Category: Immuno Oncology

FDA Approves KEYTRUDA® with Paclitaxel for Platinum-Resistant Epithelial Ovarian, Fallopian tube, or Primary Peritoneal Carcinoma

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SUMMARY: The FDA on February 10, 2026, approved Pembrolizumab (KEYTRUDA®) as well as Pembrolizumab and Berahyaluronidase alfa-pmph (KEYTRUDA QLEX®) in combination with Paclitaxel, with or without Bevacizumab (AVASTIN®), for adult patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) as determined by an FDA-authorized test, and who have received one or two prior systemic treatment regimens. The FDA also approved the PD-L1 IHC 22C3 pharmDx as a companion diagnostic device to identify patients with epithelial ovarian, fallopian tube, or primary peritoneal carcinoma whose tumors express PD-L1 (CPS≥1) for treatment with Pembrolizumab.

It is estimated that in the United States, approximately 21,010 women will be diagnosed with ovarian cancer in 2026 and 12,450 women will die of the disease. Ovarian cancer ranks fifth in cancer deaths among women. It accounts for more deaths than any other cancer of the female reproductive system. Approximately 75% of the ovarian cancer patients are diagnosed with advanced disease. Approximately 85% of all ovarian cancers are epithelial in origin, and approximately 70% of all epithelial ovarian cancers are High-Grade Serous adenocarcinomas. Patients with newly diagnosed advanced ovarian cancer are often treated with platinum-based chemotherapy following primary surgical cytoreduction. Approximately 70% of these patients will relapse within the subsequent 3 years and are incurable, with a 5-year Overall Survival rate of about 20-30%.

Platinum-resistant recurrent ovarian cancer therefore remains a significant therapeutic challenge, with historically limited options and modest improvements in survival. Previous studies, such as the Phase III AURELIA trial, established weekly Paclitaxel with Bevacizumab as an effective chemotherapy regimen. The potential for chemotherapy to enhance antitumor immune responses provided the rationale for combining Pembrolizumab, an anti–PD-1 antibody, with Paclitaxel, with or without Bevacizumab, in this patient population.

Trial Design

The ENGOT-ov65/KEYNOTE-B96 trial (NCT05116189) was a multicenter, randomized, double-blind, placebo-controlled Phase III study that enrolled 643 patients with platinum-resistant epithelial ovarian, fallopian tube, or primary peritoneal carcinoma. Eligible patients had received one to two prior systemic therapies, including at least one platinum-based regimen, and had evidence of disease progression within six months after platinum therapy. Patients with primary platinum-refractory disease were excluded.

Participants were randomized 1:1 to receive Pembrolizumab 400 mg every six weeks or placebo, in combination with weekly Paclitaxel 80 mg/m² on days 1, 8, and 15 of each 3-week cycle, with or without Bevacizumab 10 mg/kg every 2 weeks. Prior use of PARP inhibitors, Bevacizumab, or PD-1/PD-L1 agents was allowed. Patients had an ECOG performance status of 0–1, with a median age of 61–62 years and predominance of high-grade serous histology (86%). Approximately one-third of patients had PD-L1 CPS ≥10.

Efficacy Results

The Primary endpoint was Progression-Free Survival (PFS) per RECIST v1.1, with Overall Survival (OS) as a key Secondary endpoint.

  • First interim analysis (median follow-up 15.6 months):
    • Overall population: median PFS 8.3 months with Pembrolizumab vs 6.4 months with placebo (HR 0.70; P<0.0001).
    • PD-L1 CPS ≥1 population: median PFS 8.3 months vs 7.2 months (HR 0.72; P=0.0014).
  • Second interim analysis (median follow-up 26.6 months):
    • PD-L1 CPS ≥1 population: OS improved to 18.2 months with Pembrolizumab vs 14.0 months with placebo (HR 0.76; P=0.0053).
    • Benefits were observed across subgroups, including older patients, prior PARP inhibitor exposure, and short platinum-free interval.
    • Objective Response Rates were higher with Pembrolizumab (53.0% vs 46.6% in PD-L1 CPS ≥1 patients) with longer Duration of Response.

The PFS and OS improvements were consistent regardless of Bevacizumab use, supporting both doublet and triplet strategies in routine practice.

Safety Profile

Pembrolizumab combined with weekly Paclitaxel, with or without Bevacizumab, demonstrated a manageable safety profile. Adverse events were consistent with known toxicities of checkpoint inhibitors and chemotherapy, including immune-mediated events, infusion reactions, and myelosuppression. No unexpected safety signals were reported, confirming the feasibility of this regimen in a platinum-resistant population.

Clinical Implications

KEYNOTE-B96 demonstrates a clinically meaningful improvement in both Progression-Free and Overall Survival, representing one of the longest reported OS durations in platinum-resistant ovarian cancer. The regimen leverages the immune-modulating effects of weekly Paclitaxel and the potential vascular-normalizing and immunosuppressive effects of Bevacizumab, addressing multiple barriers to effective immune activation.

These results support PD-L1 CPS as a predictive biomarker while emphasizing the importance of integrating immunotherapy with established chemotherapy backbones. The findings provide a foundation for sequencing this strategy alongside emerging therapies, including antibody-drug conjugates and other targeted agents, in this difficult-to-treat population.

Conclusion

KEYNOTE-B96 establishes Pembrolizumab plus weekly Paclitaxel, with or without Bevacizumab, as a viable and effective treatment option for patients with platinum-resistant ovarian cancer, delivering meaningful improvements in survival with a manageable safety profile. This trial highlights the potential of immunotherapy combinations in a disease historically considered immunologically “cold” and provides a new evidence-based option in a setting of high unmet need.

Pembrolizumab vs placebo plus weekly paclitaxel ± bevacizumab in platinum-resistant recurrent ovarian cancer: Results from the randomized double-blind phase 3 ENGOT-ov65/KEYNOTE-B96 study. Colombo N, Zsiros E, Sebastianelli A, et al. Presented at: European Society of Medical Oncology Congress 2025; October 17–20, 2025; Berlin, Germany. Abstract LBA3.

Late Breaking Abstract – ASH 2025: Teclistamab Plus Daratumumab Redefines Outcomes in Early Relapsed Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 36,110 new cases will be diagnosed in 2025, and 12,030 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2025 remains an incurable disease.

