OncologyLive® is the flagship publication of OncLive®. Each issue delivers expert insights and clinical oncology news and updates, which impact the day-to-day clinical practice of oncology professionals who work tirelessly to help improve patient outcomes.

Several targeted chimeric antigen receptor (CAR) T-cell therapies are beginning to show early signals of efficacy for patients with solid tumors as investigators are working to translate the efficacy and safety profiles seen with these agents in hematologic malignancies to the solid tumor field. Among them are satricabtagene autoleucel (satri-cel; CT041),

 and more, according to recent data. The FDA has also granted fast track designation and regenerative medicine advanced therapy (RMAT) designation to several of these agents as they undergo further examination in early-phase trials.

“When you move from blood cancers to solid tumor cancers, the structure of the tumor is a lot different. The first thing is that there is a massive amount of target antigen heterogeneity,” Renier Brentjens, MD, PhD, said in an interview with 

. “There are 3 basic issues that are different between liquid and solid tumors: target antigen heterogeneity, an immunosuppressive microenvironment, and a fibrotic structure that makes it difficult for the CAR T cells to get into the tumor. Although the first CAR T-cell therapy was approved for pediatric acute lymphoblastic leukemia back in 2017, there haven’t been any FDA-approved CAR T-cell therapies for solid tumors because if you apply that paradigm that we did for blood cancers to solid tumors, it’s going to fail for those 3 reasons.” 

Despite these challenges that must still be addressed, Brentjens remains positive. “Do I think CAR T cells will have a role in solid tumors in the next 5 to 10 years? I absolutely do,” he said. “The concept isn’t flawed; we’re just not there with the technology [yet].” 

CLDN18.2-Targeryed Satri-Cel Generates Activity in GI Cancer 

Final results of the single-arm, open-label, phase 1 CT041-CG4006 trial (NCT03874897) published in 

 revealed that the claudin18.2 (CLDN18.2)–directed autologous CAR T-cell therapy satri-cel was well tolerated and efficacious in patients with CLDN18.2-positive advanced gastrointestinal (GI) cancer.

 No dose-limiting toxicities (DLTs) or treatment-related deaths were reported, and the overall response rate (ORR) was 38.8% in patients treated with satri-cel (n = 98). Additionally, the disease control rate was 91.8%, the median progression-free survival (PFS) was 4.4 months (95% CI, 3.7-6.6), and the median overall survival (OS) was 8.8 months (95% CI, 7.1-10.2). 

The pivotal phase 1/2 CT041-ST-01 trial (NCT04581473) examining satri-cel is underway, and the agent’s manufacturer, CARsgen Therapeutics, has announced that the study met its primary end point: There was a statistically significant improvement in PFS with satri-cel vs treatment of physician’s choice in patients with CLDN18.2-positive, advanced gastric/gastroesophageal junction cancers who experienced disease progression on at least 2 prior lines of therapy.

 The agent previously received RMAT designation from the FDA in 2022. 

“Sometimes we find reassurance if the target we’re going after [has] already been [examined in] a clinical trial with a bispecific [antibody]—if it’s well tolerated there, then you’re more confident that the CAR T cell will be well tolerated,” Brentjens noted. “Clinical trials need to be designed [where] you start at very low doses of T cells so that if there is unforeseen on-target, off-tumor toxicity, you can treat [the patients] with steroids and chemotherapies to abrogate that response.” 

CAR T-Cell Therapy Also Shows Early Efficacy Signals in Brain Tumors 

-mutated diffuse midline gliomas (n = 11) who received CAR-modified T cells targeting GD2 in arm A of a phase 1 trial (NCT04196413), major volumetric tumor reductions occurred in 4 patients, and 3 patients had smaller reductions.

 Findings also showed that 1 patient had a complete response (CR) that was ongoing for more than 30 months following enrollment. In the study, patients received 1 intravenous (IV) dose of autologous GD2-CART at 2 dose levels following lymphodepleting chemotherapy, and those with benefit were eligible for subsequent intracerebroventricular (ICV) intracranial infusions. No DLTs were observed at the first dose level, but 3 patients experienced dose-limiting cytokine release syndrome (CRS) at dose level 2. 

