Faculty Bibliography

BACKGROUND:Extensive-stage small cell lung cancer (ES-SCLC) is associated with a high symptom burden and impaired health-related quality of life (HRQoL). This prespecified analysis from the phase 3 DeLLphi-304 trial evaluated patient-reported outcomes (PROs) for tarlatamab versus standard-of-care (SoC) chemotherapy following first-line platinum-based therapy. METHODS:DeLLphi-304 is a multicenter, open-label, randomized phase 3 study in adults with ES-SCLC. PROs were assessed using validated instruments, including the EORTC QLQ-C30, EORTC QLQ-LC13, FACT-G GP5, BPI-SF, and the EQ-5D-5L visual analogue scale. Change from baseline, response rates, and time to deterioration in these PROs were analyzed. RESULTS:PRO data from all 509 patients enrolled were evaluated. Compliance with QLQ-C30 and QLQ-LC13 assessments remained above 69% through 19 weeks. A higher proportion of patients receiving tarlatamab achieved symptom or functional improvement at 19 weeks compared with SoC in chest pain (19% vs 10%), cough (35% vs 26%), dyspnea (22% vs 7%), physical functioning (13% vs 8%), and global health status (23% vs 15%), respectively. Tarlatamab also delayed deterioration in symptoms, physical functioning, and pain at worst relative to SoC. FACT-G GP5 results indicated that patients receiving tarlatamab were less bothered by treatment side effects over time. CONCLUSIONS:In addition to its previously reported antitumor activity, tarlatamab demonstrated clinically meaningful improvements in symptoms and HRQoL compared with SoC. These findings support a favorable benefit-risk profile of tarlatamab in patients previously treated for ES-SCLC.

BACKGROUND: METHODS:-mutant NSCLC and administered daraxonrasib in doses of 10 to 400 mg orally once daily in 21-day cycles. The primary end point was safety. Secondary end points included investigator-assessed objective response (complete or partial response) and the duration of response, with response assessed according to Response Evaluation Criteria in Solid Tumors, version 1.1. RESULTS:As of the data-cutoff date of July 21, 2025, a total of 136 patients with NSCLC who had been enrolled and treated with daraxonrasib at doses of 300 mg or less had been evaluated for safety and efficacy. Adverse events of any grade occurring with a dose of 300 mg or less, regardless of attribution, were reported in 99% of the patients, with rash, diarrhea, nausea, vomiting, and mucositis or stomatitis occurring in at least 30% of patients. Adverse events of grade 3 or higher were reported in 54% of the patients, with pneumonia (in 10%), diarrhea (in 9%), rash (in 8%), and anemia (in 5%) occurring in at least 5% of patients; four grade 5 adverse events occurred. The percentage of patients who had an objective response was 31% with daraxonrasib at a dose of 120 mg or less, 34% at doses of 160 to 220 mg, and 37% at a dose of 300 mg. CONCLUSIONS:-mutant NSCLC receiving daraxonrasib at a dose of 300 mg or less daily, 54% had adverse events of grade 3 or higher, and antitumor activity was reported in more than 30%. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Daraxonrasib is an orally bioavailable RAS(ON) multi-selective tri-complex inhibitor of the oncogenic mutant and wild-type variants of N, H and KRAS. We previously reported encouraging efficacy in a phase 1/2 clinical trial evaluating daraxonrasib monotherapy at clinically active dose levels in patients with previously treated, RAS mutant metastatic pancreatic adenocarcinoma (PDAC), providing the basis for confirmatory evaluation in the randomized phase 3 RASolute 302 clinical trial. Here we report mechanisms of acquired resistance to daraxonrasib monotherapy observed through targeted sequencing of over 800 genes in paired pretreatment and end of treatment circulating tumor DNA samples from 44 patients in the phase 1/2 clinical trial. Treatment-emergent genomic alterations in the RAS signaling pathway were observed in more than half (26 of 44; 59%) of these patients, including, most notably, mutant KRAS amplifications in one-third (16 of 44; 36%), as well as alterations in receptor tyrosine kinase (RTK) (4 of 44; 9%), MAPK (11 of 44; 25%) and PI3K (4 of 44; 9%) pathways. Notably, no acquired secondary KRAS mutations were observed, distinct from resistance profiles of mutant-selective KRAS G12C(OFF) inhibitors. To corroborate these clinical findings, we found, or mechanistically established, concordant mechanisms of daraxonrasib resistance in human and murine preclinical models of PDAC, including mutant KRAS and MYC amplification and RTK upregulation, with these alterations guiding various combination therapy concepts. Notably, daraxonrasib combined with agents targeting DNA damage response, RTKs or the mutant-selective RAS(ON) G12D inhibitor zoldonrasib averted resistance in preclinical models. Collectively, these results show that most daraxonrasib genomic resistance mechanisms drive reactivation of RAS pathway signaling and guide potential combination strategies in PDAC for further investigation.

