First-in-Class Mechanisms and Notable Oncology Approvals at FDA and EMA, 2025–2026

First-in-class mechanisms and notable oncology approvals at FDA and EMA, September 2025 to September 2026

Between late September 2025 and late September 2026, FDA's new molecular entity (NME) and original BLA approvals included more than a dozen oncology and malignant haematology products. The table below is selective. Lirafugratinib (Lyrfigtu), an FGFR2 kinase inhibitor, was approved on 23 September 2026 for previously treated unresectable or metastatic cholangiocarcinoma with an FGFR2 fusion or other rearrangement; it is an in-window oncology NME but not a new target class. Several introduced targets or modalities not previously approved: a cyclophilin A-dependent RAS tri-complex inhibitor, the first approved heterobifunctional protein degrader (PROTAC), and a first-in-class CD123-directed antibody-drug conjugate. Over the same period the EU authorised a cluster of oncology products, three of them conditional, and CHMP issued several negative oncology opinions. Outside oncology, FDA and CHMP documents explicitly describe a number of approvals as first-in-class or first-of-type, including the first small-molecule GLP-1 receptor agonist, the first oral PCSK9 inhibitor and a first-in-class aldosterone synthase inhibitor.

This overview summarises the mechanism, regulatory pathway and pivotal evidence for each product, using the language of the FDA review documents, labels and EMA assessment materials. Where a source does not call a product "first-in-class", this article does not either. The mechanism is described instead.

FDA oncology approvals at a glance

New target classes and first-of-type modalities

Daraxonrasib: RAS(ON) tri-complex inhibition in pancreatic cancer

Daraxonrasib binds cyclophilin A to form a binary complex that engages active, GTP-bound RAS. The resulting tri-complex blocks effector binding and promotes hydrolysis to inactive GDP-bound RAS, with activity against wild-type and mutant KRAS, NRAS and HRAS ¹³³⁰. It was approved on 26 August 2026 under priority review ¹²³⁶ for metastatic pancreatic adenocarcinoma after at least one prior systemic therapy, or in patients who are not candidates for multiagent therapy ¹³³¹.

The evidence is a randomised overall survival result. In RASolute 302, daraxonrasib (N=248) was compared with physician's-choice chemotherapy (N=252). Median OS was 13.2 vs 6.7 months (HR 0.40, 95% CI 0.30 to 0.53) and median PFS was 7.2 vs 3.6 months (HR 0.49). ORR was 30% vs 11% ¹²³⁶. Results were consistent in the RAS G12 subgroup (n=459; OS HR 0.40) ¹²³⁶. Labelled warnings cover dermatologic toxicity, stomatitis, diarrhoea, GI perforation, ILD/pneumonitis and embryo-fetal toxicity ¹³³¹. The retrieved documents do not state whether the approval was regular or accelerated.

Vepdegestrant: the first approved heterobifunctional protein degrader

Vepdegestrant is a PROTAC that binds both the estrogen receptor and the E3 ligase cereblon, driving ER polyubiquitination and proteasomal degradation ¹³⁸⁹. FDA describes the approval as the first in the heterobifunctional protein degrader established pharmacologic class, which covers PROTACs ¹³⁶⁸. The indication is ER+/HER2−, ESR1-mutated advanced breast cancer after at least one endocrine therapy ¹³⁷³.

In VERITAC-2 (vepdegestrant N=313 vs fulvestrant N=311), BICR-assessed median PFS in the ESR1-mutated population (N=270) was 5.0 vs 2.1 months (HR 0.57, 95% CI 0.42 to 0.77). Confirmed ORR was 19% vs 4%, and OS was immature ¹²⁰². QTc prolongation is a labelled warning: mean ΔQTcF was 10.9 ms, and QT-prolongation SMQ events occurred in 11% vs 1% ¹³⁷¹.

Pivekimab sunirine: first-in-class CD123 ADC for BPDCN

FDA review materials describe pivekimab sunirine as a first-in-class CD123-directed antibody-drug conjugate carrying a DNA-alkylating payload ¹³¹⁵. CD123 itself was already a validated target in BPDCN, because tagraxofusp was approved earlier ^13151316. The BLA received priority review ¹²⁹⁹. FDA supported regular rather than accelerated approval, treating CR/CRc with durability as a direct clinical-benefit endpoint in BPDCN ^13141315.

