesions such as Ductal Carcinoma In Situ (DCIS) and Lobular Carcinoma In Situ (LCIS) are well recognized precursors to invasive disease, yet clinicians currently lack precise tools to predict which patients will ultimately progress. Identifying individuals at highest risk is essential for guiding management, balancing the benefits of early intervention against the harms of overtreatment.

Epidemiologic data suggest that approximately 20–40% of untreated DCIS lesions eventually evolve into invasive breast cancer, while women diagnosed with LCIS have a 7–12-fold higher risk of developing invasive malignancy in either breast over time. Both entities also confer elevated risk for contralateral breast cancer. In this context, genomic risk stratification offers an opportunity to personalize surveillance and preventive strategies.

Understanding PRS313

The 313-SNP breast cancer Polygenic Risk Score (PRS313) quantifies an individual’s inherited susceptibility to breast cancer by integrating the effects of 313 Single Nucleotide Polymorphisms (SNPs) known to influence disease risk. Each variant contributes modestly on its own, but together they generate a composite score that captures the polygenic architecture of breast cancer predisposition.

Using DNA derived from blood or saliva, PRS313 calculates a weighted sum of risk alleles to estimate lifetime breast cancer risk. This score can stratify women into distinct risk quartiles, offering refined insight beyond traditional factors such as family history, breast density, and age. Importantly, PRS313 has been validated in population studies as a predictor of primary breast cancer risk. Recent research now explores its ability to forecast subsequent disease after an initial diagnosis of in situ carcinoma.

Study Overview

Investigators from the ICICLE (Investigate the genetiCs of In situ Carcinoma of the ductaL subtypE) and GLACIER (Genetics of LobulAr Carcinoma In situ in EuRope) studies conducted a retrospective analysis to evaluate whether PRS313 could predict subsequent breast cancer events following DCIS or LCIS.

The study included 2,169 women with DCIS and 185 with LCIS, each followed for a median of 11 years. Cox regression models assessed associations between PRS313 and several outcomes: any subsequent in situ or invasive breast cancer (including distant metastasis), ipsilateral breast disease, invasive ipsilateral disease, and contralateral breast cancer. For DCIS, results were analyzed by PRS313 quartiles; for LCIS, risk was modeled as a continuous variable.

Key Findings

Analysis revealed a significant association between increasing PRS313 and contralateral breast cancer after DCIS (hazard ratio [HR], 1.30; 95% CI, 1.08–1.56). Women in the highest PRS313 quartile were roughly twice as likely to develop contralateral disease compared with those in the lowest quartile. However, PRS313 was not significantly associated with ipsilateral recurrence in DCIS.

In contrast, among women with LCIS, higher PRS313 correlated strongly with ipsilateral breast cancer risk (HR, 2.16; 95% CI, 1.22–3.81). The association was even more pronounced among participants with a family history of breast cancer, where PRS313 increases translated to more than a threefold elevation in ipsilateral disease risk, rising to nearly fourfold when women who had undergone mastectomy or radiotherapy were excluded.

Lead investigator comments emphasized that while LCIS is often managed conservatively, these findings suggest that patients with a strong family history and high PRS313 may derive benefit from additional risk-reducing interventions, such as endocrine therapy or intensified surveillance.

Clinical Implications

This study provides compelling evidence that polygenic risk assessment can refine prognostication in women with in situ breast cancer, distinguishing those most likely to develop future disease. The results support integrating PRS313 into post-diagnosis risk discussions to help patients make informed decisions regarding surgery, chemoprevention, and long-term follow-up intensity.

“By combining genomic data with clinicopathologic features,” the authors noted, “clinicians can deliver more individualized care, moving beyond histologic appearance, to a truly personalized estimate of recurrence risk.”

Study Limitations

The researchers acknowledged several limitations. PRS313 was originally designed to predict invasive breast cancer risk rather than in situ disease specifically, and relevant genetic variants unique to DCIS or LCIS may remain undiscovered. Additionally, the relatively small LCIS cohort limited statistical power and generalizability across ancestries. Ongoing validation in larger and more diverse populations will be necessary before broad clinical implementation.

Conclusion

The ICICLE and GLACIER analyses underscore the potential of PRS313 as a predictive biomarker for future breast cancer events, particularly contralateral disease after DCIS and ipsilateral disease after LCIS. Incorporating polygenic risk profiling into the management of in situ breast lesions could help identify patients who warrant closer monitoring or preventive therapy, while sparing others from unnecessary intervention.

As genomic medicine advances, tools like PRS313 may become integral to personalized breast cancer prevention and survivorship care, aligning treatment intensity with each woman’s unique genetic risk landscape.

Breast Cancer Polygenic Risk Score Associated with Outcomes after In Situ Breast Disease. Timbres J, Kohut K, Mavaddat N, et al. Cancer Epidemiol Biomarkers Prev OF1–OF10. https://doi.org/10.1158/1055-9965.EPI-25-0529. Published: 01 October 2025.

 

FDA Approves LIBTAYO® for Adjuvant Treatment of Cutaneous Squamous Cell Carcinoma

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SUMMARY: The FDA on October 8, 2025 approved Cemiplimab-rwlc (LIBTAYO®) for the adjuvant treatment of adults with Cutaneous Squamous Cell Carcinoma (CSCC) at high risk of recurrence after surgery and radiation.

Cutaneous Squamous Cell Carcinoma (CSCC) is the second most common skin cancer worldwide, with an estimated 2.4 million new cases annually. While surgery with or without adjuvant radiotherapy achieves cure in the vast majority of patients, approximately 5% experience locoregional or distant recurrence. Patients with high-risk features, such as nodal involvement, perineural invasion, or locally recurrent disease, remain particularly vulnerable to relapse following definitive local therapy.

