Cancer Discov
· 2026 Jun · PMID 42047672
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During his address and "fireside chat" at the American Association for Cancer Research Annual Meeting 2026 in San Diego, CA, on April 20, NCI Director Anthony Letai, MD, PhD, assured the cancer community that federal sup...During his address and "fireside chat" at the American Association for Cancer Research Annual Meeting 2026 in San Diego, CA, on April 20, NCI Director Anthony Letai, MD, PhD, assured the cancer community that federal support for cancer research remains strong despite numerous challenges researchers encountered during fiscal year 2025, clarified approaches to funding, and offered encouragement to early-career investigators.
Schroeder BA, Mohindroo C, Meinhardt AL
… +38 more, Takahashi N, Zhang Y, Lee MJ, Sahoo S, Donahue RN, Kumar R, Nirula M, Yang Y, Rastogi S, Sato N, Lee S, Tsai YT, Zhuang S, Kazi A, Huang Y, Desai P, Nichols S, Sciuto L, Pinkiert D, Chrisafis G, Greenberg M, Biery DN, Al-Marayaty R, Yang HH, Lee MP, Schultz CW, El Meskini R, Atkinson D, Fousek K, Gulley JL, Schlom J, Sato M, Shrestha RL, Sharma AK, Jolly MK, Palena C, Wakefield LM, Thomas A
Cancer Discov
· 2026 Apr · PMID 42018154
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Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but their tumor-intrinsic consequences remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a b...Stromal immunosuppressive pathways are key modulators of response to immune checkpoint inhibitors, but their tumor-intrinsic consequences remain incompletely defined. We conducted a clinical trial of bintrafusp alfa, a bifunctional PD-L1/TGF-β inhibitor, in small cell lung cancer. Among 34 evaluable patients, 18% had partial responses, 20% stable disease, and 62% progressive disease; 38% of progressors met criteria for hyperprogressive disease (HPD). HPD was also observed across other tumor types (n=450), in higher frequencies with bintrafusp than PD-(L)1 blockade alone. Blood and tumor profiling showed that HPD correlated with systemic immune suppression and elevated TGF-β signaling. Functional studies demonstrated that tumor-intrinsic TGF-β signaling restrains proliferation in a subset of SCLC; pathway blockade triggers hyperproliferation. External validation across cell lines and tumor samples confirmed a tumor-intrinsic TGF-β-high transcriptional state associated with inferior survival. Together, these findings identify a context-dependent, growth-constraining function of TGF-β and support tumor-intrinsic biomarker-guidance while targeting stromal immunosuppressive pathways.
Cancer Discov
· 2026 Jun · PMID 42015631
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For patients with advanced platinum-resistant ovarian cancer, treatment options remain limited, but new agents are emerging. One is QLS5132, an antibody-drug conjugate targeting CLDN6; early data from a phase I trial ind...For patients with advanced platinum-resistant ovarian cancer, treatment options remain limited, but new agents are emerging. One is QLS5132, an antibody-drug conjugate targeting CLDN6; early data from a phase I trial indicates that it has a favorable safety profile and appears active in this disease.