The evidence came from a single-arm study, CADENZA (Phase 1/2). In the primary analysis population of 20 patients with newly diagnosed de novo BPDCN, FDA-adjudicated CR/CRc was 75% (95% CI 50.9 to 91.3) with a median DOR of 10.6 months ^13001302. In relapsed/refractory disease, CR/CRc was 15.7% ^13021310. The label carries a boxed warning for hepatotoxicity including veno-occlusive disease ¹³¹⁰.

Other mechanistically distinct oncology NMEs

• Ziftomenib (menin inhibitor). It disrupts the menin–KMT2A interaction and represses HOXA9/MEIS1 programmes ^12071209. FDA accepted the Phase 2 cohort of KO-MEN-001 plus confirmatory Phase 1b data as substantial evidence: pooled CR/CRh was 21.4% and median response duration 5.0 months. Reviewers noted uncertainty from the modest response rate and short follow-up ^12051206. Differentiation syndrome occurred in 26% of patients ¹²⁰⁶.
• Relacorilant (GR antagonist). This oral glucocorticoid receptor antagonist is proposed to restore tumour-cell sensitivity to taxane chemotherapy ¹⁴¹⁹. In ROSELLA (N=381), adding relacorilant to nab-paclitaxel improved PFS (HR 0.70) and OS (median 16.0 vs 11.9 months; HR 0.65, p=0.0004) ^14201421. Adrenal insufficiency and neutropenia are labelled risks ¹⁴²⁶.
• Rusfertide (hepcidin mimetic). Rusfertide blocks ferroportin to limit iron available for erythropoiesis ¹¹³⁷. In the placebo-controlled VERIFY trial (N=293), 76.9% vs 32.9% of patients had no phlebotomy eligibility from Week 20 to 32 (p<0.0001). Mean phlebotomies fell to 0.53 vs 1.82 ^13931132. Thrombocytosis is a labelled warning ¹¹³⁶.

Breast cancer: the estrogen receptor pathway

Several ER-pathway agents were authorised in the US or EU in the period, including an in-window FDA expansion of imlunestrant.

• Camizestrant (FDA and EU). SERENA-6 tested a ctDNA-guided switch: patients with an ESR1 mutation detected before progression on first-line AI + CDK4/6 inhibitor were randomised to switch to camizestrant or continue the AI ¹³³⁶. Median PFS was 16.0 vs 9.2 months (HR 0.44). OS was 12% mature ¹⁰¹⁷. FDA granted accelerated approval, with PFS measured from ESR1-mutation detection ¹³³⁹. The label carries a boxed warning for arrhythmia risk with QTc-prolonging drugs, particularly ribociclib ¹³³⁹. The EU authorised Etcamah on 20 July 2026 with a post-authorisation efficacy study on long-term efficacy due by 31 December 2028 ¹³²¹.
• Imlunestrant (FDA and EU). FDA approved Inluriyo monotherapy on 25 September 2025 for ER+/HER2−, ESR1-mutated advanced breast cancer after at least one endocrine therapy. The EU authorised it on 9 January 2026 as a new active substance for ESR1-mutated disease ^11451143. In EMBER-3, the ESR1-mutated monotherapy subgroup showed a PFS benefit (BIRC HR 0.657) ¹¹³⁸. The ITT monotherapy comparison missed its primary endpoint (HR 0.867, p=0.1158) ¹¹⁴⁴. CHMP flagged investigator/BIRC discordance, a small benefit after prior CDK4/6 inhibition, and an unexpectedly favourable OS signal, and required a final OS analysis after authorisation ¹¹³⁸. On 18 September 2026 FDA approved imlunestrant plus abemaciclib for the same ESR1-mutated population after endocrine therapy. In an exploratory ESR1-mutated subgroup (n=159), investigator-assessed PFS was 11.1 vs 5.5 months versus imlunestrant alone (HR 0.53, 95% CI 0.35 to 0.80). FDA did not find a monotherapy benefit versus investigator's-choice endocrine therapy in the overall or ESR1-mutation-not-detected populations.
• Gedatolisib (FDA). It targets all class I PI3K isoforms plus mTOR ¹²⁷⁰. In the three-arm VIKTORIA-1 trial in PIK3CA wild-type disease after CDK4/6 inhibition, median PFS was 9.3 months with the triplet vs 2.0 months with fulvestrant (HR 0.24). The doublet reached 7.4 months (HR 0.33) ¹²⁷⁹. Interim OS was not statistically significant (HR 0.69) ¹²⁷¹.