“I believe we were the first to recognize CRS, and there are algorithms already in place for how to limit that toxicity,” Brentjens said. “The on-target, off-tumor toxicity is always a bit more worrisome because as much as we think that the targets we go after are safe targets, there aren’t a lot of CD19-type targets out there. You always run the risk, with maybe a handful of exceptions, that the protein that you’re going after isn’t only expressed on the tumor but is expressed on normal tissues elsewhere.” 

Because 9 patients who received ICV infusions in the phase 1 trial did not experience DLTs, investigators have initiated arms B and C to test ICV-only administration with and without lymphodepleting chemotherapy. Dose level 1 was also established as the maximum tolerated IV dose. 

Furthermore, Memorial Sloan Kettering Cancer Center (MSK) investigators noted that a patient with mesothelioma who first received CAR T-cell therapy following chemotherapy in a clinical trial during the fall of 2019 and then went on to receive pembrolizumab (Keytruda), is doing well as of September 2024.

 Results of a phase 1/2 study (NCT02414269) out of MSK showed that patients with malignant pleural mesothelioma (n = 18) who received a mesothelin-targeted CAR T-cell therapy plus pembrolizumab experienced a 1-year OS rate of 83%.7 Two patients achieved a complete metabolic response on PET scan, and 8 patients sustained stable disease (SD) for at least 6 months. 

Brentjens noted that "combining CAR T cells with immune checkpoint inhibition [may be a way] to overcome limitations” with CAR T-cell therapy’s application in solid tumors. "It’s going to be a combination of technologies and a combination of immune-based therapies [that push the field forward],” he said.

Allogeneic CD70-Directed Agent Represents a Targeted CAR T-Cell Therapy of Promise 

“Nowadays, with protein maps and RNA encyclopedias, you can find potential targets on virtually any cancer cell,” Brentjens said. “Given that they now have phage display libraries, which didn’t exist when we started, finding binders to any target that you want is much easier and can be done more rapidly. If you would have asked me 20 years ago if there is a favorable solid tumor, [I would’ve said] if you had access to an antibody that binds CEA or EGFR, then those would be the favorable ones to go after. Because the tumor microenvironment is different from tumor type to tumor type, we don’t quite yet know which armoring approach or which combination approach would be more favorable for one type of tumor vs another.” 

Another promising agent appears to be ALLO316, an allogeneic CD70-directed CAR T-cell therapy, which yielded a 38% best ORR in patients with advanced renal cell carcinoma (RCC) who received dose level 2 (DL2; 80 × 10

 of CAR+ cells) of the agent following fludarabine 30 mg/m

 (n = 8) in the phase 1 TRAVERSE trial (NCT04696731).

 The confirmed ORR in this patient population was 25%, and all responses were in those with a high tumor proportion score of at least 50. Comparatively, confirmed ORRs were 22% among those who received fludarabine and cyclophosphamide alone (n = 18); 13% among those treated with fludarabine, cyclophosphamide, and ALLO-647, an anti-CD52 antibody (n = 8); and no responses occurred among the 8 patients who had CD70-negative disease or unknown status.

Additionally, 2 DLTs occurred in the study which included autoimmune hepatitis and cardiogenic shock.

 Related grade 5 adverse effects (AEs) were cardiogenic shock, sepsis, and failure to thrive. The grade 3 or higher AEs that occurred in the DL2 group (n = 11) were neutropenia (64%), anemia (46%), thrombocytopenia (27%), and infection (18%). Further data from the phase 1b expansion cohort is expected to be reported midway through 2025. 

As a result of the positive data from the trial in patients with RCC, the FDA granted ALLO-316 RMAT designation in October 2024 for patients with advanced or metastatic RCC; the agent previously received fast track designation in March 2023. Allogene Therapeutics, the drug’s developer, noted that ALLO-316’s unique features are cell expansion and persistence driven by CD70 CAR-intrinsic Dagger technology and tumor infiltration by CAR T cells.