Relapsed or Refractory Multiple Myeloma (RRMM) remains a complex clinical challenge, even as therapeutic options continue to expand. Progressive immune dysfunction, cumulative treatment toxicity, and repeated relapses often limit the durability of benefit with conventional salvage regimens. Moreover, the increasingly effective frontline landscape has raised the bar for second- and later-line therapy, leaving fewer highly active, well-tolerated options for patients early in relapse.

BCMA-directed therapies have transformed expectations in advanced disease, particularly with CAR-T cell approaches demonstrating deep responses and prolonged disease control. However, manufacturing timelines, resource intensity, and patient fitness requirements limit universal access. Consequently, there is a critical need for off-the-shelf, immunotherapy-based regimens that deliver CAR-T–like efficacy with broader applicability.

Teclistamab (TECVAYLI&reg;), a bispecific T-cell engaging antibody targeting CD3 on T cells and BCMA on myeloma cells, has previously shown meaningful and durable responses in heavily pretreated RRMM. Daratumumab (DARZALEX&reg;), an anti-CD38 monoclonal antibody, remains a foundational therapy across all disease stages, offering both direct antimyeloma activity and immune modulation. Preclinical and clinical observations suggest that Daratumumab-mediated depletion of immunosuppressive cellular subsets enhances T-cell fitness, providing a strong biological rationale for combination with BCMA-directed bispecific antibodies.

The MajesTEC-3 trial was designed to test whether combining Teclistamab with Daratumumab could improve outcomes compared with established Daratumumab-based regimens in patients with earlier-line RRMM.

Study Design and Patient Population

MajesTEC-3 (NCT05083169) is an ongoing, randomized, open-label, Phase 3 trial conducted across 150 centers in 20 countries. Eligible patients had relapsed or refractory multiple myeloma after one to three prior lines of therapy, including prior exposure to both an immunomodulatory agent and a proteasome inhibitor. Patients with prior BCMA-directed therapy or anti-CD38–refractory disease were excluded.

A total of 587 patients were randomized 1:1 to receive either:

  • Teclistamab plus subcutaneous Daratumumab, or
  • Investigator’s choice of standard Daratumumab-based therapy, consisting of Daratumumab and Dexamethasone combined with either Pomalidomide (DPd) or Bortezomib (DVd).

Randomization was stratified by choice of control regimen, International Staging System stage, prior exposure to anti-CD38 antibodies, and number of prior treatment lines. The median patient age was approximately 64–65 years, with a median of two prior lines of therapy. Importantly, more than one-third of enrolled patients had high-risk cytogenetic features, reflecting a clinically relevant population.

Treatment Administration: A Patient-Centered, Steroid-Sparing Approach

Patients in the investigational arm received subcutaneous Teclistamab using a step-up dosing strategy, followed by a progressively extended dosing interval, transitioning to monthly administration from cycle 7 onward. Daratumumab was administered subcutaneously according to its approved schedule.

Notably, the regimen became steroid-free after cycle 1, an important quality-of-life consideration for patients requiring long-term therapy. Infection prophylaxis, immunoglobulin supplementation, and monitoring of IgG levels were mandated, with protocol amendments reinforcing best practices for infection prevention during BCMA-directed therapy. The Primary end point was Progression-Free Survival (PFS), as assessed by an Independent Review Committee.

Primary Endpoint: Striking Improvement in Progression-Free Survival

At a median follow-up of 34.5 months, Teclistamab plus Daratumumab demonstrated a highly significant and clinically transformative improvement in PFS compared with DPd or DVd.

  • The estimated 36-month PFS rate was 83.4% with Teclistamab–Daratumumab versus 29.7% with standard Daratumumab-based therapy.
  • This translated into an 83% reduction in the risk of disease progression or death (HR 0.17; 95% CI, 0.12–0.23; P<0.001).
  • The prespecified boundary for superiority was crossed at the first interim analysis.

Importantly, the PFS advantage was consistent across all prespecified and clinically relevant subgroups, including patients with high-risk cytogenetics and those treated in earlier versus later relapse.

Depth and Durability of Response

Beyond delaying progression, Teclistamab–Daratumumab induced exceptionally deep and durable responses:

  • Complete Response or better was achieved in 81.8% of patients receiving the combination, compared with 32.1% in the control arm.
  • Overall Response Rates were also higher (89.0% vs. 75.3%).
  • Rates of Minimal Residual Disease negativity at a sensitivity of 10⁻⁵ were more than threefold higher with Teclistamab–Daratumumab (58.4% vs. 17.1%).

Responses occurred rapidly, with a median time to first response of just over one month, and deepened over time. At three years, nearly 90% of responders in the investigational arm remained in response, suggesting the emergence of a plateau in disease control.

Overall Survival and Symptom Outcomes

Although follow-up for overall survival continues, early analyses favored Teclistamab–Daratumumab, with a high proportion of patients remaining alive beyond two years. Improvements were also observed in time to worsening of myeloma-related symptoms, underscoring the regimen’s clinical and patient-reported benefit.

Safety and Tolerability: Manageable With Established Protocols

The safety profile of Teclistamab–Daratumumab was consistent with the known risks of BCMA-directed bispecific antibodies and Daratumumab. Serious adverse events occurred more frequently in the investigational arm, driven primarily by cytopenias and infections.

  • Cytokine Release Syndrome was common but predominantly low grade and largely confined to the step-up dosing period.
  • Importantly, the incidence of CRS was lower than that reported with Teclistamab monotherapy, supporting a favorable interaction between the two agents.
  • Fatal adverse events were infrequent and decreased following protocol-reinforced infection-prevention strategies.

The trial highlights the critical importance of early immunoglobulin replacement, antimicrobial prophylaxis, and vigilant monitoring, now well established in guidelines for patients receiving BCMA-targeted therapies.

Context Within the Evolving Treatment Landscape

The magnitude of benefit observed with Teclistamab–Daratumumab is particularly notable given the strong performance of the control arm, which exceeded historical expectations from prior DPd and DVd studies. Even in this context, the combination delivered superior depth, durability, and consistency of response. As CAR-T therapies move earlier in the disease course, off-the-shelf immunotherapies such as Teclistamab–Daratumumab offer a complementary strategy, one that combines accessibility, scalability, and sustained disease control. Monthly dosing after the initial treatment phase further supports feasibility in community oncology settings.

