Educational content on VJOncology is intended for healthcare professionals only. By visiting this website and accessing this information you confirm that you are a healthcare professional.

The Gastrointestinal Cancer Channel is supported with funding from Gilead Sciences (Silver) and Revolution Medicines (Silver).

The Lung Cancer Channel is supported with funding from Johnson & Johnson (Gold) and Takeda (Gold).

VJOncology is an independent medical education platform. Supporters, including channel supporters, have no influence over the production of content. The levels of sponsorship listed are reflective of the amount of funding given to support the channel.

DESTINY-Breast05 EFS in MATTERHORN PSMAddition OptiTROP-Lung04 C-POST

DESTINY-Breast05: trastuzumab deruxtecan vs trastuzumab emtansine in high-risk HER2+ after neoadjuvant therapy

 

Trastuzumab deruxtecan (T-DXd) has transformed outcomes in advanced HER2-positive (HER2+) breast cancer, yet recurrence rates remain for patients with high-risk early-stage disease. Antibody–drug conjugates (ADCs) have emerged as a promising strategy to deepen responses in the curative setting, aiming to eradicate micrometastatic disease that drives relapse. However, until recently, no ADC had demonstrated clear supeiority over trastuzumab emtansine (T-DM1), the standard for adjuvant treatment following incomplete response to neoadjuvant therapy.1,2

The global Phase III DESTINY-Breast05 trial (NCT04622319), presented at the European Society for Medical Oncology (ESMO) Congress 2025, addressed this unmet need by directly comparing T-DXd to T-DM1 in patients with residual invasive HER2+ breast cancer after neoadjuvant therapy. 1,635 patients were randomized 1:1 to receive adjuvant T-DXd or T-DM1 for up to 14 cycles. The primary endpoint was invasive disease-free survival (iDFS), with secondary endpoints including distant disease-free survival (DDFS), overall survival (OS), and safety outcomes.3

IDFS and DFS were statistically superior in the T-DXd group versus the T-DM1 arm: 51 and 102 patients, respectively, had iDFS events, and 52 and 103 patients, respectively, had DFS events (95% CI, 0.62-0.97). Safety findings aligned with the known profile of T-DXd, with manageable rates of nausea, cytopenias, and low-grade interstitial

 

lung disease (ILD). Importantly, the incidence of high-grade ILD remained low, and treatment-related discontinuations were infrequent.

These practice-changing results position T-DXd as the new adjuvant standard for patients with high-risk residual HER2+ breast cancer. DESTINY-Breast05 signals a shift toward earlier use of next-generation ADCs and raises the possibility of further escalating or personalizing therapy for the highest-risk patients. As T-DXd moves into routine practice, ongoing studies will clarify optimal sequencing, duration, and patient selection to maximize long-term cure rates in HER2+ disease.

EFS in MATTERHORN: durvalumab plus FLOT in resectable gastric/gastroesophageal junction cancer

 

Gastric and gastroesophageal junction (GEJ) adenocarcinomas have high recurrence rates even after surgery aimed at cure and perioperative chemotherapy. Whilst the FLOT regimen (5-fluorouracil, leucovorin, oxaliplatin, and docetaxel) is the current global standard, its effectiveness is often hindered by undetected metastatic spread. Checkpoint inhibitors, such as PD-1/PD-L1 antibodies, have proven beneficial in treating metastatic cancer, but their impact on patients with resectable disease remains uncertain.4

New data from the global Phase III MATTERHORN trial

 

(NCT04592913), presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Congress, demonstrated a significant event-free survival (EFS) advantage with perioperative durvalumab plus FLOT chemotherapy in patients with resectable gastric and gastroesophageal junction adenocarcinoma (GC/GEJC). 948 patients with treatment-naïve stage II–IVA resectable GC/GEJC were randomized 1:1 to durvalumab plus FLOT or placebo plus FLOT.5

