A comprehensive clinical reference covering the most consequential therapeutic advances across all major US cancer types — ADCs, CAR-T, bispecifics, KRAS inhibitors, radioligand therapy, and precision oncology at the frontier.
The 2025 oncology therapeutic landscape is undergoing a structural transformation. For the first time, the majority of FDA oncology approvals are mechanism-based precision agents rather than cytotoxic chemotherapy — driven by ADC engineering, bispecific antibody platforms, KRAS inhibitor breakthroughs, radioligand therapy, and next-generation CAR-T constructs. This reference synthesizes the most clinically consequential developments across all major US cancer types.
ADCs have emerged as the most productive drug class in oncology. Trastuzumab deruxtecan (T-DXd, ENHERTU) has demonstrated activity across HER2-expressing tumors regardless of histology — establishing a pan-tumor HER2-directed paradigm. The bystander killing effect of topoisomerase-I payloads enables efficacy even in HER2-low tumors. >25 ADCs now in late-stage development across all major solid tumors.
Solid tumor CAR-T is progressing from proof-of-concept to early efficacy signals. Next-gen CAR-T designs incorporate multi-antigen targeting, armored/TEAM constructs (cytokine secretion), and allogeneic off-the-shelf platforms. Hematologic CAR-T (BCMA, CD19, CD22) is increasingly reaching curative intent. TIL therapy (lifileucel) became the first solid tumor cellular therapy FDA-approved in 2024.
Sotorasib and adagrasib validated the long-considered "undruggable" KRAS G12C target, now approved in NSCLC and CRC. Pan-KRAS inhibitors targeting G12D (the most prevalent KRAS mutation, dominant in PDAC) represent the next frontier — with RMC-9805, MRTX1133, and HRS-4642 advancing through Phase 1/2. KRAS G12C covers ~13% NSCLC, ~3% CRC, ~2% PDAC; G12D covers ~40% of PDAC.
Lutetium-177 PSMA (Lu-PSMA-617, Pluvicto) in mCRPC and Lu-177 DOTATATE (Lutathera) in NETs established RLT as a clinical pillar. Actinium-225 conjugates (alpha emitters) show dramatically higher linear energy transfer — PSMA-targeted Ac-225 demonstrating deep responses in heavily pre-treated mCRPC. RLT platforms are being extended to SSTR2 (lung NETs), FAPI (fibroblast activation), GRP78, and carbonic anhydrase IX targets.
T-cell engager bispecifics (TCEs) have achieved meaningful response rates in hematologic malignancies — blinatumomab (CD19×CD3), mosunetuzumab, epcoritamab, glofitamab (CD20×CD3) are approved. In solid tumors, tarlatamab (DLL3×CD3) for SCLC received accelerated FDA approval 2024 — the first TCE approved for a solid tumor. >60 bispecific constructs now in oncology pipelines.
TMB-high (pembrolizumab), MSI-H/dMMR (pembrolizumab), NTRK fusions (larotrectinib, entrectinib), RET fusions (selpercatinib), BRAF V600E (dabrafenib+trametinib), HER2 (T-DXd) — the pan-tumor approval pathway has matured. Basket trials now routinely identify histology-independent response signals. Liquid biopsy ctDNA screening is enabling population-level tumor-agnostic drug matching that was logistically impossible 5 years ago.
KRAS G12C, EGFR exon 20, HER2, MET, RET, NTRK — most biomarker-driven of all solid tumors.
ADC revolution (T-DXd, SG), CDK4/6 combinations, PARP inhibitors, PI3K/AKT pathway.
KRAS G12C (sotorasib+cetuximab), HER2 amplification, BRAF V600E, RAS-WT EGFR therapy.
PSMA radioligand therapy, PARP inhibitors (BRCA1/2), AR pathway evolution, BiTE.
KRAS G12D inhibitors, PARP (BRCA-mutant), FOLFOX/NALIRIFOX, KRAS-targeted vaccines.
BRAF/MEK, nivolumab+relatlimab (LAG-3), TIL therapy (lifileucel), anti-PD-1 adjuvant.
CAR-T curative intent, bispecific TCEs, BTK degraders, BCL-2 inhibitors, menin inhibitors.
FGFR3 inhibitors, EV+pembrolizumab (1L mUC), ADC combinations, nectin-4 targeting.