Thoracic oncology

• Sevabertinib (FDA). Accelerated approval on 19 November 2025 for HER2 TKD-mutant non-squamous NSCLC after prior systemic therapy, based on ORR and DOR from Phase 1/2 Study 21607 ^11691168. FDA limited that indication to TKD mutations because ORR was 74.4% in TKD-mutant disease vs 25.0% in non-TKD mutations ¹¹⁶⁹. On 9 September 2026 FDA expanded the accelerated approval to HER2 TKD-mutant disease with no prior-therapy requirement, based on SOHO-01 (treatment-naive, n=69): BICR ORR 75% (95% CI 64 to 85).
• Zidesamtinib (FDA). Regular approval for ROS1+ NSCLC after a prior ROS1 TKI ¹³⁶⁰. In ARROS-1 (N=117), ORR was 44%; 69% of responders had DOR of 12 months or more ¹³⁵². Intracranial ORR was 48% ¹³⁵⁹, and 54% of patients with the G2032R solvent-front mutation responded ¹³⁴⁶.
• Tarlatamab (FDA and EU). FDA converted the 2024 accelerated approval of Imdelltra to traditional approval on 19 November 2025 for ES-SCLC after platinum chemotherapy. The EU authorised Imdylltra on 29 May 2026 for the same setting ⁹⁸⁰. DeLLphi-304 (N=509) showed OS of 13.6 vs 8.3 months vs chemotherapy (HR 0.60) ⁹⁸⁵⁹⁸¹. CHMP noted uncertain benefit where DLL3 expression is below 25% (OS HR 0.954) ⁹⁸⁵. CRS and ICANS require additional risk minimisation ⁹⁹¹.
• Lurbinectedin (FDA and EU). FDA approved Zepzelca plus atezolizumab, or atezolizumab and hyaluronidase, on 2 October 2025 as ES-SCLC maintenance after induction. The EU authorised the combination on 29 May 2026 ¹²⁸⁶. In IMforte (N=483), OS was 13.2 vs 10.6 months (HR 0.74) ¹²⁹².
• Aumolertinib (EU). Aumseqa, a mutant-selective EGFR TKI and new active substance, was authorised on 12 February 2026 ^10181026. AENEAS showed a 9.4-month median PFS gain vs gefitinib ¹⁰¹⁹. In T790M disease, the single-arm ORR was 68.9% ¹⁰¹⁹. CHMP identified VTE, rhabdomyolysis and QT prolongation as new safety issues ¹⁰²¹.

Haematologic malignancies

• Iberdomide: MRD as the basis for accelerated approval. FDA granted accelerated approval to iberdomide + daratumumab SC + dexamethasone on MRD-negative CR at any time ^11081109. In EXCALIBER-RRMM, the MRD-negative ≥CR rate was 41% vs 21% with daratumumab-bortezomib-dexamethasone (p<0.0001) ¹¹²⁴. The label carries a boxed warning for embryo-fetal toxicity (with a REMS) and thromboembolism ¹¹⁰⁹.
• Sonrotoclax. Accelerated approval in R/R MCL based on Study 201 (N=103): ORR 52.4%, CR 15.5%, median DOR 15.8 months ^140614131281.
• Belantamab mafodotin. The BCMA ADC returned to the US market on 23 October 2025 on DREAMM-7 data. In patients with at least 2 prior lines, median PFS was 31.3 vs 10.4 months vs daratumumab-bortezomib-dexamethasone (HR 0.31), with OS HR 0.49 ⁹⁷². A boxed warning and REMS for ocular toxicity apply ¹³⁹⁴. Severe or very severe blurred vision was patient-reported in 55% vs 15% ⁹⁷³.