GCC19CART Produces Objective Clinical Activity in Refractory CRC 

Further efficacy was seen in patients with solid tumors treated with CAR T-cell therapy, as those with metastatic colorectal cancer (CRC) who received DL2 (2 × 10

 cells/kg) of GCC19CART (n = 5), the guanylate cyclase-C–targeted CAR T-cell therapy, experienced an ORR of 80%. Updated data as of December 26, 2024, revealed that this encompassed 1 pathological CR and 3 confirmed partial responses (PRs), including 1 patient who had a complete metabolic response on PET/CT.

 Those treated with dose level 1 (DL1; 1 × 10

 cells/kg; n = 4) had an ORR of 25.0%; 1 patient experienced a PR, and 2 patients had a partial metabolic response on PET/CT with SD. Additionally, the median PFS was 5.0 months at a median follow-up of 16.6 months in the DL1 group and 7.8 months with a median follow-up of 7.4 months in the DL2 group. 

Regarding safety, 1 patient experienced a DLT at DL2 and presented with grade 3 diarrhea, grade 4 enterocolitis, and grade 5 sepsis. Study investigators noted that preliminary results show the AE profile of GCC19CART is in line with what has been observed with other CAR T-cell therapies and that the agent showed significant antitumor activity in patients with refractory metastatic CRC. 

Furthermore, investigators highlighted that GCC19CART is the first CAR T-cell therapy to their knowledge that has produced objective clinical activity in patients with refractory cancer.

 The agent previously received fast track status from the FDA in April 2022 for the treatment of this patient population.

Regarding next steps in the field, Brentjens said, “What needs to happen at some point is [the examination of] armored CAR T cells. Armored CARs are CAR T cells that can recognize a target on the tumor but are additionally engineered to, for example, secrete proinflammatory cytokines. What happens then is that when the CAR T cell gets into the tumor, it secretes this proinflammatory cytokine that overcomes a lot of that immune suppression and engages the patient’s immune system to recognize the cancer [similar to the] way that immune checkpoint inhibitors can overcome immune suppression.”

Qi C, Liu C, Gong J, et al. Claudin18.2-specific CAR T cells in gastrointestinal cancers: phase 1 trial final results. 

. 2024;30(8):2224-2234. doi:10.1038/s41591-024-03037-z

CARsgen announces positive topline results from China GC/GEJ pivotal phase II clinical trial of claudin18.2 CAR-T (satri-cel). News release. CARsgen Therapeutics. December 30, 2024. Accessed March 7, 2025. bit.ly/4bwD3Od

Monje M, Mahdi J, Majzner R, et al. Intravenous and intracranial GD2-CAR T cells for H3K27M

. 2025;637(8046):708-715. doi:10.1038/s41586-024-08171-9

Allogene Therapeutics announces positive phase 1 data demonstrating the potential of ALLO-316 in heavily pretreated patients with advanced renal cell carcinoma at SITC and IKCS. News release. Allogene Therapeutics. November 7, 2024. Accessed March 7, 2025. bit.ly/3FcauK4

Innovative Cellular Therapeutics (ICT) receives FDA fast track designation for GCC19CART, its lead solid tumor candidate, in the treatment of patients with relapsed or refractory metastatic colorectal cancer. News release. Innovative Cellular Therapeutics. April 19, 2022. Accessed March 7, 2025. bit.ly/4iq0sDa

Stallard J. How MSK is teaching CAR T cells to attack solid tumors. Memorial Sloan Kettering Cancer Center. September 3, 2024. Accessed March 7, 2025. bit.ly/3F809il

Adusumilli PS, Zauderer MG, Rivière I, et al. A phase I trial of regional mesothelin-targeted CAR T-cell therapy in patients with malignant pleural disease, in combination with the anti-PD-1 agent pembrolizumab. 

. 2021;11(11):2748-2763. doi:10.1158/2159-8290.CD-21-0407

Redefining the Future of CAR T: Doing What No CAR T Has Done Before

. Allogene Corporate Overview. March 2025. Accessed March 7, 2025. bit.ly/3F8cAul

Srour SA, Chahoud J, Drakaki A, et al. ALLO-316 in patients with advanced or metastatic clear cell renal cell carcinoma (ccRCC): updated safety and efficacy from the phase 1 TRAVERSE multicenter study. 