Previous efforts to improve outcomes through systemic adjuvant approaches have been largely unsuccessful. Notably, the POST/TROG 05.01 trial demonstrated no additional benefit of adjuvant Carboplatin-based chemoradiation over radiotherapy alone, underscoring the unmet need for effective systemic adjuvant strategies in this population.

Trial Design

The C-POST (NCT03969004) is an ongoing, international, randomized Phase 3 study evaluating whether adjuvant immunotherapy with Cemiplimab, a PD-1 inhibitor previously approved for advanced and metastatic CSCC, could reduce recurrence risk following surgery and postoperative radiotherapy in patients with high-risk disease. A total of 415 patients were randomized 1:1 to receive Cemiplimab-rwlc or placebo after completing adjuvant radiation therapy (within 2–10 weeks before randomization). Eligible patients had either nodal high-risk features (e.g., extracapsular extension or 3 or more positive nodes) or non-nodal features (e.g., T4 tumors with bone invasion, in-transit metastases, perineural invasion, or locally recurrent tumors with additional risk factors). Cemiplimab was administered intravenously at 350 mg IV every 3 weeks for 12 weeks, then 700 mg every 6 weeks for up to 36 additional weeks (total of 48 weeks or less). The Primary endpoint was Disease-Free Survival (DFS). Secondary endpoints included freedom from locoregional and distant recurrence, Overall Survival (OS), and safety.

Efficacy Results

After a median follow-up of 24 months, Cemiplimab demonstrated a substantial DFS benefit over placebo.

  • Events: 24 with Cemiplimab vs. 65 with placebo
  • Hazard Ratio for disease recurrence or death: 0.32 (95% CI, 0.20–0.51; P<0.001)
  • Estimated 24-month DFS: 87.1% (95% CI, 80.3–91.6) vs. 64.1% (95% CI, 55.9–71.1)

The Kaplan–Meier curves separated early and remained distinctly apart over time, indicating both a rapid and durable treatment benefit.

Patterns of Recurrence

Cemiplimab significantly reduced both locoregional and distant recurrences:

  • Freedom from locoregional recurrence at 24 months: 94.6% vs. 76.7% (HR=0.20; 95% CI, 0.09–0.40)
  • Freedom from distant recurrence at 24 months: 94.3% vs. 83.8% (HR=0.35; 95% CI, 0.17–0.72)

The benefit was observed consistently across prespecified subgroups, including those stratified by PD-L1 tumor expression (<1% or ≥1%).

Safety Profile

Adverse events (AEs) of grade ≥3 occurred in 23.9% of Cemiplimab-treated patients compared with 14.2% in the placebo group. Treatment discontinuation due to AEs occurred in 9.8% versus 1.5%, respectively. The overall safety profile was consistent with known Cemiplimab toxicities, and quality-of-life scores remained largely stable throughout treatment. One treatment-related death was reported.

At the time of analysis, Overall Survival (OS) data were immature, with 25 deaths reported (12 in the Cemiplimab group, 13 in placebo). The 2-year OS was 94.8% vs. 92.3% (HR, 0.86; 95% CI, 0.39–1.90). Subsequent analyses will clarify whether the DFS advantage translates into a survival benefit.

Clinical Implications

The C-POST trial establishes adjuvant Cemiplimab as the first systemic therapy to significantly improve DFS in patients with high-risk CSCC following curative-intent surgery and radiotherapy. The 68% reduction in recurrence or death risk, coupled with a manageable safety profile, positions Cemiplimab as a potential new standard of care for this challenging population.

Notably, most recurrences occurred within the first year after local therapy, mirroring the known natural history of CSCC, and Cemiplimab’s early and sustained benefit suggests a durable immune-mediated effect.

While OS data are pending, these findings mark a major advance in the adjuvant management of high-risk CSCC. The results also stand in contrast to the KEYNOTE-630 trial of adjuvant Pembrolizumab, which was discontinued for futility, highlighting possible differences in trial design or patient selection.

Conclusion

Adjuvant therapy with Cemiplimab significantly prolongs Disease-Free Survival compared with placebo in patients with high-risk Cutaneous Squamous Cell Carcinoma after surgery and radiotherapy. The 24-month DFS benefit, 87% versus 64%, represents a meaningful reduction in recurrence risk and provides clinicians with the first evidence-based systemic option in this setting. Ongoing follow-up will determine the ultimate impact on Overall Survival.

Adjuvant Cemiplimab or Placebo in High-Risk Cutaneous Squamous-Cell Carcinoma. Rischin D, Porceddu S, Day F, et al. for the C-POST Trial Investigators. N Engl J Med 2025;393:774-785

FDA Approves ZEPZELCA® Plus TECENTRIQ® for First-Line Maintenance in Extensive-Stage Small Cell Lung Cancer

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SUMMARY: The FDA on October 2, 2025, approved Lurbinectedin (ZEPZELCA®)  in combination with Atezolizumab (TECENTRIQ®) or Atezolizumab and hyaluronidase-tqjs (TECENTRIQ HYBREZA®), for the maintenance treatment of adult patients with Extensive-Stage Small Cell Lung Cancer (ES-SCLC) whose disease has not progressed after first-line induction therapy with Atezolizumab or Atezolizumab and hyaluronidase-tqjs, Carboplatin, and Etoposide.

The American Cancer Society estimates that for 2025, about 226,650 new cases of lung cancer will be diagnosed and 124,730 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Small Cell Lung Cancer (SCLC) originates from neuroendocrine cells and accounts for approximately 10-15% of all lung cancers diagnosed annually in the US. It is lethal and aggressive. The 5 year survival rate for Extensive Stage SCLC (ES-SCLC) is less than 5%, with a median survival of 9-10 months from the time of diagnosis.

