Highlights from ASCO 2026

The American Society of Clinical Oncology (ASCO)’s annual meeting is a mainstay in the Chicago, IL, USA calendar, bringing together up to 45,000 oncology professionals from more than 100 countries. PSI’s Rhonda Critchlow, Emily McInturf, Anupama Acheson, Nabila Chowdhury, and Jenna Zalud provide their takeaways and thoughts on some of the major stories from this year’s meeting and how they will impact clinical development, including:

  • How the RASolute 302 trial may have changed the face of pancreatic cancer treatment
  • Why the future of TCEs depends on careful engineering, finding new targets, and combination approaches
  • If immunotherapy and ADCs are living up to their revolutionary promise
  • How the evolution of personalized immunotherapy is the next oncology frontier
  • Whether China can sustain its momentum in influencing global clinical development strategies

Daraxonrasib may have changed the pancreatic cancer landscape

Widely covered across multiple news outlets worldwide, one of the biggest stories at ASCO 2026 was the positive results from Revolution Medicines, Inc.’s phase 3 RASolute 302 trial of daraxonrasib in patients with previously-treated metastatic pancreatic ductal adenocarcinoma (mPDAC) [1]

This breakthrough, presented during the plenary session, showcased improvements for the RAS G12 mutant population in median overall survival (13.2 months vs. 6.6 months with standard chemotherapy), 12-month overall survival rates (53.3%, vs. 18.7%, respectively) and median progression-free survival (7.3 months vs. 3.5 months, respectively). Additional, important measures, such as quality-of-life improvements, delayed time to deterioration in pain, and fewer treatment-related adverse events, coupled with an easier mode of administration than current standards of care, led to a standing ovation in the packed ASCO auditorium. The results are widely viewed as practice-changing and are expected to support adoption as a new standard of care pending regulatory and guideline incorporation.

The results of RASolute 302 were not an incremental gain, but a showcase of one of the most important pancreatic cancer results in decades. Finally unlocking the power of RAS (multi-selective) inhibitors in pancreatic cancer could begin renewed interest across the broader RAS-targeting space; sponsors working on difficult targets may view this as proof that persistence can eventually unlock major commercial and clinical value.

profile photo of anupama acheson

The daraxonrasib results are just part of the story – KRAS as a viable target has been elusive for more than 50 years (“undruggable”), so these results could transform RAS-directed therapies from an experimental niche to a major therapeutic class. Sponsors with RAS assets may find themselves in a significantly stronger position post-ASCO

Anupama Acheson, MD, PSI Medical Monitoring and Consulting

Advanced strategies with T-cell engagers

T‑cell engagers (TCEs) are redefining immunotherapy as off‑the‑shelf, MHC‑independent therapies that extend beyond checkpoint inhibitors. While transformative in hematologic malignancies, their application in solid tumors remains challenging, with only tarlatamab (ES‑SCLC) and the TCR-based agent tebentafusp (uveal melanoma) currently approved. Toxicities such as CRS, ICANS, and dysgeusia are generally manageable but require proactive monitoring.

Professor Ahn Myung-ju’s thought-provoking presentation on advanced T-cell engager strategies covered the current landscape and demonstrated how to tackle related challenges.

TCE development is rapidly advancing into solid tumors through diverse and increasingly sophisticated target selection, including cell surface receptors (HER2, EGFR), tight junction proteins (claudins), cancer-testis antigens (PRAME, NY‑ESO‑1), immune modulators (PD‑L1, B7‑H4), and lineage antigens (PSMA, STEAP1). Next-generation approaches prioritize tumor specificity, antigen density, and safety, supported by multi‑omics and spatial profiling, as well as dual-targeting strategies.

Three core challenges limit TCE efficacy in solid tumors:

  • Target specificity requires high tumor selectivity with minimal expression on normal tissues
  • Immunosuppressive TME drives T‑cell exhaustion and limits activity
  • Dense stroma and fibrosis restrict T‑cell trafficking and drug delivery

Innovative TCE formats aim to address these barriers:

  • 2+1 and biparatopic designs improve selectivity and tumor avidity
  • TCR-based TCEs expand targeting to intracellular antigens
  • Conditional activation: Masked or TME-activated constructs reduce systemic toxicity

Combinations are critical to unlocking TCE potential in solid tumors:

  • TCE + Chemotherapy enhances antigen release, T‑cell priming, and infiltration
  • TCE + ICI reverses T‑cell exhaustion and improves durability
  • TCE + ADC combines cytotoxic killing with immune activation

There is a clear shift toward earlier-line use, maintenance strategies, and multi-modal regimens.