EU oncology authorisations and CHMP outcomes

Beyond the thoracic and breast products above, three EU oncology authorisations were conditional marketing authorisations built on single-arm pivotal studies:

CHMP highlights at the time noted that no medicine was authorised in the EU for BCG-unresponsive CIS when Anktiva was recommended ^13241325. In September 2026, CHMP recommended three further oncology new medicines: ensartinib for ALK+ NSCLC, relacorilant for platinum-resistant ovarian cancer and senaparib for ovarian cancer maintenance ¹³²². On the negative side, CHMP issued negative opinions for Tacquell, an autologous tumour-infiltrating lymphocyte product for advanced melanoma ¹³²⁷; for Qezzaqar (catequentinib) in synovial sarcoma or leiomyosarcoma ¹³⁶², which is under re-examination ¹³²²; and for the diagnostic Deqtynet (copper-64 oxodotreotide) ¹³²⁶. The initial application for Amtagvi (lifileucel) was withdrawn ¹³²⁸. CHMP also declined the Opdualag extension to PD-L1 ≥1% melanoma ¹³⁶⁵.

First-in-class mechanisms outside oncology

The table below lists non-oncology approvals where the FDA or EMA source explicitly uses first-in-class, first-of-type or new-class language.

EMA also highlighted first-treatment milestones, supported by PRIME, for brensocatib in non-cystic fibrosis bronchiectasis ¹⁴¹⁷ and doxecitine/doxribtimine in thymidine kinase 2 deficiency, which received a positive opinion under exceptional circumstances ¹³⁶⁶.

Several other approvals act through mechanisms new to their disease, although the retrieved FDA documents do not use first-in-class wording:

• Oveporexton, an orexin-2 receptor agonist for narcolepsy type 1. MWT sleep latency improved by up to +20.1 min vs placebo ⁹⁵⁷⁹⁵¹.
• Apitegromab, an anti-latent myostatin antibody used alongside SMN2-targeted therapy in SMA. HFMSE difference +2.2; fracture warning ^115511481167.
• Garetosmab in FOP. New heterotopic ossification lesions fell by 90% to 94% in OPTIMA ¹⁰⁷².

Evidence patterns relevant to regulatory strategy

1. Surrogate endpoints for accelerated approval are broadening. FDA accelerated approvals in the period rested on MRD-negative CR (iberdomide) ¹¹⁰⁸, ORR/DOR (sonrotoclax, sevabertinib) ^12821169, PFS measured from ctDNA mutation detection (camizestrant) ¹³³⁹, CSF heparan sulfate reduction (tividenofusp alfa) ⁹⁹⁶⁹⁹⁷, and proteinuria (sibeprenlimab) ¹¹⁹⁷.
2. Single-arm data still support approval in rare or refractory settings, but with explicit caveats. FDA noted uncertainty in the ziftomenib response rate and durability ¹²⁰⁵. CHMP tied every single-arm oncology authorisation above to a conditional MA with a randomised confirmatory study ^100212251036.
3. Randomised OS benefits anchored the strongest approvals. Examples are daraxonrasib (HR 0.40) ¹²³⁶, belantamab mafodotin (HR 0.49) ⁹⁷², tarlatamab (HR 0.60) ⁹⁸¹, relacorilant (HR 0.65) ¹⁴²¹ and lurbinectedin maintenance (HR 0.74) ¹²⁹².
4. Biomarker boundaries were drawn from the data. FDA narrowed sevabertinib to HER2 TKD mutations ¹¹⁶⁹. The EU restricted imlunestrant to ESR1-mutated disease after the ITT analysis failed ¹¹⁴⁴. CHMP flagged low-DLL3 tumours as an efficacy uncertainty for tarlatamab ⁹⁸⁵.
5. FDA and EMA did not always reach the same view. FDA approved Yartemlea (narsoplimab-wuug) on 23 December 2025 for HSCT-associated thrombotic microangiopathy. Reviewers recorded an independent responder rate of 43%, against 61% reported by the applicant, and noted trial-conduct concerns, but those findings did not block approval ¹⁰¹⁶. CHMP adopted a negative opinion in June 2026, and the applicant said it would request re-examination ¹³²⁷. Belumosudil shows the effect of re-examination in the EU: CHMP gave a negative opinion in October 2025 ¹⁴¹⁷ and then recommended a conditional MA in January 2026 ¹³⁶⁶.