Treatment decisions was SCLC are typically based on the VA Lung Group 2-Staging system, which classifies disease as either Limited Stage (LS) or Extensive Stage (ES). In Limited Stage patients, the disease burden is limited to one hemithorax and regional nodes, without presence of extra-thoracic disease, and amenable to definitive-intent thoracic Radiation Therapy (RT). Extensive Stage encompasses all other SCLC patients.

Patients with ES-SCLC are often treated with chemoimmunotherapy with or without radiation in the first line setting. While initial responses to chemotherapy are often dramatic, relapse occurs in most patients, and recurrent disease typically demonstrates resistance to previously effective regimens. Consequently, extending response durability through maintenance therapy remains a key therapeutic goal.

Lurbinectedin is a selective alkylating agent that binds to guanine residues within DNA, leading to inhibition of oncogenic transcription factors and impairment of DNA repair pathways. This disrupts the cell cycle and induces tumor cell death.
Atezolizumab is a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), blocking its interaction with PD-1 and B7.1 receptors. By inhibiting PD-L1–mediated immune evasion, Atezolizumab restores anti-tumor T-cell activity and enhances immune-mediated tumor elimination.

The IMforte Trial: Study Design

The IMforte Trial is a global, open-label, randomized Phase III study (NCT05091567) conducted to evaluate the efficacy and safety of Lurbinectedin plus Atezolizumab as first-line maintenance therapy for adults with Extensive-Stage SCLC (ES-SCLC). In this study, a total of 660 treatment-naïve patients received induction therapy with Atezolizumab, Carboplatin, and Etoposide for four 21-day cycles. Of these, 483 patients without disease progression were randomized 1:1 to receive either:

  • Lurbinectedin 3.2 mg/m² IV every 3 weeks with G-CSF prophylaxis plus Atezolizumab 1200 mg IV every 3 weeks, or
  • Atezolizumab alone 1200 mg IV every 3 weeks

Treatment was continued until disease progression, unacceptable toxicity, or withdrawal. Stratification factors included baseline liver metastases, ECOG performance status, LDH levels, and receipt of prophylactic cranial irradiation. The Primary endpoints were Independent Review Facility (IRF)–assessed Progression-Free Survival (PFS) and Overall Survival (OS) from the start of maintenance therapy.

Efficacy Outcomes

After a median follow-up of 15 months, the IMforte study achieved both of its Primary endpoints:

  • Median PFS: 5.4 months with Lurbinectedin plus Atezolizumab vs 2.1 months with Atezolizumab alone (HR=0.54; 95% CI: 0.43–0.67; P<0.0001)
  • Median OS: 13.2 months vs 10.6 months, respectively (HR=0.73; 95% CI: 0.57–0.95; P=0.0174)

These outcomes reflect a 46% reduction in the risk of disease progression or death and a 27% reduction in the risk of death with the combination regimen. Median maintenance treatment duration was 4.1 months for the combination arm and 2.1 months for the monotherapy arm.

Safety and Tolerability

The combination of Lurbinectedin and Atezolizumab demonstrated a manageable safety profile with no new safety signals.

  • Any-grade treatment-related adverse events (TRAEs):5% (combo) vs 40.0% (monotherapy)
  • Grade 3–4 TRAEs: 25.6% vs 5.8%
  • Grade 5 TRAEs: 0.8% vs 0.4%

The most common adverse reactions (≥30%) were lymphopenia, thrombocytopenia, anemia, leukopenia, neutropenia, nausea, and fatigue/asthenia. Discontinuations due to adverse events occurred in 6.2% and 3.3% of patients, respectively.

Clinical Interpretation

IMforte is the first global Phase III study to demonstrate significant improvement in both PFS and OS with a first-line maintenance approach in ES-SCLC. By integrating the DNA-damaging activity of Lurbinectedin with the immune reactivation potential of PD-L1 blockade, the combination offers a dual mechanism to counter both tumor proliferation and immune evasion. These results establish Lurbinectedin plus Atezolizumab as a new standard maintenance option for patients whose disease remains controlled after induction chemoimmunotherapy, an important milestone in a disease where long-term survival has historically been rare.

Key Takeaways for Oncology Practice

  • Unmet Need: SCLC remains an aggressive malignancy with limited long-term treatment options.
  • Clinical Significance: IMforte is the first Phase III trial to demonstrate both OS and PFS gains with a first-line maintenance regimen in ES-SCLC.
  • Mechanistic Synergy: Combines DNA-targeted cytotoxic activity (Lurbinectedin) with PD-L1 blockade (Atezolizumab) for enhanced and durable tumor control.
  • Practice Impact: Establishes Lurbinectedin plus Atezolizumab as an FDA-approved maintenance option for patients with ES-SCLC who respond to induction chemoimmunotherapy.
  • Safety: Manageable toxicity profile; regular hematologic and clinical monitoring recommended.

Efficacy and safety of first-line maintenance therapy with lurbinectedin plus atezolizumab in extensive-stage small-cell lung cancer (IMforte): a randomised, multicentre, open-label, phase 3 trial. Paz-Ares L, Borghaei H, Liu SV, et al. The Lancet 2025;405:2129-2143.

Underutilization and Suboptimal Use of Hypomethylating Agents in Myelodysplastic Syndromes: Insights from a National Medicare Analysis

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SUMMARY: It is estimated that in the US approximately 13,000 people are diagnosed with MyeloDysplastic Syndromes (MDS) each year. The prevalence has been estimated to be from 60,000 to 170,000 in the US. MyeloDysplastic Syndromes are a heterogenous group of stem cell disorders characterized by marrow failure resulting in cytopenias, mainly symptomatic anemia, with associated cytogenetic abnormalities, and abnormal cellular maturation with morphologic changes in clonal cells. Majority of the individuals diagnosed with MDS are 65 years or older and die as a result of infection and/or bleeding, consequent to bone marrow failure. About a third of patients with MDS develop Acute Myeloid Leukemia (AML).