Clinical Implications

The MajesTEC-3 trial establishes Teclistamab plus Daratumumab as a highly effective immunotherapy-based option for patients with early relapsed multiple myeloma, delivering unprecedented Progression-Free Survival and deep molecular responses without the logistical barriers of cellular therapy. With appropriate supportive care and infection-prevention strategies, this regimen may meaningfully reset expectations for long-term disease control in a population historically characterized by inevitable relapse.

Conclusion

In patients with multiple myeloma who had received one to three prior lines of therapy, Teclistamab combined with Daratumumab significantly outperformed established Daratumumab-based regimens, offering durable disease control, deep responses, and a manageable safety profile. These findings position Teclistamab–Daratumumab as a potential new standard in earlier-line Relapsed or Refractory Multiple Myeloma, and signal continued progress toward prolonged survival in this traditionally incurable disease.

Teclistamab plus Daratumumab in Relapsed or Refractory Multiple Myeloma. Costa LJ,  Bahlis NJ, Perrot A, et al. for the MajesTEC-3 Trial Investigators. N Engl J Med. Published December 9, 2025. DOI: 10.1056/NEJMoa2514663

 

 

 

 

Late Breaking Abstract – ESMO 2025: Advancing First-Line Therapy in High-Risk NMIBC: Final Results from the Phase III POTOMAC Trial

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SUMMARY: The American Cancer Society estimates 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. Caucasians are more likely to be diagnosed with bladder cancer than African Americans or Hispanic Americans.

Persistent Unmet Need in BCG-Naïve High-Risk NMIBC

High-risk Non–Muscle-Invasive Bladder Cancer (NMIBC) remains a clinically challenging disease despite decades of experience with intravesical Bacillus Calmette-Guérin (BCG). Standard management consists of complete TransUrethral Resection of Bladder Tumor (TURBT) followed by BCG induction and maintenance, However, up to 40% of patients experience early recurrence or progression within two years. For those with high-risk recurrence, radical cystectomy is frequently recommended, an intervention associated with substantial morbidity and quality-of-life implications. These limitations have driven interest in immunotherapy-based strategies aimed at improving disease control earlier in the treatment course and potentially delaying or avoiding radical surgery.

Rationale for Combining PD-L1 Blockade with BCG

Durvalumab (IMFINZI&reg;), a monoclonal antibody targeting Programmed Death-Ligand 1 (PD-L1), has demonstrated clinically meaningful benefit in bladder cancer, most notably in the perioperative setting for muscle-invasive disease. Biologic rationale for combining immune checkpoint inhibition with BCG includes immune priming within the bladder microenvironment and the observation that PD-L1 expression may increase with disease progression or BCG resistance. Introducing checkpoint blockade earlier, before immune escape is fully established, may therefore enhance the durability of response to BCG.

POTOMAC Trial Design and Patient Population

POTOMAC (NCT03528694) was a global, randomized, open-label Phase III trial evaluating whether adding Durvalumab to standard BCG therapy improves outcomes in patients with BCG-naïve, high-risk NMIBC. A total of 1,018 patients from more than 120 centers across 12 countries were randomized 1:1:1 following TURBT to one of three treatment arms:

  • Durvalumab plus BCG induction and maintenance (N=339)
  • Durvalumab plus BCG induction alone (N=339)
  • BCG induction and maintenance alone (control– N=340)

Durvalumab was administered at 1,500 mg IV every four weeks for 13 cycles (one year), while intravesical BCG induction therapy was weekly for 6 weeks and maintenance therapy consisted of three doses at weekly intervals at 3, 6, 12, 18, and 24 months. Patients were stratified by Carcinoma in Situ (CIS) and higher-risk papillary disease. The Primary endpoint was investigator-assessed Disease-Free Survival (DFS) comparing Durvalumab plus BCG induction and maintenance versus BCG alone.

Durable Improvement in Disease-Free Survival

At a median follow-up of 60.7 months, POTOMAC met its primary endpoint. The addition of one year of Durvalumab to BCG induction and maintenance resulted in a 32% reduction in the risk of high-risk disease recurrence or death compared with BCG alone (HR=0.68; P=0.015). Disease-free survival curves separated early and remained consistently apart over time, underscoring both early and sustained benefit. The median DFS was not reached in either arm. Importantly, Durvalumab combined with BCG induction alone, without maintenance BCG, did not improve outcomes, reinforcing the central role of adequate BCG exposure in disease control.

Overall Survival and Long-Term Follow-Up

Although the study was not powered to detect Overall Survival differences, extended follow-up showed no evidence of harm associated with Durvalumab. Descriptive analyses suggested numerically favorable survival outcomes with the combination regimen, providing reassurance regarding long-term safety in this curative-intent population.

Safety Profile and Treatment Tolerability

The safety profile of Durvalumab plus BCG was consistent with the known toxicities of each agent. Grade 3 or 4 treatment-related adverse events occurred more frequently with combination therapy than with BCG alone, but these events were generally manageable. No treatment-related deaths were reported. Common adverse effects reflected expected urinary and immune-related events, supporting the feasibility of integrating systemic immunotherapy into NMIBC management.

Context within the Evolving NMIBC Landscape

POTOMAC represents one of the longest follow-up datasets evaluating immune checkpoint inhibition in NMIBC and adds to a growing body of evidence supporting this strategy. Together with prior positive trials exploring PD-1/PD-L1 inhibitors alongside BCG, the data suggest that immune checkpoint blockade can meaningfully augment standard therapy when combined with full-course BCG. Differences among trials highlight the importance of patient selection, adequate maintenance therapy, and sufficient duration of treatment exposure.

Clinical Implications for Practice

The POTOMAC findings reinforce several key principles for clinicians:

  • Maintenance BCG remains essential and should not be replaced by systemic immunotherapy alone
  • Early integration of immune checkpoint blockade can improve disease control in carefully selected high-risk patients
  • Long-term follow-up matters, particularly in NMIBC where durable bladder preservation is a primary goal

Conclusion

For patients with BCG-naïve, high-risk NMIBC, the addition of one year of Durvalumab to standard BCG induction and maintenance delivers a statistically significant and clinically meaningful improvement in Disease-Free Survival with a manageable safety profile. POTOMAC raises the bar for first-line NMIBC therapy and positions combined systemic and intravesical immunotherapy as a compelling new option for this high-risk population.

Durvalumab in combination with BCG for BCG-naive, high-risk, non-muscle-invasive bladder cancer (POTOMAC): final analysis of a randomised, open-label, phase 3 trial. De Santis M, Redorta JP, Nishiyama H, et al. The Lancet. 2025;406:2221-2234.