The defining shift of the current era is the collapse of the traditional histology-first treatment paradigm. Molecular profiling — not organ of origin — increasingly determines treatment selection across virtually every solid tumor type. The approvals of trastuzumab deruxtecan across multiple HER2-expressing histologies, pembrolizumab in TMB-high and MSI-H tumors regardless of site, and larotrectinib/entrectinib in NTRK-fusion positive cancers have made pan-tumor biomarker testing not merely optional but standard-of-care. Comprehensive genomic profiling (CGP) at diagnosis is now supported by NCCN guidelines across most major cancer types.
Simultaneously, the ADC platform has achieved pharmacologic critical mass. Trastuzumab deruxtecan's 5.6-month PFS improvement over physician's choice in pretreated HER2-low breast cancer — a population previously considered HER2-negative — has expanded the targetable universe of HER2 therapy to an estimated 60% of all metastatic breast cancer patients. The same bystander-killing pharmacology is being leveraged against TROP2, HER3, Nectin-4, PTK7, CDH6, and ROR1 across multiple histologies.
Select a cancer type from the navigation above to see detailed emerging therapy breakdowns, key trial data, biomarker profiles, and 2025 treatment frameworks.
MARIPOSA demonstrated amivantamab + lazertinib superiority over osimertinib monotherapy in treatment-naïve EGFR-mutant NSCLC. PFS HR 0.70 establishes the first combination challenge to osimertinib 1L dominance since FLAURA. PAPILLON independently validated amivantamab + chemo in EGFR exon 20 insertions, a historically difficult-to-treat population.
DeLLphi-301 established tarlatamab as the standard second-line option for ES-SCLC. ORR 40% and mDOR 9.7 months in an otherwise chemorefractory setting represents a meaningful clinical advance. DeLLphi-304 is now testing 1L tarlatamab + chemoradiotherapy in limited-stage SCLC with curative intent — a landmark trial for SCLC.
CodeBreaK 200 demonstrated PFS superiority for sotorasib over docetaxel in 2L KRAS G12C+ NSCLC. OS was non-significant partly due to crossover, raising questions about optimal sequencing. Combination strategies (sotorasib + pembrolizumab showing increased hepatotoxicity; sotorasib + EGFR inhibition) are being explored to deepen responses and address primary resistance.
TROPION-Lung01 confirmed Dato-DXd as a viable docetaxel alternative in pretreated non-squamous NSCLC. PFS HR 0.75 and improved tolerability profile. TROPION-Lung08, combining Dato-DXd + pembrolizumab as 1L treatment, has the potential to establish a chemo-free backbone — awaiting OS readout.
NSCLC now has more FDA-approved targeted therapies than any other cancer type — yet the majority of KRAS-mutant, STK11-mutant, and KEAP1-mutant patients still lack effective precision options. The amivantamab+lazertinib data from MARIPOSA represents the first credible challenge to osimertinib monotherapy in 1L EGFR+ NSCLC — pending OS maturity, this combination may become a new standard of care. The unresolved question is whether adding VEGFR (ramucirumab), MET (savolitinib), or bispecific targeting to osimertinib backbone can delay or prevent the inevitable C797S/MET resistance mechanisms.
In SCLC, tarlatamab's FDA approval is the most significant advance since atezolizumab was added to first-line chemo in 2019. DeLLphi-304 — testing tarlatamab in 1L limited-stage SCLC — represents potentially the highest-impact SCLC trial currently enrolling.
The HER2-low paradigm established by DESTINY-Breast04 is arguably the most consequential breast cancer approval since trastuzumab. Redefining ~60% of all mBC patients as HER2-targetable changes the fundamental treatment architecture of the disease. DESTINY-Breast06 has extended this further to HER2 ultralow — a population that was previously classified as HER2-zero and thus ineligible. The pending question is whether 1L T-DXd (DESTINY-Breast09) can displace taxane+trastuzumab in HER2-positive disease.
In HR+/HER2– disease, the convergence of CDK4/6 inhibitors, oral SERDs (elacestrant and next-generation), PI3K/AKT inhibitors, and ADCs creates an unprecedented number of sequencing options after CDK4/6+AI failure — but also a growing challenge of evidence-based sequencing in clinical practice. ESR1 mutation testing via liquid biopsy at progression is now essential.
CRC has crossed a threshold where molecular profiling at diagnosis directly changes treatment selection for ≥30% of newly diagnosed metastatic patients — MSI-H (pembrolizumab 1L), BRAF V600E (encorafenib+cetuximab), KRAS G12C (sotorasib/adagrasib+cetuximab), HER2+ (tucatinib+trastuzumab). Universal comprehensive genomic profiling at mCRC diagnosis is no longer an academic consideration — it is required to implement standard of care.