The International Prognostic Scoring System (IPSS) for MDS has 4 risk groups based on Total Risk Score (Low, Intermediate-1, Intermediate-2 and High). The three prognostic factors scored to predict the course of the patient’s disease include, percentage of blast cells in the bone marrow, type of chromosomal changes in the marrow cells and number of cytopenias (anemia, neutropenia or thrombocytopenia). Patients with low-risk MDS have an indolent disease course with a median survival of about 6 years with no therapeutic intervention. Patients with intermediate and higher-risk disease however have a shorter median survival even with treatment, with approximately a third of the patients progressing to AML within 3 years.

Patients with Low-risk MDS often present with symptomatic anemia and these patients are in chronic need for RBC transfusions. These patients are treated with Erythropoiesis Stimulating Agents (ESAs) as first line therapy. ESAs such as Darbepoetin alfa and Epoetin alfa are re-engineered and recombinant DNA technology products of Erythropoietin (EPO), and they stimulate erythropoiesis by binding and activating the EPO receptor. However, transfusion-dependent patients with serum EPO levels above 200U per liter are less likely to respond to ESAs. A majority of patients with higher-risk MDS are treated with hypomethylating agents such as Azacitidine and Decitabine and these agents can favorably modify the natural history of the disease, and have been shown to improve survival.

Despite the availability of hypomethylating agents (HMAs) for nearly two decades, survival outcomes for patients with high-risk myelodysplastic syndromes (MDS) in the United States have remained largely unchanged. New population-level data from a large Medicare-based analysis shed light on real-world utilization patterns, revealing substantial underuse and deviations from evidence-based treatment practices that may help explain the persistent gap between clinical trial efficacy and real-world effectiveness.

Clinical Context

For patients with MDS, allogeneic hematopoietic stem cell transplantation remains the only curative approach. However, most individuals are ineligible for transplant because of advanced age, comorbidities, or limited donor availability, underscoring the importance of effective pharmacologic therapies. Azacitidine and Decitabine, both FDA-approved HMAs, are the cornerstone of therapy for higher-risk disease. In pivotal trials, Azacitidine improved Overall Survival by approximately 9 months compared with conventional care regimens. Yet, real-world studies have shown little to no improvement in survival outcomes among patients with high-risk MDS over the past two decades.

Study Design and Population

Investigators conducted a retrospective cohort analysis using national Medicare claims data from 2011–2014 to explore factors associated with HMA use in clinical practice. The study identified 49,514 individuals aged ≥65 years diagnosed with incident MDS between 2012 and 2013 (median age 76 years; 53.9% male; 88.4% White). Demographic, clinical, and socioeconomic variables were analyzed to determine predictors of HMA receipt and treatment duration.

Only 16.1% of patients received HMA therapy, despite an estimated 30–40% of newly diagnosed cases representing higher-risk disease for which such therapy is indicated. Of those treated, 73% received Azacitidine, while 27% received Decitabine.

Disparities in HMA Utilization

Multivariable regression analyses revealed striking disparities across age, sex, and race. Compared with patients aged 65–74 years, those aged 75–84 years and ≥85 years had progressively lower odds of receiving HMAs (adjusted odds ratios [aOR], 0.81 and 0.41, respectively). Women were less likely than men to receive treatment (aOR, 0.81), and Black patients were significantly less likely than White patients (aOR, 0.70). These trends suggest potential access barriers, physician bias, or perceived differences in disease risk that may contribute to inequitable care delivery.

Suboptimal Treatment Duration and Adherence

Even among those initiated on therapy, adherence to recommended dosing and duration was poor. Nearly one-third of patients discontinued treatment after a single cycle, and by cycle six, up to half had stopped therapy. Only about half of patients completed the minimum four treatment cycles required to assess efficacy, with even fewer reaching six cycles. Inadequate dosing was also frequent, with 31% of patients failing to complete a full first cycle, and this proportion rose to 40% by the sixth cycle.

These findings stand in sharp contrast to clinical trial protocols, where patients received continuous therapy for at least 4–6 months before response assessment. Premature discontinuation, often due to early cytopenias, perceived lack of benefit, or logistical barriers such as weekend clinic closures, may deprive patients of therapeutic benefit.

Predictors of Shorter Treatment Duration

Factors associated with receipt of fewer than four HMA cycles included treatment with Decitabine (aOR, 0.70), presence of multiple cytopenias (aOR, 0.69), residence in a nursing home (aOR, 0.64), and high frailty scores (aOR, 0.50). These observations highlight how clinical frailty, comorbidity burden, and treatment logistics intersect to affect real-world delivery of care.

Clinical and System-Level Implications

The study underscores two major issues in MDS management: underutilization of effective therapies and nonadherence to evidence-based treatment schedules. Together, these gaps may explain why survival outcomes have not mirrored those seen in pivotal trials. The findings also raise concerns about potential inequities in care, with older, female, and non-White patients less likely to receive HMAs.

Real-world challenges, such as treatment-related cytopenias, patient fatigue, and logistical burdens associated with frequent clinic visits, likely contribute to early discontinuation. Furthermore, variable provider familiarity with MDS treatment guidelines and limited access to pathologic and genomic expertise in community settings may exacerbate these gaps.

Expert Perspective

As study investigators noted, clinical response to HMAs often requires patience and persistence: “Things tend to get worse before they get better.” Awareness of expected early cytopenias and reassurance that delayed response is typical are essential to avoid premature discontinuation. Provider education and patient counseling can play critical roles in improving adherence to treatment duration recommendations.

The authors also emphasize the potential value of consultation at specialized MDS centers or centers of excellence, even if only once at diagnosis. Such consultations can facilitate individualized treatment planning, ensure proper risk stratification, and enable shared-care models with community oncologists, approaches that have been associated with improved outcomes in rare hematologic malignancies.