At a median follow‑up of 31.5 months, the primary endpoint of EFS was reached (95% CI: 0.58–0.86), and interim OS favored durvalumab (95% CI, 0.62-0.97). Grade 3/4 adverse events (AEs) were similar in both arms, where the most frequent toxicities included neutropenia, diarrhea, nausea, alopecia, and decreased appetite. Importantly, durvalumab did not delay surgery or adjuvant treatment. 5 Additional data presented at ESMO GI 2025 highlighted no significant differences in quality of life (QoL) between the two arms.6

MATTERHORN marks the first Phase III trial to demonstrate improved EFS in resectable GC/GEJC with perioperative durvalumab, setting a new standard of care. The findings ultimately led to the U.S. Food and Drug Administration (FDA) approval of durvalumab in this setting on November 25, 20257, highlighting the practice-changing nature of this trial.

PSMAddition: [177Lu]Lu-PSMA-617 with ADT and ARPI in PSMA-positive metastatic hormone-sensitive prostate cancer

 

Prostate-specific membrane antigen (PSMA) radioligand therapy has reshaped treatment for metastatic castration-resistant prostate cancer, yet men with metastatic hormone-sensitive prostate cancer (mHSPC) continue to face high rates of disease progression despite combination androgen deprivation therapy (ADT) and androgen receptor pathway inhibitors (ARPIs). While intensified systemic therapy has improved outcomes, many patients still experience early radiographic progression, highlighting the need for novel approaches.8,9

The Phase III PSMAddition trial (NCT04720157) evaluated whether adding the PSMA-targeted radioligand 177Lu-PSMA-617 to standard ADT plus an ARPI could improve outcomes in men with PSMA-positive mHSPC. 1,144 treatment-naïve patients were randomized 1:1 to triple therapy (177Lu-PSMA-617 + ADT + ARPI) or the control arm (ADT + ARPI alone). Eligible patients had documented PSMA-positive metastatic disease on PET imaging. The primary endpoint was radiographic progression-free survival (rPFS), with secondary endpoints including OS, objective response rate (ORR), safety, and QoL.10

Results were presented at ESMO 2025, where at a median follow-up of approximately 29 months, a significant improvement in rPFS with the addition of 177Lu-PSMA-617 was reported (95% CI 0.58-0.90). Whilst OS is still immature, a favourable OS trend was observed in

 

the 177Lu-PSMA-617 arm (95% CI, 0.64-1.13). The safety profile was consistent with prior experience, where hematologic toxicities, dry mouth, and fatigue were more common in the triple-therapy arm. However, this did not significantly affect QoL in these patients.10

PSMAddition overall demonstrated the potential benefits of adding 177Lu-PSMA-617 in PSMA-positive mHSPC, which could redefine the standard of care in this setting by establishing triple therapy as a viable treatment option. As radioligand therapy moves earlier in the disease continuum, ongoing research will refine patient selection and explore combination strategies to maximize long-term survival.

OptiTROP-Lung04: sacituzumab tirumotecan vs chemotherapy in pre-treated EGFR-mutated non-small cell lung cancer

 

EGFR-mutated non-small cell lung cancer (NSCLC) remains a therapeutically challenging setting once patients progress on targeted therapies. While third-generation EGFR tyrosine kinase inhibitors (TKIs) such as osimertinib have extended survival, resistance inevitably develops, and subsequent chemotherapy offers limited benefit. This has created a significant unmet need for effective post-TKI treatment options that can overcome antigen heterogeneity and resistant subclones. ADCs targeting trophoblast cell-surface antigen 2 (TROP2) have shown encouraging activity in pre-treated NSCLC, providing a rationale for evaluation in EGFR-mutated disease.11

 

The Phase III OptiTROP-Lung04 trial (NCT05870319), presented at ESMO 2025, investigated sacituzumab tirumotecan (sac-TMT), a next-generation TROP2-directed ADC, in patients with metastatic EGFR-mutated NSCLC who had progressed after at least one EGFR TKI. 376 patients were randomized 1:1 to receive sac-TMT or investigator’s choice chemotherapy (docetaxel or pemetrexed with carboplatin). The primary endpoint was progression-free survival (PFS), with OS as a key secondary endpoint.12