BACKGROUND:Immunotherapies have improved survival in patients with metastatic non-small cell lung cancer (mNSCLC), yet a substantial fraction of eligible patients remain untreated with immunotherapy in routine clinical practice. This study examined treatment patterns and factors associated with receipt of non-immunotherapy-containing first-line (1L) regimens among patients with mNSCLC not eligible for targeted therapies. METHODS:This retrospective, observational study used the Flatiron Health Research Database and included patients diagnosed with mNSCLC not eligible for targeted therapy who initiated 1L treatment on or after July 1, 2019 (data cutoff: September 30, 2023). Treatment patterns, classified by inclusion of an FDA-approved immunotherapy, and patient and disease characteristics were summarized. Logistic regression was used to identify factors that were associated with receipt of a non-immunotherapy-containing 1L regimen. RESULTS:In total, 13,223 patients were included in the study. Overall, 25% received a non-immunotherapy-containing 1L regimen, which was similar across study years. Platinum-based chemotherapy was the most common non-immunotherapy-containing 1L regimen. In a multivariable model, a wide range of factors were associated with use of non-immunotherapy-containing 1L regimens, including age, ethnicity, year of diagnosis, programmed death-ligand 1 (PD-L1) expression status, prior treatment with immunotherapy, practice type, geographical region, smoking status, and stage at initial diagnosis. CONCLUSIONS:A sizeable proportion of patients with mNSCLC continue to receive non-immunotherapy-containing 1L regimens, despite widespread availability and guideline recommendations as the preferred 1L therapy. These findings suggest that non-use of immunotherapy is influenced by clinical and structural factors, highlighting persistent gaps in equitable access to 1L immunotherapy.

Immune checkpoint inhibitors (ICIs) in non-small cell lung cancer (NSCLC) have improved survival for patients with early-stage NSCLC who are candidates for surgical resection. ICIs enhance antitumor responses and improve a variety of perioperative outcomes when used in the neoadjuvant, adjuvant, or perioperative setting. This review summarizes immunotherapies currently approved for neoadjuvant, adjuvant, and perioperative treatment of resectable NSCLC and the supporting evidence for approval. Gaps in data and future areas of clinical interest of using immunotherapies to maximize survival outcomes are also discussed.

Adoptive cellular immunotherapy (ACT) has revolutionized hematologic malignancies, yet translation to solid tumors has historically been limited. This landscape shifted significantly in 2024 with US Food and Drug Administration approvals of lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy for advanced melanoma, and afamitresgene autoleucel, an engineered T-cell receptor (TCR) therapy for synovial sarcoma. These approvals mark the clinical arrival of ACT for solid tumors and highlight a rapidly expanding therapeutic landscape. Beyond these indications, multiple ACT platforms including TIL, TCR, chimeric antigen receptor (CAR) T-cell, CAR-natural killer, and CAR-macrophage therapies are under active clinical investigation across diverse solid tumor indications. Clinical experience to date has defined key barriers to efficacy, including impaired tumor trafficking, antigen heterogeneity, immunosuppressive tumor microenvironment, and limited cellular persistence. In parallel, rapid advances in cellular engineering are reshaping the field, with the development of armored constructs, logic-gated and multiantigen targeting strategies, innate immune-based platforms, and novel manufacturing approaches including allogeneic and in vivo cell engineering. As ACT enters clinical practice for select solid tumors, distinct toxicity profiles and logistical requirements necessitate careful patient selection and multidisciplinary coordination. Early biomarker testing, timely referral to specialized centers, and familiarity with evolving toxicity management frameworks are increasingly critical. Here, we seek to provide a practice-oriented framework for understanding emerging ACT platforms, clinical data, toxicity considerations, and implementation strategies relevant to contemporary solid tumor oncology care.

BACKGROUND:mutations occur in more than 90% of PDAC tumors. Daraxonrasib (RMC-6236) is an oral RAS(ON) multiselective inhibitor that targets guanosine triphosphate-bound mutant and wild-type RAS. METHODS:-mutated PDAC. RESULTS:G12, G13, or Q61 mutations, 29% (95% CI, 15 to 46) had an objective response. The median duration of response was 8.2 months (95% CI, 3.8 to 8.8), with median values of 8.1 months for progression-free survival and 15.6 months for overall survival. CONCLUSIONS:-mutated PDAC; antitumor activity was also reported. (Funded by Revolution Medicines; RMC-6236-001 ClinicalTrials.gov number, NCT05379985.).