Conclusion

This large, population-based study exposes significant real-world deficiencies in the use of hypomethylating agents for MDS, both in treatment initiation and duration. Despite clear clinical guidelines and two decades of experience with these agents, underuse, early discontinuation, and inequities in care persist. Strengthening adherence to guideline-based therapy, expanding access to specialized expertise, and addressing system-level barriers may help realize the survival benefits long demonstrated in clinical trials.

Key Takeaways

  • Underuse of HMAs: Only 16% of older adults with MDS received hypomethylating agents, despite 30–40% having high-risk disease warranting treatment.
  • Disparities in Care: Older age, female sex, and Black race were independently associated with lower odds of receiving HMA therapy.
  • Suboptimal Treatment Duration: Nearly half of patients discontinued therapy before completing the minimum 4–6 recommended cycles, often due to early cytopenias or logistical barriers.
  • Practice Implications: Improved adherence to guideline-based therapy, enhanced education for community clinicians, and access to expert consultation at MDS specialty centers could help narrow the survival gap between clinical trials and real-world outcomes.

Disparities in Real-World Treatment Patterns of Hypomethylating Agents Among Patients with Myelodysplastic Syndromes in the US. Mukherjee S, Dong W, Gerds AT, et al. Blood Neoplasia. 2025;doi:10.1016/j.bneo.2025.100156. 

FDA Approval of INLURIYO® for ESR1-Mutated ER-positive, HER2-negative Metastatic Breast Cancer: Insights from EMBER-3

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SUMMARY: The FDA on September 25, 2025, approved Imlunestrant (INLURIYO®), an Estrogen Receptor antagonist, for adults with Estrogen Receptor (ER)-positive, Human Epidermal growth factor Receptor 2 (HER2)-negative, ESR1-mutated advanced or metastatic breast cancer with disease progression following at least one line of endocrine therapy. FDA also approved the Guardant360 CDx assay as a companion diagnostic device to identify patients with breast cancer with ESR1 mutations for treatment with Imlunestrant.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that in the US, approximately 316,950 new cases of female breast cancer will be diagnosed in 2025, and about 42,170 women will die of the disease, largely due to metastatic recurrence.

Approximately 70% of breast tumors express Estrogen Receptors and/or Progesterone Receptors. The most common subtype of metastatic breast cancer is Hormone Receptor-positive (HR-positive), HER2-negative breast cancer (65% of all metastatic breast tumors), and these patients are often treated with anti-estrogen therapy as first line treatment. However, resistance to hormonal therapy occurs in a majority of the patients, with a median Overall Survival (OS) of 36 months. With the development of Cyclin Dependent Kinases (CDK) 4/6 inhibitors, endocrine therapy plus a CDK4/6 inhibitor is the mainstay, for the management of ER+/HER2-negative metastatic breast cancer, as first line therapy. Even with this therapeutic combination, most patients will eventually experience disease progression, with up to 50% of patients acquiring ESR1 (Estrogen Receptor gene alpha) mutations after exposure to prior endocrine therapy in combination with CDK4/6 inhibitors. These mutations enable constitutive activation of the estrogen receptor, rendering tumors less responsive to traditional endocrine agents. Although Selective Estrogen Receptor Degraders (SERDs) such as Fulvestrant are often used in this setting, their clinical activity is modest and limited by pharmacokinetic and mechanistic constraints, especially in heavily pretreated, endocrine-resistant disease.

Imlunestrant: A Next-Generation ER Antagonist
Imlunestrant is an oral selective estrogen receptor antagonist and degrader designed to provide continuous ER inhibition, including in ESR1-mutated cancers. By binding, blocking, and promoting degradation of the receptor, Imlunestrant aims to suppress ER-driven tumor growth beyond the limits of standard endocrine therapy. Further, Imlunestrant crosses the blood-brain barrier.

The EMBER-3 Trial: Pivotal Data Supporting Approval
The efficacy and safety of Imlunestrant were evaluated in the Phase 3 EMBER-3 trial (NCT04975308), an open-label randomized study that enrolled 874 patients with ER-positive, HER2-negative locally advanced or metastatic breast cancer. All participants had received prior treatment with an aromatase inhibitor, either as monotherapy or in combination with a CDK4/6 inhibitor, but were ineligible for PARP inhibitor therapy.

Patients were randomized (1:1:1) to one of three arms:

  • Arm A: Imlunestrant monotherapy 400 mg orally once daily (N=331)
  • Arm B: Investigators choice of Fulvestrant or Exemestane (N=330)
  • Arm C: Imlunestrant plus Abemaciclib (N=213, investigational)

Randomization was stratified by prior CDK4/6 inhibitor exposure, visceral disease status, and geographic region. ESR1 mutation status was determined via ctDNA analysis using the Guardant360 CDx assay, restricted to defined ligand-binding domain mutations.

The FDA approval was specifically based on results in the ESR1-mutated cohort (N=256). In this subgroup, 21% received therapy as first-line treatment for metastatic breast cancer (following recurrence on adjuvant Aromatase Inhibitor-AI) and 79% as second-line treatment (post-progression on AI, with or without prior CDK4/6 inhibitor).

Efficacy Outcomes

  • Primary endpoint (PFS): Median Progression-Free Survival was 5.5 months with Imlunestrant vs. 3.8 months with standard endocrine therapy (HR 0.62; 95% CI: 0.46–0.82; P=0.0008).
  • Objective Response Rate (ORR): 14.3% with Imlunestrant vs. 7.7% with investigator’s choice.
  • Overall Survival (OS): Data remain immature, with 31% of deaths reported at the time of analysis.