Clinical validation is emerging as well: the Phase 1b DeLLphi‑303 study demonstrated encouraging survival outcomes with tarlatamab + PD‑L1 blockade following chemo‑immunotherapy in ES‑SCLC, supporting ongoing Phase 3 development.

The DLL3 landscape highlights rapid TCE evolution beyond first-generation therapies:

  • Tarlatamab (approved)
  • Obrixtamig (CD3 × DLL3)
  • MK‑6070 (trispecific CD3 × DLL3 × albumin)
  • Alvetamig (2+1 biparatopic)

These next-generation agents aim to improve pharmacokinetics, selectivity, and durability of response.

The future success of T‑cell engagers will depend on integrating optimal target selection, innovative molecular design, and effective combination strategies to achieve meaningful and durable benefit in solid tumors.

Nabila Chowdhury, MD, PSI Medical Monitoring and Consulting

For sponsors, this means TCEs are entering a new phase of innovation, driven by broader, smarter target selection, advanced engineering strategies, and combination-based treatment paradigms. Success will depend on effectively integrating these elements to overcome the biological complexity of solid tumors.

Integrating immunotherapy and targeted therapy for synergistic effects

Why do we need immunotherapy combinations?

While immune checkpoint inhibitors (ICIs) have transformed outcomes across multiple solid tumors, primary and acquired resistance remain major clinical challenges – hence the field is shifting from sequential treatment strategies toward biologically-driven combination therapies. Dr. Bernadett Szabados spoke on some of the challenges seen with immunotherapy regimens:

  • Oncogenes and oncoproteins producing an immunosuppressive TME
  • Genetic and epigenetic dysfunction
  • Loss of sufficient/suitable antigens
  • Dysfunctional T-cells
  • Lack of inflammation in the TME
  • Deregulated tumor immunometabolism
  • Microbiome influence
  • Inept host immunity

Combining different ICIs, and combining ICIs with other partners (including, but not limited to, costimulatory checkpoint agonists, targeted therapies, chemo/radiotherapy, and adoptive T-cell therapy) has thus far produced promising early results.

The shift to earlier use of biologic therapies

In solid tumor management, the traditional sequential model (patients receive chemotherapy first, and only access immunotherapy after disease progression) is being supplanted by the use of highly active, biologically driven therapies in a frontline setting. Rather than reserving novel agents for later lines of treatment, the focus is on intervening before disease progression and combining complementary mechanisms of action to maximize efficacy. Examples include enfortumab vedotin and pembrolizumab in the EV302 trial of patients with urothelial cancer (combining an ADC payload with PD-1 blockade) [3].

For sponsors, this reflects broader strategic shifts from treatment sequencing to rational combination design, with increasing emphasis on where to intervene earliest to improve long-term outcomes.

Antibody-drug conjugates – reshaping treatment paradigms

ADCs have rapidly reshaped outcomes in solid and hematologic malignancies over the past few years, moving beyond the concept of “smart chemotherapy” considering their direct impact on the immune microenvironment. Common approved targets include HER2, NECTIN-4, and TROP2, with most payloads currently based on microtubule inhibitors or topoisomerase-1 inhibitors.

ADCs indirectly enhance immune interactions in the TME through T-cell priming and T-cell mediated effects, and through directing NK cell cytotoxicity. A number of new ADCs have immune-stimulating agents (TLR agonists, or STING agonists) as the payload – directly stimulating the immune microenvironment.

The results from the aforementioned EV302 trial (pairing ADC-driven cell killing with ICIs) meant this is now the new first-line standard of care in metastatic urothelial cancer, and has been recently approved by the FDA for muscle-invasive bladder cancer in the perioperative setting [4].

Emerging ADCs and overcoming toxicity

  • Biparatopic ADCs (same target but different epitopes, meaning better internalization)
  • Bispecific ADCs (two different targets, meaning higher specificity) – for example BMS’s izalontamab brengitecan in triple-negative breast cancer and esophageal squamous cell carcinoma [5]
  • Dual payload ADCs (synergistic effect, and could help overcome resistance)
profile picture for Rhonda Critchlow

ADC toxicity has become a key development constraint – reflecting a combination of on-target effects (NECTIN-4 skin toxicity, HER2-associated cardiotoxicity…), Fc-mediated immune activation, and payload-driven toxicities, such as neuropathy, myelosuppression, and GI effects. These risks increase with higher potency, drug-antibody ratios, and linker instability, meaning that design choices are made to directly trade off against safety. In combination settings, overlapping toxicities further complicate development, making therapeutic index optimization a central challenge for sponsors. Overall, ADCs are becoming a foundational platform, and we expect lots of activity in the coming years.