Advanced solid tumors remain largely incurable, with most patients ultimately progressing despite modern therapies, including immune checkpoint blockade. The limited impact of these approaches reflects the biological complexity of solid tumors, including intratumoral heterogeneity, an immunosuppressive microenvironment, and the predominance of "undruggable" oncogenic drivers. Adoptive cellular therapy (ACT) offers a complementary strategy by delivering tumor-specific lymphocytes directly into patients. Among ACT modalities, T-cell receptor (TCR)-engineered T cells stand out for their ability to recognize intracellular neoantigens presented by MHC molecules, thus accessing a broader antigenic landscape. Early successes, such as the FDA approvals of lifileucel and afamitresgene autoleucel, highlight the promise of these approaches, while proof-of-concept clinical studies demonstrate activity of personalized neoantigen-reactive TCRs in advanced solid tumors. Major challenges remain, including safety concerns from off-tumor toxicities and resistance mechanisms such as HLA loss of heterozygosity. Ongoing innovations in target discovery, TCR engineering, and combination strategies aim to overcome these barriers and establish mutant-selective TCR therapy as a viable therapeutic strategy in the treatment of solid tumors.

Tri-complex inhibitors (TCIs) are molecular glues that bind the active, guanosine triphosphate (GTP)-bound state of RAS and recruit cyclophilin A (CYPA) to form a synthetic complex that blocks oncogenic signaling. Although these agents have shown clinical activity in RAS mutant cancers, resistance mechanisms remain poorly defined. Here, we analyzed paired baseline and end-of-treatment samples from 40 patients treated with the RAS inhibitor daraxonrasib and identified recurrent alterations in 18 cases. Structural and functional analyses revealed that acquired mutations confer resistance by disrupting interactions essential for daraxonrasib binding to RAS, including RAS Y64 mutations, or by enhancing the RAS-RAF interaction, thereby favoring native RAS-RAF signaling, including RAS Y71 or kinase-dead/hypoactive BRAF mutations. We then identified a TCI that targets RAS Y64 mutants and combination therapies to target resistance driven by kinase-dead BRAF. These findings uncover convergent resistance mechanisms that undermine the molecular glue function and offer a mechanistic blueprint for enhancing therapeutic efficacy in RAS-driven malignancies.

OBJECTIVE/UNASSIGNED:Identifying eligible patients for precision oncology clinical trials is challenging, particularly for rare molecular subpopulations. To address this challenge, A2 Biotherapeutics developed BASECAMP-1 (NCT04981119), a non-interventional master screening study to identify patients eligible for interventional studies of logic-gated Tmod chimeric antigen receptor T-cell therapies. Eligible patients for these interventional trials have an advanced solid malignancy and are germline human leucocyte antigen (HLA)-A*02 heterozygous, with tumour-associated HLA-A loss of heterozygosity (LOH). HLA-A LOH occurs in ~16% of advanced solid malignancies; therefore, an efficient screening strategy is required. This report describes BASECAMP-1; compares the efficiency of two screening methods; and discusses the broader advantages of BASECAMP-1 beyond efficient enrolment. METHODS AND ANALYSIS/UNASSIGNED:Patients are identified for BASECAMP-1 using two approaches. In the traditional approach, common for clinical trials, investigators consent and screen all patients who might be good candidates for cell therapy trials, with no prior knowledge of patient HLA-A type or LOH status. To further optimise our approach, we co-developed with Tempus AI (Tempus) the bioinformatic programme Aware, which identifies potentially eligible patients with tumour-associated HLA-A*02 LOH within a clinico-genomic database that includes linked genomic and transcriptomic sequencing and clinical data collected during routine care. RESULTS/UNASSIGNED:Over 42 months of using a traditional approach to identify eligible patients, 1918 patients at 13 study sites were consented and screened for BASECAMP-1; of these, 30 patients with tumour-associated HLA-A*02 LOH were enrolled (~0.7 participants per month). Over the last 30 months of that same period, Tempus Aware screening was implemented and 55 patients with tumour-associated HLA-A*02 LOH were enrolled (~1.8 participants per month). The bioinformatic approach identified more patients than the traditional approach and used sequencing results produced as part of the standard clinical tumour sequencing workflow, reducing resource use and study staff burden. Additional advantages of using a screening study, such as BASECAMP-1, include manufacturing efficiencies and collection of a large dataset of molecular and clinical parameters that can be used to supplement trial analyses. CONCLUSIONS/UNASSIGNED:The BASECAMP-1 study demonstrates a clinico-genomic screening approach can more efficiently identify patients for precision oncology trials. Furthermore, precision oncology can be enhanced through collaborative data-sharing. TRIAL REGISTRATION NUMBER/UNASSIGNED:NCT04981119.