These findings demonstrate a statistically and clinically meaningful improvement in PFS for patients with ESR1-mutant disease, a group with limited therapeutic options following resistance to aromatase inhibitors.

Safety Profile
The safety profile of Imlunestrant was consistent with ER-targeting strategies. Common adverse events (≥10%) included hematologic abnormalities (decreased hemoglobin, neutrophils, platelets), musculoskeletal pain, fatigue, gastrointestinal effects (diarrhea, nausea, constipation, abdominal pain), and laboratory changes such as elevated liver enzymes, triglycerides, or cholesterol.

Looking Ahead: Ongoing EMBER Program
Beyond metastatic disease, Imlunestrant is being studied in earlier disease settings. The EMBER-4 trial is enrolling about 8,000 patients worldwide to evaluate Imlunestrant in the adjuvant treatment of ER-positive, HER2-negative early breast cancer, at elevated risk of recurrence. Combination strategies, including Imlunestrant plus Abemaciclib, are also under active investigation to further enhance ER pathway blockade.

Clinical Perspective
The approval of Imlunestran marks an important advance in precision endocrine therapy, particularly for patients with ESR1-mutated metastatic breast cancer, a population historically limited to suboptimal options after progression on aromatase inhibitors. By offering a targeted, oral agent with meaningful PFS benefit, Imlunestran provides oncologists with a new tool to extend disease control in a challenging clinical context.

Imlunestrant with or without Abemaciclib in Advanced Breast Cancer. Jhaveri KL, Neven P, Casalnuovo ML, et al. for the EMBER-3 Study Group. N Engl J Med 2025;392:1189-1202 

MRD-Guided Ibrutinib-Venetoclax Therapy Shows Durable Survival Benefit in CLL: Results from the Phase 3 FLAIR Trial

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SUMMARY: The American Cancer Society estimates that for 2025, about 23,690 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4460 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children. Patients with CLL often receive continuous therapy with either Brutons Tyrosine Kinase (BTK) inhibitors, time limited therapy with BCL2 inhibitor Venetoclax (VENCLEXTA®) given along with anti-CD20 antibody Obinutuzumab, or under certain circumstances, chemoimmunotherapy.

BTK inhibitors approved in the US include first-generation irreversible inhibitor Ibrutinib (IMBRUVICA®), second-generation covalent inhibitors Acalabrutinib (CALQUENCE®) and Zanubrutinib (BRUKINSA®), and the third-generation, reversible (non-covalent) inhibitor Pirtobrutinib (JAYPIRCA®).

Continuous BTK inhibition improves outcomes but is associated with resistance and toxicity over time. Given the complementary mechanisms of action, the combination of Ibrutinib and Venetoclax has been evaluated in multiple trials. Notably, fixed-duration combination therapy improved Progression-Free Survival (PFS) and Overall Survival (OS) compared with chemoimmunotherapy in the GLOW and CAPTIVATE studies, while the CLARITY trial demonstrated the feasibility of Measurable Residual Disease (MRD)-guided therapy in relapsed/refractory CLL.

The Phase 3 FLAIR trial expands this investigation in previously untreated CLL patients, testing whether MRD-guided Ibrutinib–Venetoclax can improve long-term outcomes compared with Ibrutinib alone or Fludarabine, Cyclophosphamide and Rituximab combination (FCR).

Trial Design

  • Population: Patients with previously untreated CLL.
  • Randomization (1:1:1):
    • Ibrutinib–Venetoclax (N=260)
    • Ibrutinib monotherapy (N=263)
    • FCR (N=263)
  • Treatment Regimens:
    • FCR: Six 28-day cycles of Fludarabine, Cyclophosphamide, and Rituximab.
    • Ibrutinib monotherapy: 420 mg orally daily, up to 6 years.
    • Ibrutinib–Venetoclax: Eight-week Ibrutinib lead-in followed by Venetoclax ramp-up to 400 mg daily. Treatment duration (2–6 years) was MRD-guided, with discontinuation allowed after sustained MRD negativity.
  • Primary endpoints:
    • Undetectable MRD in bone marrow within 2 years (Ibrutinib–Venetoclax vs single agent Ibrutinib).
    • PFS (Ibrutinib–Venetoclax vs FCR).
  • Secondary endpoints: PFS (Ibrutinib–Venetoclax vs Ibrutinib alone), OS, and safety.

Key Results

With a median follow-up of 62.2 months, the findings strongly favored the Ibrutinib–Venetoclax combination arm:

  • MRD Negativity (Bone Marrow, ≤2 years):
    • 66.2% with Ibrutinib–Venetoclax combination vs 0% with Ibrutinib alone (P<0.001)
    • 48.3% with FCR
  • Progression-Free Survival (5 years):
    • 93.9% (Ibrutinib–Venetoclax) vs 79.0% with Ibrutinib alone and 58.1% with FCR
      • HR for progression or death = 0.29 (Ibrutinib–Venetoclax vs single agent Ibrutinib, P<0.001), and 0.13 (Ibrutinib–Venetoclax vs FCR, P<0.001)
  • Estimated Overall Survival (5 years):
    • 95.9% (Ibrutinib–Venetoclax) vs 90.5% with Ibrutinib alone and 86.5% with FCR
      • HR for death: 0.41 (Ibrutinib–Venetoclax vs Ibrutinib), and 0.26 (Ibrutinib–Venetoclax vs FCR)
  • IGHV Subgroup Analysis:
    • Unmutated IGHV: Strongest OS benefit with Ibrutinib–Venetoclax compared to Ibrutinib alone (HR for death = 0.30), and compared to FCR (HR for death = 0.16). The Ibrutinib alone group and the FCR group had similar results for OS.
    • Mutated IGHV: Overall Survival outcomes were similar between Ibrutinib–Venetoclax and Ibrutinib alone.
  • Treatment Exposure:
    Median duration of Ibrutinib–Venetoclax was 35 months. The percentage of patients with undetectable MRD in peripheral blood at 2 years was 73.1% in the Ibrutinib–Venetoclax group, 0% in the Ibrutinib-alone group, and 60.8% in the FCR group. The median time to the first occurrence of undetectable MRD in peripheral blood was 13.0 months in the Ibrutinib–Venetoclax group, and was 8.9 months in the FCR group.
  • Safety:
    No new safety signals were reported. Atrial fibrillation and hypertension were more frequent in Ibrutinib-containing arms than FCR, but were manageable with cardiovascular risk optimization. Rates of sudden death were low and similar across groups.