Campbell KM, Chen DG, Bustami ZE
… +40 more, Naser Al Deen N, Medina E, Gonzalez CR, Maxey J, Thompson MA, Samorodnitsky S, Kuklinski LF, Perez Garcilazo I, Baselga-Carretero I, Vega-Crespo A, Chen JM, Elumalai R, Visitacion M, Schiemann R, Padron L, Chang C, Zelin AE, Chelluri SS, Boffo S, Kendra KL, Chmielowski B, Truong TG, Khushalani NI, Collichio F, Ikeguchi AP, Victor AI, Margolin KA, Johnson DB, Chen Y, Sosman JA, Patel SP, Hu-Lieskovan S, Moon J, Wells DK, Spencer CN, Bellasea S, Vanderwalde AM, Wu MC, Scumpia PO, Ribas A
Cancer Discov
· 2026 Apr · PMID 42013417
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In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with contin...In the phase 2 trial SWOG S1616 (NCT03033576), patients with advanced melanoma with primary resistance to anti-PD-1/L1 therapies had improved outcomes on the combination of the anti-CTLA-4 antibody ipilimumab with continued anti-PD-1 with nivolumab, over ipilimumab alone. Baseline biopsies from patients responsive to combination therapy had increased transcriptomic expression of complement by myeloid cells, interferon pathways by endothelial cells, and oxidative phosphorylation and lipid metabolism by melanoma cells. Using spatial proteomics, some on-therapy biopsies from patients responding to combination therapy had networks of activated CD8 T cells nearby melanoma cells, while others had T cells and myeloid cells, reflective of different timepoints in a dynamic antitumor response. Conversely, biopsies from patients progressing on combination immunotherapy displayed impaired T-cell infiltration adjacent to plasma cells. Our results define cellular neighborhoods and transcriptomes in melanoma biopsies when reversing resistance to anti-PD-1 with the addition of anti-CTLA4, and plasma cell sheets in non-responding biopsies.
Min J, Schweizer L, Zonderland G
… +18 more, Selvanesan BC, Thomsen JH, Oldenburg L, Bae SW, Kim B, Hernández SD, Jez G, Bernard V, Swanson BJ, Klute KA, Wang H, Caffrey TC, Grandgenett PM, Hollingsworth MA, Ummat I, Strauss MT, Mund A, Maitra A
Cancer Discov
· 2026 Jul · PMID 42013410
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UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) evolves through precursors, yet the protein programs governing early progression remain poorly defined. We applied Deep Visual Proteomics (DVP)-integrating computationa...UNLABELLED: Pancreatic ductal adenocarcinoma (PDAC) evolves through precursors, yet the protein programs governing early progression remain poorly defined. We applied Deep Visual Proteomics (DVP)-integrating computational pathology, laser microdissection, and mass spectrometry (MS)-to profile normal ducts, acinar-to-ductal metaplasia (ADM), low-grade (LG) and high-grade (HG) pancreatic intraepithelial neoplasia (PanIN), and invasive carcinoma from organ donors and patients with PDAC. Quantifying 9,181 proteins from ∼100 cells per region, we uncovered a molecular field effect in histologically normal ducts and proteomic divergence of LG-PanINs by cancer context. We identified four stage-associated molecular programs. Stress adaptation and immune engagement emerged early in cancer-associated normal ducts. Metabolic reprogramming initiated in normal ducts and intensified across PanIN progression. Mitochondrial remodeling became prominent in HG-PanINs before invasion. MS detected KRAS hotspot mutant peptides within incidental precursor lesions from cancer-free individuals. These findings demonstrate that molecular reprogramming precedes histologic transformation, creating opportunities for earlier detection of lethal cancer. SIGNIFICANCE: Artificial intelligence (AI)-guided DVP represents the first in-depth assessment of the proteomic landscapes observed during the multistep progression of pancreatic adenocarcinoma, including histologically normal ducts, ADM, and LG- and HG-PanIN lesions. These data represent a unique resource of candidate biomarkers and interception targets against this lethal disease. See related commentary by Yang and Fan, p. 1255.
DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatel...DNA mismatch repair (MMR) detects and corrects post-replicative DNA alterations; it is deregulated in up to 20% of human cancers. MMR-deficient (MMR-d) cancers display increased tumour mutational burden (TMB), microsatellite instability (MSI) and are eligible for checkpoint inhibitor (CPI) immunotherapy which commonly elicits durable responses. We reasoned that pharmacological blockade of MMR could broaden the patient population eligible for immunotherapy. Here we reveal MMR protein PMS2 as a druggable target and describe the discovery and characterisation of first-in-class small molecule MMR pathway modulator NP1867. In vitro treatment of murine cancer cells abrogates MMR function and elicits an MMR-d genotype including increased TMB, MMR-d mutational signatures, and MSI-High (MSI- H) status. Inoculation of syngeneic immunocompetent mice with cancer cells pretreated with NP1867 leads to CPI sensitivity, tumour growth delay, and complete responses. For the first time, we demonstrate pharmacological targeting of MMR to proactively rewire the tumour-host relationship for therapeutic purposes.