Rhonda Critchlow, Head Therapeutic Strategy PSI

Personalized immunotherapy: The future?

Targeted immunotherapy is moving beyond single targets. Personalized vaccines, engineered cell therapies, and conditional therapeutics are programmable, and can be tailored, combined, and adapted. Dr. Bridget Keenan presented her thoughts on the future of personalized immunotherapy – our take is that the future strategy is not more powerful treatments, but choosing the right immune strategy for the right patient at the right time.

Expanding on existing immunotherapy targets

The number of targets for TCEs and ADCs have rapidly expanded over the past years, typically targeting the cell surface, although there are some examples of intracellular targeting.

TCR-based therapies enable the recognition of intracellular tumor antigens (via HLAs) previously considered inaccessible to conventional antibodies, and while highly specific (reducing off-target recognition), this introduces additional patient identification and enrollment challenges. In addition to the TCR-engager tebentafusp, TCR T-cell therapies such as afamitresgene autoleucel (targeting MAGE-A4 in patients with HLA-A*02 alleles) have been approved for selected sarcoma indications [6].

ASCO 2026 provided some early readouts of creative targeting to improve specificity (e.g., dual antigen targeting with CAR-T or TCE approaches), non T-cell immune targets (such as APCs), and also targeting the TME.

Highlighting new modalities

Conditionally-active therapeutics

Delivering therapies specifically to the TME (and having them otherwise inactive in systemic circulation) decreases toxicity. In the presence of particular molecules or the characteristics of TME, they become activated. Approaches with multiple examples include:

  • pH-mediated: The activation signal is low pH, or the presence of a metabolite such as ATP [7]
  • Protease-activated: A peptide mask on the drug is cleaved by tumor-specific proteases, allowing the active drug to penetrate the tumor [8]
  • TME-targeted [9]
  • Avidity based: Binding to a receptor on the cell surface within the TME allows for enhanced binding and activation through another receptor [10]

Personalized vaccines

Personalized vaccines can enhance target specificity through mRNA platforms and neoantigen selection. One of the most ideal settings to improve on these vaccines is the adjuvant [11], and minimal residual disease setting (where tumor burden is low and immune responses may be more effective) [12]. Emerging evidence suggests patients who mount vaccine-induced immune responses to neoantigens can experience improved recurrence-free survival. Vaccines are also being explored in preventive settings for individuals at high risk of cancer development [13], and as combination partners for targeted therapies.

Integrating clinical and tumor features

Resistance mechanisms can vary substantially across tumor types, even when targeting the same molecular alteration. While tumor-agnostic therapies enable treatment based on shared molecular alterations across tumor types, understanding the environment in which the tumor-agnostic therapy will be used remains important. For example, KRAS-targeted therapies may demonstrate different efficacy and resistance patterns in colorectal, pancreatic, and lung cancers. Resistance can also be influenced by location of metastatic disease (e.g., liver metastases can drive resistance to ICIs in colorectal cancer and melanoma [14]).

A growing appreciation of tumor heterogeneity is shaping treatment strategies. Resistance mechanisms may differ not only between patients, but also among distinct metastatic lesions within the same patient, driven by tumor-intrinsic and TME factors. Prior therapies complicate treatment selection, as they can influence subsequent sensitivity, or resistance to therapies targeting the same pathway or antigen. Understanding these dynamics will be critical for optimizing treatment strategies and minimizing cross-resistance.

We are now moving beyond mutations, microsatellite status, and tumor mutational burden to incorporate a broader understanding of tumor biology. Integrating multiple layers of information – histology, metastatic patterns, molecular targets, HLA type, neoantigen burden, immune microenvironment – to better match patients with the most appropriate therapies.

For example, tumors with a high neoantigen burden may be particularly suited to vaccines or TCR therapies, whereas immune-excluded tumors may first require TME-modulating approaches. Antigen-defined tumors with well-characterized targets will benefit from cell therapies, TCEs, ADCs, and ICIs.

This increasing level of personalization brings significant challenges, including greater treatment complexity, uncertainty around optimal sequencing, the potential for additive or unexpected toxicities, and – most importantly for all – the challenges of implementing highly individualized treatment strategies in academic, clinical trial, and community care settings

Emily McInturf, Feasibility Director, PSI

RET testing: Moving from metastatic to early-stage disease

Eli Lilly’s phase 3 LIBRETTO-432 trial evaluated adjuvant selpercatinib in patients with stage 1b to 3a RET fusion-positive NSCLC who had already undergone curative-intent treatment. In the primary analysis population (stages 2-3a), selpercatinib reduced the risk of recurrence, progression, or death by 83% overall, median event-free survival in patients receiving selpercatinib hadn’t been reached by 2 years in the treatment group – meaning more than half of the patients in this group were alive and did not have recurrence or progression. The planned 3-year follow-up is ongoing.