The KRAS G12C breakthrough (CodeBreaK 300, KRYSTAL-10) is particularly consequential because it validates combination KRAS+EGFR co-targeting as a pharmacologic principle — demonstrating that KRAS inhibitor monotherapy is insufficient in CRC due to EGFR-mediated feedback reactivation. This principle is informing rational pan-RAS+EGFR combination design for G12D and G12V mutations.
The PSMA theranostic platform — PET/CT for selection, lutetium for treatment — has become the defining advance in mCRPC management. PSMAfore's data establishing Lu-177-PSMA before docetaxel (rPFS HR 0.41) positions radioligand therapy as potentially a second-line standard before chemotherapy, restructuring the mCRPC treatment sequence. If PSMAddition's OS results demonstrate benefit in the mHSPC 1L setting, PSMA-directed therapy will move into the hormone-sensitive disease space.
The alpha emitter (Ac-225 PSMA) data in Lu-177-refractory patients represents the most active therapeutic signal in that population and may define a sequential RLT paradigm. Combining PSMA radioligand therapy with PARP inhibitors (for DNA damage repair synergy) and AR pathway agents is the most scientifically rational combination strategy and is actively being explored.
PDAC stands at a historic inflection point. KRAS has been mutated in ~95% of PDAC for 40 years and considered entirely undruggable — the validation of KRAS G12C inhibition in NSCLC and CRC, combined with first-in-human KRAS G12D inhibitor data now emerging from Phase 1, represents the most consequential mechanistic advance in pancreatic oncology since gemcitabine. KRAS G12D (~40% PDAC), G12V (~32%), and G12R (~16%) collectively cover ~88% of KRAS-mutant PDAC — the pipeline now targets all three.
The autogene cevumeran mRNA vaccine data — demonstrating that 50% of adjuvant PDAC patients mounted measurable T-cell immunity against their personal KRAS neoantigens, with the T-cell responders showing dramatically improved recurrence-free survival — is the strongest signal for immunotherapy in PDAC ever reported. The Phase 3 confirmatory trial is the most important PDAC trial currently enrolling.
Melanoma continues to be the proving ground for cancer immunotherapy. The mRNA-4157 neoantigen vaccine data from KEYNOTE-942 — a 44% reduction in recurrence risk when added to adjuvant pembrolizumab — is the strongest signal for therapeutic cancer vaccination ever reported in a randomized trial. If the Phase 3 confirmatory trial (V940-001) replicates this, individualized mRNA cancer vaccines will enter the oncology mainstream with immediate applicability to other cancer types including NSCLC and TNBC.
Lifileucel's FDA approval as the first TIL therapy in any cancer is a regulatory milestone, even with a modest 31.5% ORR in a heavily pre-treated population. The precedent — that expanded autologous tumor-infiltrating lymphocytes can achieve durable responses in IO-refractory patients — is directly enabling next-generation TIL engineering (PD-1 knockout, cytokine armoring, TCR-enhanced) across multiple solid tumors.
CAR-T cell therapy has moved from salvage therapy to earlier lines of treatment in multiple myeloma — CARTITUDE-4's PFS HR of 0.26 in patients with only 1–3 prior lines essentially establishes ciltacabtagene autoleucel as a potentially curative-intent intervention in transplant-ineligible myeloma patients. The convergence of CAR-T (cidta-cel, ide-cel) and bispecific TCEs (teclistamab, elranatamab, talquetamab) has created a completely new treatment architecture for relapsed myeloma that renders older triplet regimens largely obsolete.
In AML, the menin inhibitor class (revumenib, ziftomenib) represents the most mechanistically novel advance in decades — directly reversing the transcriptional program driven by KMT2A rearrangements that has resisted targeted therapy for 30 years. Combination with venetoclax+azacitidine backbone is now the priority development direction.
EV-302 has fundamentally restructured mUC treatment. An OS HR of 0.47 versus gemcitabine-platinum — and an ORR of 68% in an all-comer population — makes EV+pembrolizumab one of the most impactful combination approvals in solid tumor oncology of the past decade. The fact that this combination works regardless of cisplatin eligibility eliminates the fitness-based treatment bifurcation that complicated mUC management for 20 years.
The critical emerging challenge is now defining optimal treatment after EV+pembrolizumab failure — a population that will grow substantially as 1L EV-pembro becomes universal. Sacituzumab govitecan, HER2-directed ADCs, and FGFR3 inhibitors (for the ~20% FGFR3-altered subpopulation) are the leading candidates for this emerging post-EV-pembro treatment space.