Pelzer B, Meydan C, Spiegel IM
… +45 more, Karagiannidis I, Xia M, Teater M, Welter EM, Searcy ZE, Hilton LK, Barisic D, Fong A, Fa P, Sethi S, Isgor IS, Fielding JJ, Karbalayghareh A, Burdette CS, Tumuluru S, Debek SM, Lee S, Massoni-Badosa R, Durmaz C, Salataj E, Pararajalingam P, Chen Z, Pelzl RJ, Shah S, Rivas MA, Hoehn KB, Mlynarczyk C, Isles HM, Wang X, Dogan A, Elenitoba-Johnson KSJ, Scott DW, Dreval K, Morin RD, Leslie CS, Puri R, Geri JB, Chin CR, Chadburn A, Mason CE, Reinhardt HC, Anguera MC, Béguelin W, Venturutti L, Melnick AM
Cancer Discov
· 2026 Apr · PMID 42013317
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Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune...Diffuse large B-cell lymphomas (DLBCL) are genetically and phenotypically heterogeneous, making diagnosis and treatment challenging. Current models suggest DLBCL derive from follicular B cells engaged in adaptive immune responses. By studying co-occurring truncating mutations in SPEN and NOTCH2 in the BN2-DLBCL subtype, our data suggest a previously unrecognized extra-follicular trajectory. Using animal models and human specimens, we find this cooperative mutational axis supports expansion of putative clonal precursors with features of marginal zone, memory and a distinct, autoimmune B-cell-like state. This trajectory is associated with sex-biased outcomes: female patients and mice exhibit reduced survival compared to males in our cohorts. Further analysis links this disparity to enhanced X-chromosome-linked expression and functionality of toll-like receptor signaling. We show that IRAK inhibition represents a potential sex-specific therapeutic strategy in preclinical models. These findings support a distinct developmental origin for BN2-DLBCL and identify a high-risk female population with actionable targets for precision therapy.
Ren T, Zhao F, Chen C
… +5 more, Zhou L, Wu LY, Mills GB, Coussens LM, Xia Z
Cancer Discov
· 2026 May · PMID 42013315
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UNLABELLED: Survival analysis is fundamental to cancer research. Advances in technology have enabled an increasing number of cohort-level cancer studies to incorporate single-cell sequencing alongside clinical survival d...UNLABELLED: Survival analysis is fundamental to cancer research. Advances in technology have enabled an increasing number of cohort-level cancer studies to incorporate single-cell sequencing alongside clinical survival data. However, no effective strategy currently exists for directly modeling survival outcomes from single-cell data. To address this gap, we present scSurvival, an attention-based multiple-instance Cox regression framework that models each tumor sample as an ensemble of cells to predict survival outcomes at both the patient and single-cell levels. To handle high dimensionality, sparsity, and batch effects, scSurvival integrates a variational autoencoder-based feature extraction module with generative modeling to enhance feature robustness and cross-batch generalizability. Comprehensive simulations demonstrate scSurvival's superior performance and scalability. In melanoma and liver cancer single-cell RNA sequencing (scRNA-seq) cohorts, scSurvival accurately predicts patient outcomes and identifies the cell subpopulations most critical to survival. Overall, scSurvival enables robust prediction of patient survival while uncovering survival-associated cell subpopulations, advancing single-cell survival analysis in cancer research. SIGNIFICANCE: Survival analysis is central to clinical oncology, yet no effective tools currently model survival outcomes directly from single-cell data. scSurvival bridges this gap by predicting patient outcomes and identifying key subpopulations from scRNA-seq with survival information, enabling scalable analyses and promoting broader adoption of cohort-level single-cell profiling in cancer research.