Durvalumab + FLOT Establishes New Benchmark in Curative-Intent Therapy for Gastric and GEJ Cancers

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SUMMARY: The American Cancer Society estimates that in the US about 30,300 new gastric cancer cases will be diagnosed in 2025 and about 10,780 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for gastric cancer. Additionally, one of the strongest risk factors for gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Despite the intent of cure in resectable gastric and GastroEsophageal Junction (GEJ) cancers, long-term survival remains suboptimal, with fewer than half of patients alive at five years. Current perioperative chemotherapy strategies, such as the FLOT regimen (5-FU, Leucovorin, Oxaliplatin, and Docetaxel), are widely accepted as the standard of care, particularly in Western countries. However, recurrence remains a frequent challenge, underscoring the need for enhanced systemic control.

The global, randomized, double-blind Phase 3 MATTERHORN trial evaluated whether adding the immune checkpoint inhibitor Durvalumab to FLOT could improve clinical outcomes in patients with resectable, locally advanced gastric or GEJ adenocarcinoma. This approach leverages prior success of immunotherapy in metastatic settings, where checkpoint inhibitors are already approved in combination with chemotherapy, but expands the strategy into the curative-intent, perioperative context.

Durvalumab (IMFINZI&reg;) is a human immunoglobulin G1 monoclonal antibody that binds to the PD-L1 protein and blocks the interaction of PD-L1 with the PD-1 and CD80 proteins, countering the tumor’s immune-evading tactics, and unleashes the T cells.

Trial Design and Treatment Protocol
In this study, a total of 948 treatment-naïve patients with Stage II to IVa resectable gastric or GEJ adenocarcinoma were randomized 1:1 to receive either Durvalumab plus FLOT (N=474) or placebo plus FLOT (N=474).  Treatment consisted of Durvalumab 1500 mg or Placebo every 4 weeks (Q4W) on Day 1 + FLOT (5-Fluorouracil, Leucovorin, Oxaliplatin and Docetaxel) on Days 1 and 15 for 4 cycles (2 cycles each neoadjuvant/adjuvant), followed by Durvalumab 1500 mg or Placebo on Day 1 Q4W for 10 cycles. Participants were enrolled across Asia, Europe, North America, and South America, reflecting the global burden of disease. Key stratification factors included geographic region (Asia vs non-Asia), nodal status, and PD-L1 expression. The median age was approximately 62 years, and around 70% of patients had gastric tumors, with the remainder involving the GEJ. Most patients (70%) had node-positive disease at baseline. Treatment groups were well balanced. Treatment was administered perioperatively, consisting of two neoadjuvant and two adjuvant cycles. Durvalumab or placebo was continued post-chemotherapy as monotherapy for 10 additional cycles. The Primary endpoint was Event-Free Survival (EFS), with Secondary endpoints including Overall Survival (OS), pathologic Complete Response (pCR), and Safety.

Efficacy Findings
At a median follow-up of 31.5 months, the addition of Durvalumab to FLOT significantly improved EFS compared to placebo. The median EFS had not yet been reached in the Durvalumab arm, whereas it was 32.8 months in the placebo group (Hazard Ratio [HR] 0.71; 95% CI, 0.58–0.86; P<0.001), translating to a roughly 30% reduction in the risk of progression, recurrence, or death. Importantly, Durvalumab did not delay surgery or adjuvant therapy initiation. Notably, 24-month EFS rates were higher with Durvalumab (67.4%) compared to placebo (58.5%), indicating a durable benefit. Subgroup analyses consistently favored the Durvalumab combination across clinical and demographic variables, including PD-L1 expression status, nodal involvement, and geographic region, although some subgroups lacked sufficient power for statistical significance.

An early OS analysis, though not yet mature, suggested a favorable trend for the Durvalumab arm (HR 0.78; 95% CI, 0.62–0.97), with median OS not reached in that group compared to 47.2 months in the placebo group.

In addition to EFS, the Durvalumab-containing regimen improved pathologic Complete Response rates as well as Major Pathological Response, suggesting more effective eradication of micrometastatic disease with immunotherapy-enhanced perioperative treatment.

The final Overall Survival results from the MATTERHORN trial were presented at the ESMO Congress 2025. In this definitive analysis, perioperative Durvalumab added to FLOT chemotherapy delivered a statistically significant and clinically meaningful survival advantage over placebo plus FLOT (HR=0.78; 95% CI, 0.63–0.96; P=0.021). Notably, the OS benefit was observed across PD-L1 expression levels, with comparable hazard ratios in both the TAP <1% and TAP ≥1% subgroups, suggesting that the activity of Durvalumab in the perioperative setting is not restricted to PD-L1–positive disease.

Durvalumab also enhanced pathological response metrics. Patients treated with Durvalumab achieved substantially higher nodal negativity rates (ypN0, 58.2% vs 44.8%), indicating deeper locoregional tumor clearance and supporting the biologic premise that checkpoint inhibition can potentiate chemotherapy-mediated cytoreduction. Improvements in Event-Free Survival were consistent across the spectrum of pathological response categories including partial, major, and complete responders, highlighting that meaningful clinical benefit extends beyond patients achieving ypCR.

Safety and Tolerability
The addition of Durvalumab did not compromise surgical outcomes or delay the initiation of adjuvant therapy. The incidence of grade 3/4 adverse events was similar between arms (72% with Durvalumab vs 71% with placebo), as were rates of serious adverse events (48% vs 44%) and treatment-related deaths (5% vs 4%). These findings reinforce the safety of incorporating immunotherapy into the perioperative setting without increasing toxicity burden or interfering with multimodal management.

Biomarker Insights and Future Directions
Approximately 90% of patients were PD-L1–positive in both groups, and 5% had MicroSatellite Instability–High (MSI-H) tumors (lower than the rates of 7% to 9% commonly seen). Although these biomarker-defined subpopulations are known to respond favorably to immunotherapy, their relatively small representation in the study suggests the observed benefits were driven by broader immunomodulatory effects rather than biomarker enrichment alone.

The optimal duration of adjuvant Durvalumab remains an open question. In MATTERHORN, Durvalumab was continued for 10 cycles post-chemotherapy, but further investigation may determine whether shorter courses or biomarker-guided de-escalation could yield similar benefits while minimizing toxicity and cost.