PARP inhibitor frontline maintenance has achieved its maximum impact in BRCA-mutant and HRD+ ovarian cancer — SOLO-1's 7-year OS data confirming HR 0.55 in BRCA-mutant patients represents the most durable improvement in high-grade serous EOC ever documented. The critical question now is managing PARP resistance and treating the ~50% HRD-negative population that derives limited PARP inhibitor benefit. Mirvetuximab soravtansine (MIRASOL OS benefit confirmed) is the first ovarian cancer ADC approval and validates FRα as a target — now being explored in earlier lines and non-HGSOC histologies.
UPLIFT's NaPi2b-ADC Phase 3 readout is the most anticipated ovarian trial of 2025. If ORR signals from Phase 2 (43%) translate to OS benefit over paclitaxel, UpRi will become the preferred second ADC option in platinum-resistant ovarian cancer — and will sharpen the question of FRα vs NaPi2b testing and sequencing.
HCC has undergone a fundamental shift from a disease with essentially one active systemic agent (sorafenib, 2008–2018) to a disease with three competing 1L immunotherapy-based combinations. The adjuvant nivolumab approval post-resection/ablation (CheckMate 9DX, FDA April 2024) represents a new treatment paradigm for curative-intent HCC management — for a cancer where ~70% of patients recur within 5 years post-resection, adjuvant IO could be practice-changing if the DFS benefit is confirmed to translate to OS.
GPC3-directed cellular therapy and ADC development is the most distinctive HCC-specific pipeline — the high and specific GPC3 expression in ~75% of HCC tumors provides both selectivity and a biomarker-selectable patient population. CAR-T in HCC faces the core solid tumor obstacles (trafficking, TME immunosuppression, antigen heterogeneity) but the GPC3 target remains one of the cleanest solid tumor CAR-T opportunities in the field.
Zolbetuximab's FDA approval in 2024 marks the most significant paradigm shift in gastric cancer biomarker testing since HER2 in 2010. CLDN18.2 testing is now mandated at initial mGAC diagnosis — creating a new molecularly stratified treatment decision that was not possible before SPOTLIGHT/GLOW. The rapid pipeline evolution to CLDN18.2-directed ADCs (CMG901, SYSA1801) and bispecifics (AMG 910) suggests CLDN18.2 antibody monotherapy may be superseded by ADC-based approaches within 2–3 years, pending Phase 3 data.
HER2+ gastric has the most active pipeline of any gastric subtype — KEYNOTE-811 (pembro+trastuzumab+chemo), T-DXd (2L), and zanidatamab (HER2-biparatopic bispecific) collectively provide potentially curative-intent options in a previously 14-month median OS disease. EBV-positive gastric cancer remains the most under-recognized IO-exceptional subtype in GI oncology — ORR >50% with pembrolizumab monotherapy warrants universal EBER IHC testing at diagnosis.
Thyroid cancer has transformed from a disease managed almost entirely with RAI and surgery into one of the most molecularly actionable cancers in oncology. RET inhibitor therapy (selpercatinib, pralsetinib) has achieved ORRs of 60–89% in RET-altered thyroid cancer — response rates that rival the best TKI approvals in any cancer type. LIBRETTO-531's PFS HR of 0.28 versus the prior cabozantinib/vandetanib standard has made selpercatinib the unambiguous preferred treatment for RET-mutant MTC.
The outstanding challenge is anaplastic thyroid cancer in the ~60% without BRAF V600E — a population with essentially no effective systemic options and median OS under 6 months. Immune combinations, RAS-directed approaches, and anti-CTLA4 strategies are all under investigation, but ATC in the BRAF-WT population remains one of the most urgent unmet needs in all of oncology.
The pediatric oncology molecular revolution was catalyzed by the RACE for Children Act (2017) — which mandated that adult oncology clinical trials include pediatric cohorts when biologically relevant. The result has been a 10-fold increase in pediatric oncology FDA approvals between 2017 and 2025, with NTRK inhibitors (larotrectinib, entrectinib), ALK inhibitors, and BRAF/MEK combinations leading the approvals.
The most profound advance is ONC201 (dordaviprone) in H3 K27M-mutant DIPG — a tumor that has killed children within 9 months of diagnosis for decades with no proven systemic therapy. FDA accelerated approval in 2024 marks the first regulatory approval specifically for DIPG in history. The H3 K27M mutation's near-universal presence in DIPG (~80%) makes this an unusually biomarker-homogeneous target population. ONC206 and next-generation compounds building on this mechanism are the immediate clinical priority.