Clinical Implications

The FLAIR trial reinforces MRD-guided Ibrutinib–Venetoclax as a highly effective strategy for previously untreated CLL, achieving durable disease control and survival benefits beyond both continuous BTK inhibitor monotherapy and FCR.

Key takeaways for practice:

  • Deep remissions: Two-thirds of patients achieved bone marrow MRD negativity with Ibrutinib–Venetoclax combination, within 2 years, a strong surrogate for long-term disease control.
  • Superior survival: The 5-year PFS and OS rates with Ibrutinib–Venetoclax combination therapy exceed historical outcomes with continuous BTK inhibition or fixed-duration Venetoclax regimens.
  • IGHV status matters: Patients with unmutated IGHV appear to derive the greatest benefit, whereas outcomes are more similar across strategies in mutated IGHV.
  • Individualized therapy feasible: MRD-guided discontinuation allowed many patients to stop treatment early, balancing efficacy with reduced exposure.

While questions remain regarding optimal duration, cost-effectiveness, and the logistics of real-time MRD monitoring, FLAIR provides compelling evidence that tailored combination therapy could redefine first-line management of CLL, particularly for patients with unmutated IGHV.

Measurable Residual Disease–Guided Therapy for Chronic Lymphocytic Leukemia. Munir T,  Girvan S,  Cairns DA, et al. for the UK CLL Trials Group. N Engl J Med 2025;393:1177-1190

FDA Approves First Subcutaneous Formulation of KEYTRUDA®: KEYTRUDA QLEX®

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SUMMARY: The FDA on September 19, 2025 approved Pembrolizumab and berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) for subcutaneous injection for adult and pediatric (12 years and older) solid tumor indications, approved for the intravenous formulation of Pembrolizumab (KEYTRUDA®).

KEYTRUDA® is a fully humanized, Immunoglobulin G4, monoclonal antibody and checkpoint inhibitor, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells.

KEYTRUDA QLEX® is a fixed-dose combination of Pembrolizumab and Berahyaluronidase alfa, a recombinant variant of human hyaluronidase that enhances drug dispersion and absorption to enable subcutaneous delivery.

Clinical Evidence Supporting Approval

The regulatory decision was based on results from the MK-3475A-D77 trial (NCT05722015), a randomized, open-label, multicenter Phase 3 study in treatment-naïve metastatic Non–Small Cell Lung Cancer (NSCLC) without EGFR, ALK, or ROS1 alterations.

  • Design: 377 patients were randomized 2:1 to receive either subcutaneous KEYTRUDA QLEX® (790 mg/9,600 units) plus platinum doublet chemotherapy every six weeks (N=251) or KEYTRUDA® 400 mg IV plus platinum doublet chemotherapy every six weeks (N=126).
  • Primary Objective: Pharmacokinetic (PK) comparability, with dual endpoints of Cycle 1 AUC 0-6 weeks and Cycle 3 steady-state trough concentration (C trough).
  • Descriptive Outcomes: Objective Response Rate (ORR), Progression-Free Survival (PFS), and Overall Survival (OS) assessed by Blinded Independent Central Review (BICR).

Key findings:

  • The PK exposure of subcutaneous KEYTRUDA QLEX® met predefined comparability criteria, with geometric mean ratios exceeding the prespecified threshold of 0.8.
  • Confirmed ORR was 45.4% with KEYTRUDA QLEX® versus 42.1% with IV KEYTRUDA® (ORR ratio 1.08, 95% CI 0.85-1.37)
  • No clinically meaningful differences were observed in PFS or OS between the two treatment groups.
  • Safety profile was consistent with IV KEYTRUDA®. The most common adverse reactions (≥20%) with KEYTRUDA QLEX® plus chemotherapy included nausea (25%), fatigue (25%), and musculoskeletal pain (21%).

Clinical and Practical Implications

While the pivotal data were generated in NSCLC, the FDA approval extends to all solid tumor indications where KEYTRUDA® is currently approved, offering oncologists a new delivery option across a broad spectrum of cancers.

The subcutaneous formulation provides substantial administration advantages:

  • Time savings: injection takes ~1–2 minutes versus ~30 minutes for IV infusion.
  • Patient convenience: fewer logistical barriers, particularly relevant for patients requiring long-term therapy.
  • System efficiency: reduced chair time and preparation burden for healthcare providers.

The approved dosing schedules are:

  • KEYTRUDA QLEX® 395 mg/4,800 units SQ every 3 weeks, or
  • KEYTRUDA QLEX® 790 mg/9,600 units SQ every 6 weeks,
    continued until disease progression, unacceptable toxicity, or as otherwise specified in the prescribing information.

Takeaway for Practice

The approval of KEYTRUDA QLEX® represents an important advancement in immuno-oncology care delivery. By maintaining clinical efficacy and safety while significantly streamlining treatment administration, this new formulation has the potential to improve both the patient experience and healthcare system efficiency. For busy oncology practices, it provides a practical alternative to infusion without compromising the therapeutic benefits of KEYTRUDA®.

Subcutaneous versus intravenous pembrolizumab, in combination with chemotherapy, for treatment of metastatic non-small-cell lung cancer: the phase III 3475A-D77 trial. Felip E, Rojas CI, Schenker M, et al. Ann Oncol. 2025;36:775-785.