Clinical Implications

The MATTERHORN findings reinforce that integrating Durvalumab into the perioperative FLOT regimen confers durable improvements in both Overall and Event-Free Survival for patients with resectable gastric or gastroesophageal junction (GEJ) adenocarcinoma. Importantly, the magnitude of benefit remained stable across key clinical and biological subgroups, including PD-L1 status and nodal involvement, underscoring the robustness and generalizability of the treatment effect.

Combined with the earlier JCO publication detailing significant gains in Event-Free Survival, these results strengthen the rationale for incorporating immunotherapy into curative-intent treatment pathways for early-stage upper gastrointestinal cancers. Durvalumab + FLOT is poised to emerge as a new global standard of care, reflecting the broader paradigm shift toward perioperative immune-checkpoint blockade in resectable solid tumors.

Final overall survival (OS) and the association of pathological outcomes with event-free survival (EFS) in MATTERHORN: A randomised, phase III study of durvalumab (D) plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) in resectable gastric / gastroesophageal junction (G / GEJ) adenocarcinoma. Tabernero J, Al-Batran, Wainberg ZA, et al. LBA81- Presented at ESMO Congress 2025, Berlin.

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.

CAN-2409 in Advanced NSCLC: Turning Tumors into Vaccines

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SUMMARY: 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. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer.

A New Approach to Overcoming Resistance
For patients with advanced Non-Small Cell Lung Cancer (NSCLC), Immune Checkpoint Inhibitors (ICIs) have changed the treatment landscape. Yet, many patients develop resistance or fail to respond altogether, leaving clinicians with limited options. A novel gene therapy, CAN-2409, is offering a different strategy, one that uses the tumor itself as a source of immune activation.

How It Works: An In Situ Vaccination
CAN-2409 is an engineered, replication-defective adenovirus designed to deliver the Herpes Simplex Virus thymidine kinase (HSV-tk) gene directly into tumor cells. Once inside, the cells express HSV-tk. When patients take the oral prodrug Valacyclovir, the enzyme HSV-tk converts it into a toxic metabolite, selectively killing the tumor cells.

But the therapeutic effect goes far beyond cell death.

  • Immunogenic cell death releases tumor-specific antigens and creates a pro-inflammatory environment.
  • The adenovirus itself adds inflammatory cues.
  • Dendritic cells capture and present these antigens, training cytotoxic T cells to recognize the tumor.

The result is a two-step, multimodal effect: localized destruction followed by a systemic immune response. This “in situ vaccination” primes the immune system not just against the injected lesion, but also against distant metastases, creating the potential for durable control.

Clinical Trial in ICI-Refractory NSCLC
A Phase IIa open-label trial evaluated CAN-2409 plus Valacyclovir in patients with unresectable Stage III/IV NSCLC who had failed to respond adequately to anti-PD-(L)1 therapy. Patients continued on their checkpoint inhibitor therapy and received two intratumoral injections of CAN-2409 (5 × 10^11 vp) five to seven weeks apart via bronchoscopic or percutaneous injection into lung tumor, disease-positive lymph node, or peripheral metastasis, followed by oral prodrug Valacyclovir administered for 15 days. The median age was 67 yrs, 44% were female, 68% were on checkpoint inhibitor therapy alone and 32% were on checkpoint inhibitor therapy plus Pemetrexed regimen. Majority of patients (90%) had Stage IV disease, 46% had PD-L1 TPS < 1%, 91% were former or current smokers.

Participants were enrolled into two cohorts:

  • Cohort 1: Stable disease while on ICI therapy
  • Cohort 2: Progressive disease despite ICI therapy

The goal was to assess Overall Survival (OS), abscopal responses, and immune correlates.

Extended Follow-Up Results
Seventy-six patients were enrolled, of whom 46 patients were considered evaluable

At a median follow-up of 32.4 months, the findings were striking:

  • Median OS (all evaluable patients): 24.5 months
  • Median OS in Cohort 2 (progressive disease): 21.5 months
  • Long-term survival: 37% alive beyond 2 years
  • Histology-specific benefit: Patients with nonsquamous disease had longer OS than those with squamous histology (25.4 vs. 13.3 months).

Notably, patients with nonsquamous tumors showed greater expansion of cytotoxic T cells, B cells, and dendritic cells, suggesting that histology-linked biology may shape immune responsiveness to CAN-2409.

Evidence of Systemic Immune Activation
One of the most compelling signals came from the observation of abscopal responses. Among patients with multiple lesions, 69% experienced shrinkage at uninjected sites, confirming that local therapy could indeed drive a systemic anti-tumor effect.

Safety and Tolerability
Throughout extended follow-up, CAN-2409 maintained a favorable safety profile. The most common Treatment Related Adverse Events (TRAEs) were Grade 1/2, with fatigue, fever, and chills in 18-39% of patients. No dose-limiting toxicities or Grade 4 or more treatment-related AEs were noted. No new safety signals emerged, underscoring its feasibility as a repeat intratumoral intervention alongside checkpoint blockade.

Looking Ahead
These results highlight the promise of CAN-2409 as a next-generation immunotherapy platform for patients with advanced NSCLC resistant to ICIs. With durable survival in a subset of patients, particularly those with nonsquamous histology, the findings support the initiation of a larger, randomized trial to validate efficacy and refine patient selection strategies.

Key Takeaway for Oncology Practice
CAN-2409 represents a novel paradigm in NSCLC, transforming tumors into personalized vaccines that harness both direct cytotoxicity and immune training. For patients progressing on ICIs, this dual mechanism could offer a meaningful new avenue of durable disease control.

MA10.02 CAN-2409 With Continued Immune Checkpoint Inhibitor (ICI) in Patients With Stage III/IV NSCLC With Inadequate Response to ICI. Aggarwal C, Sterman D, Nicholas G, et al. Presented at the 2025 World Conference on Lung Cancer. September 6-9, 2025. Barcelona, Spain.

Tarlatamab Sets New Standard in Recurrent Small Cell Lung Cancer: Results from DeLLphi-304

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SUMMARY: 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. Nearly all patients with SCLC experience disease recurrence during or after standard platinum-based chemotherapy, underscoring the need for novel treatment strategies Second-line treatment options are limited, and the response duration is short varying from 3-5 months, with Overall Survival rarely exceeding 8 months. There are presently no approved therapies for third line and beyond and these patients face a dire prognosis.