. 2024;12(suppl 2). doi:10.1136/jitc-2024-SITC2024.0322

Keenan BP, Lieu CH, Fakih M, et al. A phase 1 dose-escalation study of GCC19CART: a novel CAR T-cell therapy for metastatic colorectal cancer in the United States. 

. 2025;43(suppl 4):175. doi:10.1200/JCO.2025.43.4_suppl.175

Chen N, Pu C, Zhao L, et al. Chimeric antigen receptor T cells targeting CD19 and GCC in metastatic colorectal cancer: a nonrandomized clinical trial. 

. 2024;10(11):1532-1536. doi:10.1001/jamaoncol.2024.3891

Articles

Chimeric antigen receptor (CAR) T-cell therapies are showing promising efficacy in solid tumors, with several agents like satricabtagene autoleucel (satri-cel) and ALLO-316 receiving FDA designations for further study. Challenges in solid tumors include antigen heterogeneity, immunosuppressive microenvironments, and fibrotic structures. Despite these, early trials demonstrate potential, with satri-cel showing significant activity in gastrointestinal cancers and GD2-CART in brain tumors. Combining CAR T-cells with immune checkpoint inhibitors may enhance efficacy. Advances in targeting and technology are crucial for overcoming current limitations in solid tumor applications.

Renier Brentjens, MD, PhD, discusses the current landscape of CAR T-cell agents in patients with solid tumors.

Targeted CAR T-Cell Therapies Show  Early Efficacy in Solid Tumors With  Focus on Mitigating Toxicity

The Inflation Reduction Act (IRA), which was signed into law in 2022, contains provisions designed to lower drug prices for Medicare beneficiaries.

 Although significant savings have already been reported,

 the legislation may have unintended consequences on oncologic drug development, access, and innovation, according to Frank S. David, MD, PhD.

“There are 3 main provisions of the IRA that affect pharmaceuticals,” David wrote in a statement to 

. “First, it lets the federal government demand lower prices for some drugs that account for a large amount of Medicare spending. Manufacturers must accept the new ‘negotiated’ price if they want their drugs to remain available under Medicare. Second, it penalizes manufacturers for raising the list prices of Medicare-covered drugs faster than inflation. Third, it limits patients’ out-of-pocket costs for prescription medicines covered by Medicare Part D. In cancer, the first round of price setting, set to take effect in 2026, affects ibrutinib [Imbruvica]. The second round, which will be implemented in 2027, includes enzalutamide [Xtandi] and palbociclib [Ibrance]. Although there are hypotheses of which drugs will be affected in 2028 and beyond, we don’t know for sure yet.”

David is a professor of the practice of biotechnology at Tufts University in Medford, Massachusetts, and managing director of biotechnology research and development strategy consulting firm Pharmagellan.

In an article published in JAMA Oncology, David and his coauthor, Stacie B. Dusetzina, PhD, of Vanderbilt University Medical Center in Nashville, Tennessee, argued that certain aspects of the oncologic drug pipeline could be affected by both the positive and negative effects of the incentives of the IRA.3 Under the parameters of the IRA, an agent’s price can be negotiated when it has been at least 9 or 13 years since the FDA approval of its active ingredients for small molecules and biologics, respectively. Prices can also be negotiated if the drug is one of the top-spend products in Medicare or if it has no generic/ biosimilar competitor.

David noted that the IRA considers a drug component used for multiple indications as a single product in terms of price negotiation eligibility, which could discourage pharmaceutical companies from conducting further trials. This could be especially damaging in oncology by disincentivizing postapproval studies. It could also lead the companies to delay an agent’s launch for a smaller patient population if it would lead to a faster price negotiation and affect future revenues for a larger population.