De-escalated Adjuvant Radiotherapy Demonstrates Reduced Long-Term Toxicity in HPV-Associated Oropharyngeal Cancer

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SUMMARY: The American Cancer Society estimates that about 59,660 new cases of oral cavity and pharynx cancer will be diagnosed in the US in 2025 and about 12,770 patients will die of the disease. According to the CDC, about 46,711 Human PapillomaVirus (HPV)-associated cancers occur in the United States each year (25,689 among women, and 21,022 among men). Cervical cancer is the most common HPV-associated cancer among women, and Oropharyngeal cancers are the most common among men. There has been a significant increase in the incidence during the past several decades, due to changes in sexual practices.

HPV-positive Oropharyngeal Squamous Cell Carcinoma (OPSCC) is an entirely distinct disease entity from HPV-negative OPSCC. Patients with HPV-positive OPSCC tend to be younger males, who are former smokers or nonsmokers, with risk factors for exposure to High Risk HPV. The HPV-positive primary Squamous Cell Carcinoma tend to be smaller in size, with early nodal metastases, and these patients have a better prognosis compared with patients with HPV-negative Head and Neck Squamous Cell Carcinoma (HNSCC) when treated similarly. Expression of tumor suppressor protein, known as p16, is highly correlated with infection with HPV in HNSCC. Accurate HPV assessment in Head and Neck cancers is becoming important as it significantly impacts clinical management. HPV status is considered the most important prognostic indicator in patients with Head and Neck cancer, and p16 status is now included in the American Joint Committee on Cancer (AJCC) Staging System.

HPV-positive OPSCC is more sensitive to chemotherapy and radiotherapy than is HPV-negative OPSCC, which translates to a much better prognosis and survival, when treated with a combination of platinum based chemotherapy and radiotherapy. This treatment however can be associated with substantial morbidity and lifelong toxicities such as dry mouth, difficulty swallowing, and loss of taste. These tumors, typically being more responsive to therapy than their non-HPV counterparts, appear to benefit from reduced radiation doses, potentially minimizing the severe toxicities linked with conventional radiotherapy, without compromising oncologic outcomes.

Adjuvant chemoradiotherapy has been a mainstay of treatment for patients with surgically resected HPV-positive OPSCC, offering excellent oncologic control. However, standard radiotherapy regimens, typically 60-66 Gy with concurrent chemotherapy, are associated with substantial treatment-related morbidity, particularly long-term dysphagia and feeding tube dependence. With the rising incidence of HPV-driven OPSCC in younger patients with favorable prognoses, interest has grown in identifying de-escalated approaches that maintain efficacy while reducing toxicity.

Trial Overview
The MC1675 Phase III trial (NCT02908477), conducted at two Mayo Clinic sites, directly compared a de-intensified adjuvant regimen against the conventional standard of care. Eligible participants were adults with resected, pathologic Stage III–IV HPV-associated OPSCC (≥70% p16 expression) and at least one intermediate-risk pathological feature. Patients had an ECOG performance status of 0-1 and were stratified by extranodal extension and smoking history.

A total of 194 patients were randomized 2:1 to receive either:

  • De-escalated regimen (DART): 30-36 Gy delivered in 1.5-1.8 Gy twice-daily fractions over 2 weeks, with Docetaxel 15 mg/m² IV on days 1 and 8.
  • Standard of care (SOC): 60 Gy delivered in 2 Gy daily fractions over 6 weeks, with concurrent weekly IV Cisplatin at 40 mg/m².

The Primary endpoint was the cumulative incidence of chronic grade ≥3 toxicity between 3 and 24 months post-treatment.

Key Findings
With a median follow-up of 37.3 months, the trial confirmed that de-escalated adjuvant therapy significantly reduced late high-grade toxicities:

  • Cumulative grade ≥3 toxicity: 3% with DART vs 11% with SOC (P=0.042).
  • Feeding tube dependence: 2% with DART vs 8% with SOC (p=0.039).
  • Most frequent toxicities: Dysphagia (2%) and esophagitis (1%) in the DART arm vs dysphagia (8%), fatigue (2%), pain (2%), and osteonecrosis of the jaw (2%) in the SOC arm.

Importantly, no new unexpected safety signals emerged, and the reduction in morbidity was consistent across subgroups.

Clinical Implications
These findings add to the growing body of evidence that de-intensification strategies can safely reduce long-term treatment burden for patients with HPV-associated OPSCC, a population with excellent baseline prognosis. The DART approach, using half the standard radiation dose combined with Docetaxel, achieved meaningful reductions in swallowing dysfunction and PEG tube dependence, two of the most disabling toxicities after chemoradiation.

While efficacy outcomes were not the primary endpoint, the trial’s results suggest that oncologic control can be preserved even with substantially lower radiation exposure, provided patient selection is stringent. Longer follow-up and confirmatory studies will be critical to define which subsets of patients may benefit most, and whether this regimen could shift practice standards for intermediate-risk HPV-positive disease.

Looking Ahead
The MC1675 trial underscores a pivotal movement in head and neck oncology, tailoring therapy intensity to disease biology and patient risk, rather than applying a uniform high-intensity standard. For the increasing number of younger patients facing decades of survivorship, approaches like DART may offer durable disease control with far less long-term morbidity. Ongoing research will clarify whether such regimens could become a new benchmark for adjuvant treatment in this favorable-risk population.

De-escalated adjuvant radiotherapy versus standard adjuvant treatment for human papillomavirus-associated oropharyngeal squamous cell carcinoma (MC1675): a phase 3, open-label, randomised controlled trial. Ma D, Price K, Moore E, et al. The Lancet Oncology. 2025;26:1227-1239