Immune checkpoint blockers (ICBs) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab...Immune checkpoint blockers (ICBs) improve outcomes in metastatic melanoma (MM), but resistance limits benefit. This phase I/II (NCT02706353) study evaluated intratumoral sotigalimab (anti-CD40 agonist) with pembrolizumab in 32 ICB-naïve MM patients. Primary endpoints were safety, and objective response rate (ORR). Sotigalimab was well tolerated. At the recommended phase 2 dose (RP2D), the ORR was 50% and the disease control rate (DCR) was 92%, with ORR of 67% in injected and 50% in non-injected tumors. Multiomic analyses of tumor and blood showed sotigalimab effectively engaged the CD40 pathway, boosting infiltration and activation of myeloid cells, including CD11c+DC-LAMP+ dendritic cells (DCs) and macrophages. The combination therapy activated innate and adaptive immunity in injected tumors and cytotoxic responses in non-injected tumors. TCR sequencing showed increased T-cell clonality with expanded new clones shared across tumors. Clinical responses correlated with these immunologic changes, but not with baseline features associated with response to anti-PD1 monotherapy.
Cancer Discov
· 2026 Jun · PMID 42012894
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In a phase I clinical trial, patients with oral precancers who received immunotherapy injected directly into their lesions experienced tumor shrinkage and no dose-limiting toxicities. The findings suggest that immunother...In a phase I clinical trial, patients with oral precancers who received immunotherapy injected directly into their lesions experienced tumor shrinkage and no dose-limiting toxicities. The findings suggest that immunotherapy could play a role in cancer prevention.
Cancer Discov
· 2026 Jun · PMID 42012882
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According to a new study, exposure to smoke from wildfires is associated with lung, colorectal, breast, bladder, and blood cancers, highlighting the long-term health risks it poses.According to a new study, exposure to smoke from wildfires is associated with lung, colorectal, breast, bladder, and blood cancers, highlighting the long-term health risks it poses.
Cancer Discov
· 2026 Jun · PMID 42010749
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In a phase I/II clinical trial, patients with locally advanced or metastatic KRAS G12C-mutant non-small cell lung cancer treated with the next-generation KRASG12C inhibitor elisrasib showed robust and durable clinical re...In a phase I/II clinical trial, patients with locally advanced or metastatic KRAS G12C-mutant non-small cell lung cancer treated with the next-generation KRASG12C inhibitor elisrasib showed robust and durable clinical responses. Patients naïve to KRASG12C inhibitors, as well as those refractory to other such drugs, experienced high rates of disease control-98.5% and 83.9%, respectively.
Pillai R, Rashidfarrokhi A, Hao Y
… +34 more, Wu WL, Mancini MCS, Karadal-Ferrena B, Dimitriadoy SG, Cross M, Yeaton AH, Huang SM, Bhutkar A, Herrera AM, Rajalingam S, Hayashi M, Huang KL, Bartnicki E, Zavitsanou AM, Ivanova E, Wohlhieter C, LeBoeuf SE, Chen T, Loomis CA, Kulicke R, Davis FP, Stransky N, Smolen GA, Tsay JJ, Simabuco FM, Rudin CM, Moreira AL, Khanna KM, Pass HI, Wong KK, Koide S, Tsirigos A, Koralov SB, Papagiannakopoulos T
Cancer Discov
· 2026 Jul · PMID 42008781
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UNLABELLED: LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstra...UNLABELLED: LKB1 mutations in lung cancer promote an immunosuppressive tumor microenvironment, but the underlying mechanisms remain unknown. Using genetically engineered mouse models and human tumor samples, we demonstrate that LKB1 loss leads to high expression of the cytokine leukemia-inhibitory factor (LIF), which through a cancer cell-autonomous autocrine loop, orchestrates the infiltration of immunosuppressive SiglecFHi neutrophils and Arg1+ interstitial macrophages. Genetic deletion of Lifr, the receptor for LIF, on Lkb1-mutant lung tumors revealed that autocrine LIF signaling induces tumor plasticity and the emergence of a Sox17+ dedifferentiated inflammatory cell state. Antibody-mediated LIF neutralization selectively eliminates the Sox17+ tumor cell state, reduces immunosuppressive myeloid cells, and enhances antitumor T-cell responses. Our study uncovers a novel LKB1-LIF axis driving immune evasion and identifies LIF as a potential therapeutic target in LKB1-mutant lung cancer. This work highlights the interplay between tumor genetics, cellular plasticity, and immune regulation in lung cancer progression. SIGNIFICANCE: LKB1-mutant lung cancers express LIF, which induces an immunosuppressive Sox17+ tumor state. Anti-LIF therapy eliminates this state and restores antitumor immunity, revealing a novel vulnerability in this aggressive cancer subtype lacking effective targeted therapies.