“Anecdotally, the main impact I’ve heard of in oncology is that some companies are re-examining their plans for postapproval trials in additional indications,” David explained. “If a cancer drug is likely to have a short window before it’s subject to IRA price setting, then it may not make sense to run a lot more long trials in other tumor types because it will be hard to recoup the investment. Many [people] have proposed other impacts of the IRA, [such as] an even greater shift toward biologics vs small molecules or shifts away from early-stage R&D [research and development] in areas where a major player is likely to have its price cut soon under the IRA.”

David also argued that the shorter time before price negotiations for small molecule drugs compared with biologics could lead to companies investing less in the development of these agents. Companies and investors could also reduce or forgo altogether their investment in areas that have a higher chance for price negotiation, instead concentrating on therapeutics for younger individuals who are not Medicare beneficiaries.

“The concern is that companies and investors will support less R&D aimed at drugs that treat Medicare patients, including many cancer therapies, if they believe their revenues from these medicines might get capped in the future under the IRA,” David explained. “This is a reasonable hypothesis because we know that the industry’s R&D activities have historically shifted toward higher-revenue areas and away from lower-revenue ones. But even if that happens, we don’t know what the magnitude of the effect might be in general or specifically in oncology.”

®, investigators sought to describe the potential effect of the IRA on research and development investments toward subsequent indications of small molecule agents included in Medicare Part D.4 Data showed that 30 of the drugs with the highest gross spending by Medicare Part D in 2020 (n = 50) were small molecule agents that gained subsequent indications. Oncologic drugs were tied with cardiology/endocrinology for the most common therapeutic areas included in the study, at 26.7% each.

Among the 30 small molecule drugs, subsequent indications represented 72% of all indications, and postapproval studies or real-world evidence supported most of the subsequent indications (55.3%). Subsequent indications were granted FDA approvals at a mean time of 5.4 years (SD, 3.40; range, 0.3-13.4) following the approval of the initial indication.

Subsequent indications supported by preapproval clinical studies (n = 34) received FDA approval at a mean time of 2.9 years (SD, 2.46; range, 0.3-11.2) after a drug was first approved. Additionally, indications supported by postapproval studies or real-world evidence (n = 42) received FDA approval at a mean time of 7.5 years (SD, 2.60; range, 3.7-13.4) after the initial approval. Most of the subsequent indications (55.8%) were granted FDA approval more than 7 years after the initial approval. The study authors concluded that the timelines outlined in their research showed the potential of the IRA to decrease economic incentives for companies to develop drugs for multiple indications.

Beyond the potential negative effects of the IRA on drug development, David noted that patients should benefit from the reduction in their out-ofpocket cost maximum under Medicare Part D. Moreover, the savings could lead to patients filling their prescriptions more consistently, which could partially offset the negative effect on drug development by increasing revenues to pharmaceutical companies. Although the future of the IRA is unclear and it is too early to know its exact ramifications, the effect of the act on oncologic drug development and innovation remains an area of research that warrants further exploration, David said.

“Many of us who do research in this area are interested in rigorously quantifying the impact of the IRA on drug development,” David said. “In addition, many tweaks have been proposed to modify the IRA, and many of us are interested in modeling their potential impacts to see if we can predict which ones would have the most beneficial effects on biopharma investment, drug R&D, and patient care without significantly undermining the cost savings from the law.”

Inflation Reduction Act of 2022, HR 5376, 117th Cong (2022). Updated August 16, 2022. Accessed March 5, 2025. https://www.congress.gov/bill/117th-congress/house-bill/5376

Biden-Harris administration’s Inflation Reduction Act saves Medicare enrollees nearly $1 billion in just the first half of 2024. News release. US Department of Health and Human Services. October 22, 2024. Accessed March 5, 2025. https://public3.pagefreezer.com/browse/HHS.gov/02-01-2025T05:49/ https://www.hhs.gov/about/news/2024/10/22/biden-harris-administrations-inflation-reduction-actsaves-medicare-enrollees-nearly-1-billion-just-first-half-2024.html

Dusetzina SB, David FS. Cancer drug access and innovation under the Inflation Reduction Act-a balancing act. JAMA Oncol. 2024;10(12):1614-1615. doi:10.1001/jamaoncol.2024.4745