At a median follow-up of 18.9 months, a statistically significantly improvement in PFS was observed in patients receiving sac-TMT, where PFS was 8.3 months in the sac-TMT arm (95% CI: 6.7-9.9) and 4.3 months in the chemotherapy arm (95% CI: 4.2-5.5). The ADC additionally resulted in clinically meaningful improvements in OS. The safety profile reflected known class effects, and discontinuation rates were low, where toxicities were manageable with standard supportive care.12

The trial has established sac-TMT as a promising new treatment option for patients with pre-treated EGFR-mutated NSCLC, marking one of the first Phase III successes for ADCs in this molecularly defined population. As resistance continues to evolve, the trial reinforces the role of ADCs as an important therapeutic class capable of addressing unmet needs in EGFR-driven lung cancer.

C-POST: adjuvant cemiplimab versus placebo for high-risk cutaneous squamous cell carcinoma

 

Cutaneous squamous cell carcinoma (CSCC) is one of the most common cancers worldwide, and while most cases are cured with surgery, patients with high-risk features remain vulnerable to recurrence and metastasis. Until recently, no adjuvant systemic therapy had demonstrated a clear benefit in reducing relapse risk for this population.13

The Phase III C-POST trial (NCT03969004), presented at ASCO 2025, directly addressed this unmet need by evaluating adjuvant cemiplimab in patients with resected high-risk CSCC. In this global, randomized, double-blind study, 415 patients who had undergone complete resection and, when indicated, adjuvant radiation were assigned 1:1 to receive 350mg cemiplimab or placebo every three weeks for 12 weeks and additional 700mg cemiplimab or placebo every 6 weeks for up to 38 weeks. The primary endpoint was DFS, with key secondary endpoints including freedom from local-regional recurrence (FFLRR), freedom from distant recurrence (FFDR), OS, and safety outcomes.14

At a median follow-up of approximately 24 months, the primary endpoint was met; patients receiving cemiplimab had a DFS rate of 87.1% (95% CI: 80–92) compared to 64% (95% CI: 56–71) in patients receiving placebo. Cemiplimab also improved FFLRR (HR 0.20; 95% CI: 0.09–0.40) and FFDR (HR 0.35; 95% CI: 0.17–0.72) compared to

 

placebo. The safety profile was consistent with known PD-1 inhibitor toxicities, with fatigue, rash, and endocrinopathies being the most common immune-related adverse events.14

C-POST represents the first Phase III trial to show a statistically and clinically meaningful benefit with adjuvant immunotherapy in high-risk CSCC, leading to the FDA approval of adjuvant cemiplimab in this setting on October 8, 2025.15 These practice-changing results fill a long-standing therapeutic gap and support earlier integration of PD-1 blockade to reduce recurrence risk and improve long-term outcomes in patients with aggressive CSCC.