Cancer Discov
· 2026 May · PMID 42008780
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Advancing global health equity requires a paradigm shift in precision oncology, which currently remains inaccessible to most patients worldwide because of the high cost and long turnaround time of sequencing-based biomar...Advancing global health equity requires a paradigm shift in precision oncology, which currently remains inaccessible to most patients worldwide because of the high cost and long turnaround time of sequencing-based biomarkers. Recent developments in artificial intelligence inference from routine histopathology slides and blood tests are now enabling rapid cost-effective prediction of survival of patients with cancer and treatment response in both developed and under-resourced regions globally.
Leongamornlert D, Lee J, Kamizela AE
… +16 more, To K, Myers D, Williams N, Nyamondo K, Wang X, Guo J, Dissanayake RK, Price J, Durrani AJ, Lambert J, Spencer Chapman M, Pimanda JE, Baxter EJ, Green AR, Godfrey AL, Nangalia J
Cancer Discov
· 2026 Apr · PMID 42008361
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Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome...Philadelphia-negative myeloproliferative neoplasms are chronic blood neoplasms. Treatments control blood counts but disease can progress to myelofibrosis or acute myeloid leukaemia. We performed longitudinal whole-genome and targeted sequencing in 30 patients, integrating clonal dynamics with 7,986 blood counts and clinical histories. Distinct evolutionary patterns distinguished stable from progressive disease, with leukaemic transformation arising via TP53 loss, stepwise driver mutation acquisition within complex clones, or emergence of independent leukaemic clones. In contrast, stable disease showed long-term clonal equilibrium without new drivers. Phylogenetic analysis using 203 whole-genomes of haematopoietic colonies revealed age-appropriate polyclonal haematopoiesis in triple-negative essential thrombocythaemia and germline predisposition to thrombocytosis, supporting non-neoplastic origins. Therapy-associated mutagenesis was observed, including C>G mutations following azacitidine and characteristic T>A/T>G after hydroxycarbamide exposure in blood cells, although not in skin where UV damage predominated. These findings demonstrate progression is genomically encoded years in advance and support serial monitoring and further study of treatment-related mutagenesis.
When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creatin...When tumor suppressor genes are lost through chromosomal deletion, deletion of adjacent genes can generate therapeutic vulnerabilities. MTAP is frequently co-deleted with the Chr9p21 tumor suppressor gene CDKN2A, creating synthetic lethal dependency on PRMT5. Telomeric to MTAP lies FOCAD, whose loss induces dependency on the HBS1L/PELO ribosome-rescue complex for translational maintenance. FOCAD is deleted in ~1/3 of MTAP-deleted cancers. We screened an IMiD-focused diversity library and identified a weak hit that bound cereblon, promoted HBS1L-CRBN-compound complex formation, and induced E3-ligase-dependent HBS1L ubiquitination and degradation. Guided by cryo-EM structures and proteome selectivity we developed TNG961, a potent, selective HBS1L degrader that disrupts the HBS1L/PELO complex, inducing translational arrest, unfolded protein response activation, and growth inhibition in FOCAD-negative models. Oral administration of TNG961 regresses FOCAD-negative xenografts, including PRMT5 inhibitor-refractory models, establishing HBS1L degradation as a strategy to exploit FOCAD loss and supporting clinical evaluation of TNG961 as a first-in-class precision oncology therapeutic.