Delta-Like Protein 3 also known as DLL3, is encoded by the DLL3 gene and is expressed on the surface of tumor cells but not in normal adult tissues. Patients with high-grade pulmonary NeuroEndocrine Tumors, Small Cell Lung Cancer (SCLC) and Large Cell NeuroEndocrine Carcinoma (LCNEC) have increased expression of DLL3 protein (increased expression seen in approximately 85-96% of the SCLC tumors), making this a a potential target in the treatment of Small Cell Lung Cancer.

Tarlatamab (IMDELLTRA®) is a first-in-class bispecific T-cell engager immunotherapy that directs the patients T cells to cancer cells expressing Delta-Like Ligand 3 (DLL3), independent of Major Histocompatibility Complex (MHC) class I. Tarlatamab binds to both DLL3 on cancer cells and CD3 on T cells, leading to T-cell–mediated lysis of cancer cells.

In May 2024, the U.S. FDA granted accelerated approval to Tarlatamab for adult patients with extensive-stage SCLC whose disease progressed after platinum-based chemotherapy. This decision was based largely on early clinical benefit observed in the Phase 2 DeLLphi-301 trial, where Tarlatamab demonstrated a 40% Overall Response Rate (ORR) in previously treated patients. Now, confirmatory results from the Phase 3 DeLLphi-304 trial further support the role of Tarlatamab in the treatment landscape, and mark a potential new standard of care for recurrent SCLC.

Phase 3 DeLLphi-304: Study Design and Population
DeLLphi-304 was a global, randomized, open-label trial comparing Tarlatamab, with standard-of-care chemotherapy which included Topotecan, Lurbinectedin, or Amrubicin, in patients with extensive-stage SCLC, whose disease progressed after platinum-based chemotherapy. A total of 509 patients were randomized 1:1 to receive either Tarlatamab (N=254) or chemotherapy (N=255). The median patient age was 65 yrs, Approximately 45% of randomized patients had current or previous brain metastases, 35% had liver metastases, 71% had received previous therapy with checkpoint inhibitors and 44% had platinum-resistant disease. Stratification factors included prior PD-L1 inhibitor treatment, chemotherapy-free interval, presence of brain metastases, and intended chemotherapy regimen. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression-Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR), Disease Control Rate (DCR), Patient-Reported Outcomes (PROs), and Safety.

Tarlatamab Demonstrates Significant Survival Benefit
At a median follow-up of approximately 11 months, Tarlatamab demonstrated a statistically and clinically significant improvement in OS:

  • Median OS: 13.6 vs 8.3 months (HR 0.60; 95% CI: 0.47–0.77; P<0.001)
  • Median PFS: 4.2 vs 3.2 months (HR 0.72; 95% CI: 0.59–0.88; P<0.001)

This translated to a 40% reduction in the risk of death for patients receiving Tarlatamab. The survival benefit extended across all prespecified subgroups, including age, gender, race, and prior anti–PD-L1 therapy. The ORR was 35% in the Tarlatamab group and 20% in the chemotherapy group.

Improved Symptom Control and Quality of Life
Beyond survival, Tarlatamab provided clinically meaningful improvements in Patient-Reported Outcomes, including relief from hallmark symptoms of SCLC:

  • Dyspnea score improved at 18 weeks: –1.94 with Tarlatamab vs +7.20 with CTx (mean difference –9.14; P< 0.001)
  • Cough improvement: 16% vs 9% (Odds Ratio 2.04; P = 0.012)
  • Chest pain improvement: 9% vs 4% (Odds Ratio 1.84; P = 0.100) – not significant

These findings reflect an overall better patient experience and potential Quality-of-Life benefit with Tarlatamab therapy.

Safety Profile and Tolerability
Tarlatamab was associated with a more favorable safety profile compared to chemotherapy:

  • Grade 3 or more Treatment-Related Adverse Events (TRAEs): 27% (Tarlatamab) vs 62% (Chemotherapy)
  • Discontinuations due to TRAEs: 3% vs 6%
  • Most common Grade 3 or more TRAEs with Tarlatamab were neutropenia (4%) and lymphopenia (4%)
  • Cytokine Release Syndrome (CRS) occurred in 56% of patients (mostly grade 1-2) and was manageable in clinical settings

These safety results support Tarlatamab as a more tolerable alternative to conventional chemotherapy.

Looking Ahead: Optimizing Treatment Sequencing
While the DeLLphi-304 trial has established Tarlatamab as an effective option post-platinum therapy, questions remain regarding its integration into the broader SCLC treatment paradigm. PD-L1 inhibitors already form part of standard first-line and maintenance therapy. Early-phase studies have shown that Tarlatamab can be safely combined with anti–PD-L1 agents, and this is being further evaluated in the ongoing DeLLphi-305 trial, a Phase 3 study assessing Tarlatamab plus PD-L1 inhibition as first-line maintenance following chemotherapy. Additionally, biomarker-driven analyses from DeLLphi-304 are underway to help identify patients most likely to benefit from Tarlatamab and those who may achieve durable responses.

Conclusion
The DeLLphi-304 trial positions Tarlatamab as a practice-changing therapy for patients with SCLC that has progressed after platinum-based chemotherapy. With significant improvements in Overall and Progression-Free Survival, better symptom control, and a favorable safety profile, Tarlatamab redefines second-line treatment for a historically underserved patient population. These results not only represent a meaningful advance in SCLC therapy but also signal a broader shift toward targeted immunotherapy strategies in aggressive thoracic malignancies.

Tarlatamab in Small-Cell Lung Cancer after Platinum-Based Chemotherapy. Mountzios G, Sun L, Cho BC, et al. for the DeLLphi-304 Investigators. N Engl J Med 2025;393:349-361

 

Adjuvant Atezolizumab in Resected NSCLC: Five-Year Outcomes from IMpower010

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SUMMARY: Lung cancer is the second most common cancer in both men and women and 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. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers and Adenocarcinoma is now the most frequent histologic subtype of lung cancer. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Atezolizumab (TECENTRIQ®) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

IMpower 010 is a global, multicentre, open-label, randomized Phase III study evaluating the efficacy and safety of Atezolizumab compared with Best Supportive Care (BSC), in patients with stage IB-IIIA NSCLC, following surgical resection and up to 4 cycles of adjuvant Cisplatin-based chemotherapy. In this study, 1005 patients were randomized 1:1 to receive Atezolizumab 1200 mg IV every 3 weeks for 16 cycles, or BSC. Both study groups were well balanced and eligible patients had an ECOG PS of 0-1. The Primary endpoint was Disease Free Survival (DFS) in the PD-L1-positive (1% or more) stage II-IIIA patients, all randomized stage II-IIIA patients and Intent to Treat (ITT) stage IB-IIIA populations. Key Secondary endpoints included Overall Survival (OS) in the overall study population and ITT stage IB-IIIA NSCLC patients.