Patterson J, Motyka J, O’Brien JM. Unintended consequences of the Inflation Reduction Act: clinical development toward subsequent indications. Am J Manag Care. 2024;30(2):82-86. doi:10.37765/ ajmc.2024.89495

The Inflation Reduction Act (IRA) aims to reduce drug prices for Medicare beneficiaries but may impact oncologic drug development and innovation. Key provisions include government-negotiated drug prices, penalties for price hikes, and caps on out-of-pocket costs. Concerns arise over potential disincentives for pharmaceutical companies to conduct postapproval studies or invest in small molecule drugs due to shorter negotiation timelines. While patients benefit from reduced costs, the act's long-term effects on drug development remain uncertain, necessitating further research to balance cost savings with innovation incentives.

Oncology Business Management 

Challenges may arise as there could be unintended consequences on
oncologic drug development, access, and innovation.

Inflation Reduction Act Leads to Seesaw Effect Between Oncologic Drug Savings and Development 

Non–small cell lung cancer (NSCLC) causes approximately 2 million deaths each year worldwide.

 Approximately one-third of patients initially present with locally advanced disease, meaning that the cancer is bulky and/or involves regional lymph nodes but has not spread to distant locations.

A standard treatment for patients with locally advanced NSCLC consists of a 6-week course of daily thoracic radiotherapy along with concurrent radiosensitizing chemotherapy, often followed by adjuvant immunotherapy.

 With respect to radiotherapy dosing, systemic agents used, and treatment sequencing, patients are currently treated with a one-size-fits-all approach. Some patients may experience severe adverse effects (AEs) during or after chemoradiotherapy, including esophagitis, lung inflammation, and immuno- suppression.

Many patients never reach the adjuvant immunotherapy phase because they experience severe AEs from chemoradiotherapy. In addition, immunosuppression resulting from chemoradiotherapy may render immunotherapy ineffective. Five-year survival rates remain below 50% for this patient population.

New lung cancer treatment options have emerged in recent years, and several groups are exploring personalized treatment strategies that omit chemotherapy for some patients with locally advanced NSCLC. Chemotherapy-free lung cancer treatment would be especially helpful for patients who are frail or older, or who have biopsy findings that suggest that immunotherapy would be effective.

Advancing Personalized Lung Cancer Treatment 

Chemotherapy can cause significant toxicity and is not always effective in preventing disease spread. Establishing chemotherapy-free treatment approaches for locally advanced NSCLC using biomarker testing to identify patients who could be treated effectively without chemotherapy would represent a major advance.

The phase 2 SPRINT trial (NCT03523702) was recently completed at Montefiore Einstein Comprehensive Cancer Center (MECCC), an National Cancer Institute–designated Comprehensive Cancer Center, Bronx, New York. Investigators evaluated patients with locally advanced NSCLC with high expression of PD-L1, which is a predictor of immunotherapy efficacy.

Unlike many other studies testing chemotherapy-free treatment for locally advanced NSCLC, the SPRINT trial enrolled patients who were fit enough to receive standard chemotherapy and radiotherapy.

 Additionally, SPRINT participants received induction immunotherapy before radiotherapy to shrink their tumors and ensure they received immunotherapy, as most patients following the existing protocol do not make it to that phase of treatment. SPRINT participants then received 3 cycles of induction pembrolizumab (Keytruda); a 4-week course of personalized radiotherapy, often with lower doses; and additional pembrolizumab. SPRINT’s personalized radiotherapy strategy, which was piloted at MECCC to minimize the risk of treatment toxicity and risk of acute and delayed AEs (including immunosuppression) without compromising disease control, was another novel aspect of SPRINT that took treatment personalization to a new level.

Few serious AEs related to study therapy occurred, and approximately 50% of treated patients (n = 25) had significant disease shrinkage after induction immunotherapy. Progression-free survival and overall survival rates exceeded expectations for this patient population, and disease improvement after induction immunotherapy was identified as a powerful predictor of long-term treatment efficacy (Figure).