Brady SW, Arnold MA, Wang M
… +37 more, Alsallaq R, Dong L, Khan MA, Yang W, Stratton KL, Liu W, Chen Y, Plyler E, Steele JA, Powers BB, Rosenfeld D, Edmonson MN, Feng Y, Terekhanova NV, Hagiwara K, Arunachalam S, Mulder HL, Srivastava DK, Rusch M, Nolan VG, McDonald A, Sapkota Y, Gramatges MM, Turcotte LM, Im C, Howell RM, Easton J, Ma X, Wang Z, Leisenring WM, Conces M, Neglia JP, Yasui Y, Bhatia S, Ellison DW, Zhang J, Armstrong GT
Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed...Childhood cancer survivors have heightened risk of developing subsequent neoplasms (SNs) related to therapy. We analyzed whole-genome, exome and RNA sequencing of 200 breast, meningioma, and thyroid SNs, which developed a median of 26.4 years after childhood cancer, among 160 survivors. Meningioma and thyroid SNs were enriched for driver gene rearrangements compared to de novo tumors, including NF2-disrupting alterations and kinase fusions potentially induced by radiation. Radiation correlated with increased insertion-deletion signature ID5. Nitrogen mustard treatment correlated with elevated "flat" signature SBS5 in breast and meningioma SNs; in vitro, these agents caused an unresolved flat signature associated with multiple flat COSMIC signatures. In meningioma, platinum therapy correlated with NF2 splice-site variants. Analysis of 19 multi-sample survivors revealed intrapatient heterogeneity in meningioma, including clonally independent tumors. These results demonstrate the long-term impact of childhood cancer treatment on the genomes of SNs developing in adulthood, which may guide SN treatment and prevention.
Winslow MM, Ahmed MA, Berg CD
… +19 more, Black JRM, Downward J, Govindan R, Herbst RS, Heymach JV, Jaffee EM, Kraut N, Merad M, Meyerson M, Pandya T, Politi K, Rao AV, Rudin CM, Soria JC, Tang YJ, Wong KK, Yap TA, Swanton C, AACR Lung Cancer Task Force
Cancer Discov
· 2026 Jun · PMID 42001483
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UNLABELLED: Advances in targeted therapies, immunotherapy, and early detection have revolutionized lung cancer treatment and extended survival. Nonetheless, lung cancer remains highly fatal. Here, we identify knowledge g...UNLABELLED: Advances in targeted therapies, immunotherapy, and early detection have revolutionized lung cancer treatment and extended survival. Nonetheless, lung cancer remains highly fatal. Here, we identify knowledge gaps and propose critical areas of future research, aligning with the mission of the American Association for Cancer Research (AACR) Lung Cancer Task Force. We delineate research priorities, including advancing prevention initiatives, enhancing early detection strategies, developing novel treatments, and refining patient stratification. Addressing disparities and increasing efforts on relatively neglected lung cancer subtypes are also essential. Finally, international collaboration, centralized clinical trial databases, novel clinical trial designs, and artificial intelligence-driven analytics should accelerate precision medicine and aid in elucidating drug resistance mechanisms. Together, these efforts promise to improve patient outcomes. SIGNIFICANCE: Despite substantial progress in understanding disease biology and improving therapy, lung cancer remains the leading cause of global cancer-related deaths. The members of the AACR Lung Cancer Task Force describe areas of unmet need and define near-term research priorities and opportunities to reduce lung cancer morbidity and mortality.
Cancer Discov
· 2026 Jun · PMID 42001453
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In updated phase I clinical trial results, patients treated with zoldonrasib, a KRASG12D-selective inhibitor under study in non-small cell lung cancer, showed an objective response rate of 52%, a disease control rate of...In updated phase I clinical trial results, patients treated with zoldonrasib, a KRASG12D-selective inhibitor under study in non-small cell lung cancer, showed an objective response rate of 52%, a disease control rate of 93%, a median progression-free survival of 11.1 months, and a 73% overall survival at 12 months.