Initial DFS Results at a Median Follow-Up of 32.2 Months
Adjuvant Atezolizumab demonstrated a clinically meaningful DFS advantage:

  • Stage II–IIIA, PD-L1 1% or more: 34% reduction in risk of recurrence or death vs. BSC (HR 0.66; P=0.0039); median DFS not reached vs. 35.3 months for BSC
  • Stage II–IIIA, PD-L1 50% or more: 57% risk reduction (HR 0.43)
  • All stage II–IIIA: HR 0.79 (P=0.02), median DFS gain of 7 months
  • No statistically significant DFS improvement in the ITT population
  • OS data immature at this stage

These findings led to regulatory approval of adjuvant Atezolizumab in resected stage II–IIIA PD-L1–positive NSCLC following chemotherapy.

Updated 5-Year Outcomes
Final DFS analysis and second OS interim analysis were reported with an additional 36 and 21 months of follow-up, respectively (clinical cutoff: January 26, 2024).

Disease-Free Survival:

  • Stage II–IIIA, PD-L1 ≥1% (N=476): HR 0.70 (95% CI, 0.55–0.91) – More than 30-month median DFS difference between arms
  • Stage II–IIIA, PD-L1 ≥50% (N=229): HR 0.48 (95% CI, 0.32–0.72)
  • All stage II–IIIA (N=882): HR 0.83 (95% CI, 0.69–1.00)
  • ITT (N=1005): HR 0.85 (95% CI, 0.71–1.01; P=0.07) – numerical improvement, not statistically significant
  • All randomized Stage II–IIIA (N=882): HR 0.83 (95% CI, 0.69–1.00)
  • PD-L1 ≥50% without EGFR/ALK alterations (N=209): HR 0.49 (95% CI, 0.32–0.75)

Overall Survival:

  • ITT: HR 0.97 (95% CI, 0.78–1.22)
  • Stage II–IIIA: HR 0.94 (95% CI, 0.75–1.19)
  • PD-L1 ≥1%: HR 0.77 (95% CI, 0.56–1.06)
  • PD-L1 ≥50%: HR 0.47 (95% CI, 0.28–0.77)

Since DFS in the ITT population did not cross the statistical significance boundary, formal OS testing was not conducted. OS data remain immature given a low event-to-patient ratio (~31%).

Clinical Perspective
IMpower010 remains the only Phase III trial with more than 5-year follow-up evaluating a checkpoint inhibitor as adjuvant therapy in resectable stage II–IIIA NSCLC. The most pronounced and durable benefits continue to be seen in PD-L1–selected populations, particularly those with PD-L1 50% or more and without EGFR/ALK alterations. These findings reinforce PD-L1 testing as a critical step in the adjuvant treatment algorithm for NSCLC, and they differentiate Atezolizumab from other checkpoint inhibitors evaluated in similar settings, where results have varied (e.g., KEYNOTE-091, BR.31)

Key Takeaways for Oncology Practice

  • Patient selection matters – Benefit is greatest in PD-L1–positive, especially PD-L1 50% or more
  • Durable effect – DFS benefit persists beyond 5 years in high PD-L1 subgroups
  • Ongoing OS follow-up – OS data are still maturing; future analyses may clarify survival impact
  • Safety reassurance – No new safety concerns after extended follow-up

Five-Year Survival Outcomes With Atezolizumab After Chemotherapy in Resected Stage IB-IIIA Non–Small Cell Lung Cancer (IMpower010): An Open-Label, Randomized, Phase III Trial. Felip E, Altorki N, Zhou C, et al. J Clin Oncol. 2025;43:2343-2349. 

Neoadjuvant PD-1 Blockade Promotes Organ Preservation in Early Stage Mismatch Repair–Deficient Solid Tumors

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SUMMARY: Colorectal cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 154,270 new cases of CRC will be diagnosed in the United States in 2025 and about 52,900 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23. The majority of CRC cases (about 75 %) are sporadic whereas the remaining 25 % of the patients have a family history of the disease. Only 5-6 % of patients with CRC with a family history background are due to inherited mutations in major CRC genes, while the rest are the result of accumulation of both genetic mutations and epigenetic modifications of several genes. Colorectal Cancer is a heterogeneous disease classified by its genetics, and even though the diagnosis of Colorectal Cancer in the US is dropping among people 65 years and older, the incidence has been rising in the younger age groups, with 12% of Colorectal Cancer cases diagnosed in people under age 50.

The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, with the expression of tumor-specific neoantigens at the surface of cancer cells, triggering an enhanced antitumor immune response. MSI is therefore a hallmark of defective/deficient DNA MisMatchRepair (dMMR) system and occurs in 15% of all colorectal cancers. Defective MMR can be a sporadic or heritable event. Approximately 65% of the MSI high colon tumors are sporadic and when sporadic, the DNA MMR gene is MLH1. Defective MMR can manifest as a germline mutation occurring in MMR genes including MLH1, MSH2, MSH6 and PMS2. This produces Lynch Syndrome often called Hereditary Nonpolyposis Colorectal Carcinoma–HNPCC, an Autosomal Dominant disorder that is often associated with a high risk for Colorectal and Endometrial carcinoma, as well as several other malignancies including Ovary, Stomach, Small bowel, Hepatobiliary tract, Brain and Skin. MSI is a hallmark of Lynch Syndrome-associated cancers. MSI high tumors tend to have better outcomes and this has been attributed to the abundance of tumor infiltrating lymphocytes in these tumors from increase immunogenicity. These tumors therefore are susceptible to blockade with immune checkpoint inhibitors.

MSI testing is performed using a PCR or NGS based assay and MSI-High refers to instability at 2 or more of the 5 mononucleotide repeat markers and MSI-Low refers to instability at 1 of the 5 markers. Patients are considered Micro Satellite Stable (MSS) if no instability occurs. MSI-L and MSS are grouped together because MSI-L tumors are uncommon and behave similar to MSS tumors. Tumors considered MSI-H have deficiency of one or more of the DNA MMR genes. MMR gene deficiency can be detected by ImmunoHistoChemistry (IHC). NCCN Guidelines recommend MMR or MSI testing for all patients with a history of Colon or Rectal cancer. Unlike Colorectal and Endometrial cancer, where MSI-H/dMMR testing is routinely undertaken, the characterization of Lynch Syndrome across heterogeneous MSI-H/dMMR tumors is unknown.