These results are particularly notable as RET fusions occur in only 1–2% of NSCLC patients [15], and no approved adjuvant targeted therapy had previously existed. These findings position selpercatinib as a potential new standard of care for resected RET-positive NSCLC, and further reinforce the importance of comprehensive genomic testing at diagnosis, even in early-stage disease.

LIBRETTO-432 is another major example of targeted therapies moving from metastatic to early-stage disease – demonstrating biomarker-driven treatment can substantially reduce recurrence risk after surgery. For sponsors, it underscores the growing value of routine molecular testing and precision oncology in adjuvant settings.

China is an oncological powerhouse

Beyond clinical breakthroughs, the emergence of China as a leading force in global oncology innovation was evident with Akeso’s ivonescimab (in the HARMONi-6 trial for squamous NSCLC [10]) being the first China-developed asset to secure a plenary presentation at ASCO 2026. Some of the congress’ most-discussed datasets included Kelun-Biotech’s TROP2 ADC sac-TMT [16], Dizal’s EGFR inhibitor sunvozertinib [17], and Innovent’s PD-1/IL-2 bispecific IBI363 [16], further demonstrating the country’s maturity and capability of reshaping treatment paradigms. At the same time, questions remain regarding the broader applicability of certain datasets.

For sponsors, the implications are significant:

  • China is a source of innovation, not just patients
  • Global development strategies will start earlier, incorporating China as a lead contributor
  • Competition for sites and patients in China will intensify, shifting operations to better integration in Asia
  • Development timelines will continue to compress
  • Greater attention will be required around patient selection, population characteristics, and the generalizability of clinical trial results across regions
  • Regulatory agencies may increasingly scrutinize the applicability of data generated predominantly in Chinese patient populations when assessing global registration strategies
  • Distinct competitive strengths are emerging, with Chinese companies demonstrating excellence in discovery, translational research, and early clinical execution, while multinational pharma companies retain advantages in global regulatory, development, and commercialization infrastructure.

Future clinical development strategies are more likely to become globally integrated from the outset, with China playing a central role. ASCO 2026 underscored that some of the most important oncological innovations in the next decade may emerge in China, and sponsors failing to properly engage with this ecosystem will fall behind.

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Abbreviations

ADC, antibody-drug conjugate;
APC, antigen presenting cell;
ASCO, American Society of Clinical Oncology;
ATP, adenosine triphosphate;
B7-H4, B7 homolog 4;
B-ALL, B-cell acute lymphoblastic leukemia;
BMS, Bristol Myers Squibb;
CAR-T, Chimeric Antigen Receptor T-cell;
CD, cluster of differentiation;
CRS, cytokine release syndrome;
DLL3, Delta-like ligand;
EGFR, epidermal growth factor receptor;
ES-SCLC, extensive stage small cell lung cancer;
FDA, Food and Drug Administration;
GI, gastrointestinal;
HER2, Human Epidermal growth factor Receptor 2;
HLA, human leukocyte antigen;
ICANS, immune effector cell-associated neurotoxicity syndrome;
ICI, immune checkpoint inhibitor;
IL, interleukin;
KRAS, Kirsten Rat Sarcoma Virus;
MAGE-A4, Melanoma-associated antigen 4;
MHC, major histocompatibility complex;
mPDAC, metastatic pancreatic ductal adenocarcinoma;
mRNA, messenger RNA;
NECTIN-4, Nectin Cell Adhesion Molecule 4;
NK, Natural Killer;
NSCLC, non-small cell lung cancer;
NY-ESO-1, New York esophageal squamous cell carcinoma-1;
PD-1, Programmed Death-1;
PD-L1, Programmed Death Ligand-1;
PRAME, Preferentially Expressed Antigen of Melanoma;
RET, Rearranged during Transfection;
SCLC, small cell lung cancer;
STEAP1, Six-Transmembrane Epithelial Antigen of the Prostate 1;
STING, Stimulator of Interferon Genes;
TCE, T-cell engagers;
TCR, T-cell receptor;
TLR, Toll-like Receptor;
TME, tumor microenvironment;
TMEFF2, Transmembrane protein with an EGF-like and two follistatin-like domains 2;
TROP2, Trophoblast cell-surface antigen 2.

References

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