 This finding indicates that measuring responses to induction therapy could help researchers quickly determine which novel immunotherapy agents should be tested in large trials for the management of locally advanced NSCLC to improve patient outcomes.

Future Immunotherapy and Chemotherapy-Free Studies

Clinical trials offer patients with locally advanced NSCLC access to novel treatments, along with the support of their respective health care team.

Building on the SPRINT findings, MECCC investigators are leading the multi-institutional phase 2 TRIPL (NCT06865339) and SPRINT2 trials in 2025, testing combinations of promising novel immunotherapy drugs targeting LAG3, NKG2A, and CD73, and more established drugs targeting PD-1/PD-L1. Both trials will incorporate induction dual-agent immunotherapy, which will be followed by personalized radiotherapy and then additional immunotherapy. Favorable results from these trials would support subsequent pivotal phase 3 trials looking to establish new treatment options for patients with locally advanced NSCLC.

In addition to these clinical trials, other treatment approaches being taken by MECCC investigators include the use of proton beam radiotherapy as well as primary tumor stereotactic body radiotherapy, the latter of which is being tested in the phase 3 NRG-LU008 trial (NCT05624996), with the overarching goal of improving cure rates and reducing treatment toxicity.

Nitin Ohri, MD, MS, is a professor of radiation oncology at Montefiore Einstein Comprehensive Cancer Center in Bronx, New York. 

Li C, Lei S, Ding L, et al. Global burden and trends of lung cancer incidence and mortality. 

. 2023;136(13):1583- 1590. doi:10.1097/CM9.0000000000002529

Antonia SJ, Villegas A, Daniel D, et al. Durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

. 2017;377(20):1919-1929. doi:10.1056/NEJMoa1709937

Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer. 

. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308

Bradley JD, Hu C, Komaki RR, et al. Long-term results of NRG oncology RTOG 0617: standard-versus high-dose chemoradiotherapy with or without cetuximab for unresectable stage III non-small-cell lung cancer. 

. 2020;38(7):706- 714. doi:10.1200/JCO.19.01162

Ohri N, Jolly S, Cooper BT, et al. Selective personalized radioimmunotherapy for locally advanced non-small-cell lung cancer trial (SPRINT). 

. 2024;42(5):562-570. doi:10.1200/JCO.23.00627

Ohri N, Bodner WR, Kabarriti R, et al. Positron emission tomography-adjusted intensity modulated radiation therapy for locally advanced non-small cell lung cancer. 

. 2018;102(4):709-715. doi:10.1016/j.ijrobp.2017.10.032

Giaddui T, Chen W, Yu J, et al. Establishing the feasibility of the dosimetric compliance criteria of RTOG 1308: phase III randomized trial comparing overall survival after photon versus proton radiochemotherapy for inoperable stage II-IIIB NSCLC. 

. 2015;11:66. doi:10.1186/s13014-016-0640-8

Non-small cell lung cancer (NSCLC) remains a significant global health challenge, with high mortality rates and limited five-year survival for locally advanced cases. Traditional treatment involves chemoradiotherapy, often leading to severe adverse effects and immunosuppression. Recent advancements focus on personalized, chemotherapy-free strategies, particularly for patients with high PD-L1 expression. The SPRINT trial demonstrated promising results with induction immunotherapy and personalized radiotherapy, reducing toxicity and improving survival outcomes. Future trials, such as TRIPL and SPRINT2, aim to further explore novel immunotherapy combinations, potentially transforming NSCLC management.

New lung cancer treatment options have emerged, and several groups are exploring treatment strategies that omit chemotherapy for locally advanced NSCLC. 

Personalizing Lung Cancer Treatment Reduces Toxicity and Improves Cure Rates

With the development of novel RAS(ON) inhibitors such as zoldonrasib (RMC-9805) and daraxonrasib (RMC-6236), investigators are aiming to surmount acquired resistance in patients with pretreated solid tumors following treatment with currently available RAS inhibitors. 

KRAS is the most common altered oncogenic protein in solid tumors and was thought to be resistant to drug therapy until recent improvements in drug design, leading to the development of the FDA-approved KRAS G12C inhibitors sotorasib (Lumakras) and adagrasib (Krazati).