Background
Checkpoint inhibitors have revolutionized the treatment landscape for MisMatch Repair–deficient (dMMR) metastatic solid tumors, offering durable responses across tumor types. This paradigm is now being explored in early-stage settings. Dostarlimab (JEMPERLI®) is a monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. Building on prior success in dMMR rectal cancer, this Phase 2, multicenter study investigated the feasibility of using neoadjuvant PD-1 blockade with Dostarlimab to achieve organ preservation in early-stage, surgically resectable dMMR solid tumors, potentially shifting the standard of care away from surgery and cytotoxic therapies.

Study Design and Patient Population
Conducted at Memorial Sloan Kettering Cancer Center, Hartford HealthCare, and Baptist Health Miami Cancer Institute, the study enrolled patients with newly diagnosed Stage I–III dMMR solid tumors, defined by loss of MLH1, PMS2, MSH2, or MSH6 expression on immunohistochemistry, that were amenable to curative-intent surgery. Two cohorts were formed:

  • Cohort 1: Patients with locally advanced rectal cancer.
  • Cohort 2: Patients with nonrectal dMMR solid tumors (including esophagogastric, colon, hepatobiliary, genitourinary, and gynecologic cancers).

All patients received Dostarlimab 500 mg IV every 3 weeks for 6 months (nine cycles). Clinical response was assessed within 8 weeks of completing therapy via tumor-specific imaging, endoscopy, and biopsy where applicable. Patients with residual disease were offered standard neoadjuvant therapy and surgery, while those achieving a clinical Complete Response (cCR) could opt for nonoperative management.

Primary and Exploratory Endpoints

  • Cohort 1: Co-primary endpoints were Overall Response Rate and sustained cCR at 12 months post-treatment.
  • Cohort 2: Exploratory analyses evaluated cCR rates, Recurrence-Free Survival (RFS), safety, and molecular correlates of response, including circulating tumor DNA (ctDNA).

Results
A total of 117 patients were analyzed:

  • Cohort 1 (Rectal Cancer): All 49 patients who completed therapy achieved a cCR and declined surgery. At 12 months, 37 maintained a sustained cCR, meeting the efficacy threshold.
  • Cohort 2 (Nonrectal Tumors): Of 54 patients, 35 achieved a cCR, with 33 choosing nonoperative management.

Across both cohorts:

  • 103 patients completed Dostarlimab therapy.
  • 84 (82%) achieved cCR.
  • 82 patients (80%) avoided surgery.
  • Two-year RFS: 92% (95% CI, 86–99).
  • Median follow-up for recurrence: 20 months (range, 0–60.8).
  • Safety: Most adverse events were grade 1–2 (60%), with 35% reporting no treatment-related events. No patient lost the opportunity for curative surgery due to disease progression.

Genomic and ctDNA Findings

  • Germline dMMR variants were present in 44% of patients.
  • Tumor-informed ctDNA testing tracked up to 50 tumor-specific mutations using a highly sensitive and specific assay.
  • ctDNA clearance correlated strongly with cCR: all patients with a cCR showed complete ctDNA clearance by end of treatment.
  • Persistently detectable ctDNA was associated with residual disease or eventual recurrence, reinforcing its value as a real-time, noninvasive biomarker for treatment response and residual disease monitoring.

Discussion
The findings underscore the transformative potential of neoadjuvant PD-1 blockade for early-stage dMMR cancers. Key takeaways include:

  • Tumor-Agnostic Efficacy: Dostarlimab elicited robust responses across a variety of histologies, suggesting that dMMR status, rather than tumor origin, may drive sensitivity to immunotherapy.
  • Organ Preservation: Surgery, and its associated morbidities, was avoided in the majority of patients, including those with rectal cancers where standard treatment often compromises fertility, continence, or other organ functions. Three women with rectal cancer treated in this trial successfully conceived and delivered children.
  • Variable Responses by Histology: While responses were highest in rectal, colon, hepatobiliary, and urothelial cancers, lower cCR rates were observed in prostate and upper gastrointestinal tumors. This suggests underlying biological variability despite shared dMMR status.
  • Monitoring Strategy: Integration of imaging, endoscopy, and ctDNA is critical. Liquid biopsy offered a reliable surrogate for tumor biopsy, particularly in inaccessible tumors, but caution is warranted as ctDNA alone may miss certain cases.
  • Safety and Feasibility: The 6-month regimen was generally well tolerated, and no patient lost surgical eligibility due to disease progression. This supports the feasibility of prolonged neoadjuvant immunotherapy in appropriately selected patients.

Clinical Implications and Future Directions
This study lays the groundwork for a paradigm shift in the management of early-stage dMMR tumors. However, key questions remain:

  • Long-Term Durability: While initial outcomes are promising, especially in rectal cancer, longer follow-up and additional data are necessary to confirm sustained benefit across nonrectal histologies.
  • Histology-Specific Trials: Basket trials and single-arm studies may suffice for anatomically sensitive tumors (e.g., rectum, bladder), but randomized trials may still be appropriate in less morbidly resectable cancers (e.g., colon).
  • Treatment Optimization: Determining the minimal effective duration of immunotherapy could reduce adverse events and cost. Median times to biopsy negativity (1.5 months) and imaging response (6.1 months) suggest a window for shortening therapy in responders.
  • Shared Decision-Making: Given the potential for curative nonoperative management, multidisciplinary care teams must align on strategies and engage patients in informed decision-making, particularly where standard surgery entails long-term quality-of-life tradeoffs.

Conclusion
Neoadjuvant PD-1 blockade with Dostarlimab achieved clinical Complete Responses in a substantial majority of patients with early-stage dMMR tumors, offering a path to organ preservation without compromising curative potential. These results highlight the tumor-agnostic power of checkpoint inhibitors and present a compelling case for redefining the treatment of dMMR solid tumors. As follow-up data matures and histology-specific nuances are better understood, immunotherapy may become the new cornerstone of early-stage dMMR cancer management.

Nonoperative Management of Mismatch Repair–Deficient Tumors. Cercek A, Foote MB, Rousseau B, et al. N Engl J Med 2025;392:2297-2308.