References

  1. Martín M, Atanasio Pandiella, Vargas-Castrillón E, Díaz-Rodríguez E, Iglesias-Hernangómez T, Concha Martínez Cano, et al. Trastuzumab deruxtecan in breast cancer. Critical reviews in oncology/hematology. 2024 Apr 1;104355–5.
  2. Harbeck N, Penault-Llorca F, Cortes J, Gnant M, Houssami N, Poortmans P, et al. Breast cancer. Nature Reviews Disease Primers. 2019 Sep 23;5(1)
  3. Geyer CE, Park YH, Shao Z-M, Huang C-S, Barrios CHE, Abraham J, et al. LBA1 Trastuzumab deruxtecan (T-DXd) vs trastuzumab emtansine (T-DM1) in patients (pts) with high-risk human epidermal growth factor receptor 2–positive (HER2+) primary breast cancer (BC) with residual invasive disease after neoadjuvant therapy (tx): Interim analysis of DESTINY-Breast05. Annals of Oncology. 2025 Sep 1;36:S1671–2.
  4. Karim F, Amin A, Liu M, Vishnuvardhan N, Amin S, Shabbir R, et al. Role of Checkpoint Inhibitors in the Management of Gastroesophageal Cancers. Cancers. 2023 Aug 14;15(16):4099.
  5. Janjigian YY, Salah-Eddin Al-Batran, Wainberg ZA, Muro K, Molena D, Cutsem EV, et al. Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). Journal of Clinical Oncology. 2025 Jun 4;43(17_suppl).
  6. S-E. Al-Batran, Z.A. Wainberg, Muro K, Molena D, E. Van Cutsem, W.J. Hyung, et al. LBA4 Event-free survival (EFS) and patient-reported outcomes (PROs) in MATTERHORN: A randomised, phase III study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel (FLOT) chemotherapy in resectable gastric/gastroesophageal junction (G/GEJ) adenocarcinoma. Annals of Oncology. 2025 Jul 1;36:S150–1.
  7. Center for Drug Evaluation and Research. FDA approves durvalumab for resectable gastric or gastroesophageal junction adenocarcinoma [Internet]. U.S. Food and Drug Administration. 2025 [cited 2025 Dec 11]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-durvalumab-resectable-gastric-or-gastroesophageal-junction-adenocarcinoma
  8. Capasso G, Stefanucci A, Tolomeo A. A systematic review on the current status of PSMA-targeted imaging and radioligand therapy. European Journal of Medicinal Chemistry. 2023 Nov 17;263.
  9. Tsung I, Yentz SE, Reichert ZR. Controversies in metastatic hormone‐sensitive prostate cancer. Cancer. 2025 Aug 7;131(16):e70030–
  10. Sartor O, J.M. Piulats, Saad F, K. Fizazi, Beltran H, Kramer G, et al. LBA6 Phase III trial of [177Lu]Lu-PSMA-617 combined with ADT + ARPI in patients with PSMA-positive metastatic hormone-sensitive prostate cancer (PSMAddition). Annals of Oncology. 2025 Sep 1;36:S1742–3.
  11. Zhao J, Xu W, Zhou F, Zhang X, Zhou M, Miao D, et al. Navigating the landscape of EGFR TKI resistance in EGFR-mutant NSCLC — mechanisms and evolving treatment approaches. Nature Reviews Clinical Oncology. 2025 Nov 11;.
  12. Zhang L, Fang WF, Wu L, Meng X, Yao Y, Zuo W, et al. LBA5 Sacituzumab tirumotecan (sac-TMT) vs platinum-based chemotherapy in EGFR-mutated (EGFRm) non-small cell lung cancer (NSCLC) following progression on EGFR-TKIs: results from the randomized, multi-center phase III OptiTROP-Lung04 study. Annals of Oncology. 2025 Sep;36:S1728–9.
  13. Dessinioti C, Stratigos AJ. Recent Advances in the Diagnosis and Management of High-Risk Cutaneous Squamous Cell Carcinoma. Cancers. 2022 Jul 21;14(14):3556.
  14. Rischin D, Porceddu SV, Day F, Brungs D, Christie HR, Jackson JE, et al. Phase 3 trial of adjuvant cemiplimab (cemi) versus placebo (pbo) for high-risk cutaneous squamous cell carcinoma (CSCC). Journal of Clinical Oncology. 2025 May 28;43(16_suppl):6001–1.
  15. Center for Drug Evaluation and Research. FDA approves cemiplimab-rwlc [Internet]. U.S. Food and Drug Administration. 2025 [cited 2025 Dec 11]. Available from: https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-cemiplimab-rwlc-adjuvant-treatment-cutaneous-squamous-cell-carcinoma

Written by Stephanie Coombe-Whitlock

The content of VJOncology is intended for healthcare professionals