 These agents are RAS(OFF) inhibitors, meaning they bind to a switch II region pocket accessible when KRAS is in the GDP-bound inactive state; the agents covalently engage with the mutant cysteine and lock the oncogene in its inactive state.2 Although sotorasib and adagrasib have displayed impressive efficacy in non–small cell lung cancer and colorectal cancer, patients often develop resistance to these agents.

Comparatively, RAS(ON) inhibitors target the active, GTP-bound state of RAS.1 Targeting RAS in this manner has shown the potential to overcome resistance to RAS(OFF) inhibitors in preclinical studies.

Multiple RAS(ON) inhibitors in the development pipeline are showing promise. During the American Society of Clinical Oncology 2025 Gastrointestinal Cancers Symposium (ASCO GI), investigators presented early data from clinical trials evaluating the RAS(ON) inhibitors zoldonrasib and daraxonrasib in advanced solid tumors, including pancreatic ductal adenocarcinoma (PDAC).

Zoldonrasib and Daraxonrasib Display Early Signs of Efficacy in PDAC

Zoldonrasib is a potent RAS(ON) G12D-selective covalent tricomplex inhibitor designed to directly inhibit uncontrolled RAS(ON) signaling.

 In a phase 1 study (NCT06040541), investigators evaluated the agent in adult patients with KRAS G12D–mutated advanced solid tumors who had received prior standard therapy appropriate for their disease.

Data from the dose-escalation portion of the study presented during ASCO GI demonstrated that patients with PDAC who received zoldonrasib at a dose of 1200 mg either once or twice daily (n = 40) achieved an overall response rate (ORR) of 30%. The disease control rate (DCR) was 80%. Additionally, among the patients evaluable for changes in KRAS G12D variant allele frequency (VAF; n= 28), 86% had at least a 50% decrease and 39% had a 100% decrease in KRAS G12D VAF after treatment with zoldonrasib.

“[The VAF data] tell us that patients who are responding but have not demonstrated [a response] on imaging are also doing very well,” Alexander I. Spira, MD, PhD, FACP, FASCO, said in an interview with 

. “That [contributes] to clinical benefit rate and, hopefully, the overall survival [OS] rate. We’re getting a benefit from the drug in multiple ways, which can lead us to bigger, phase 3 studies and likely improvements in OS and progression-free survival [PFS].”

Spira is codirector of the Virginia Cancer Specialists Research Institute in Fairfax and director of the Thoracic and Phase I Program and a clinical assistant professor at Johns Hopkins School of Medicine in Baltimore, Maryland. He also presented the findings from the phase 1 study during ASCO GI.

Regarding safety, no patients across disease groups who received zoldonrasib (n = 179) experienced a treatment-related adverse effect (TRAE) that led to treatment discontinuation, and only 3% of patients had an event leading to a dose reduction. Common any-grade TRAEs included nausea (30%), diarrhea (16%), and vomiting (15%). There were no grade 4 or 5 TRAEs or serious AEs.

“[Zoldonrasib] was a very well-tolerated drug, [with] very [few] grade 3 and 4 AEs,” Spira noted. “Because this is an allele-specific [drug], we did not see [AEs] we’ve seen with other RAS inhibitors. [There was] a very low incidence of rash and very few dose reductions.”

In a phase 1 study (NCT05379985), daraxonrasib, another RAS(ON) tricomplex inhibitor, is being examined in adult patients with advanced solid tumors harboring RAS mutations who had received prior standard therapy appropriate for tumor type and stage.

 Daraxonrasib is a multiselective inhibitor that also directly inhibits uncontrolled RAS(ON) signaling.

Patients with RAS-mutated PDAC who received daraxonrasib at the recommended phase 2 dose (RP2D) of 300 mg daily (n= 37) achieved a median PFS of 8.5 months (95% CI, 5.9-not evaluable [NE]). The median OS was NE (95% CI, 8.5-NE), and the 6-month OS rate was 97% (95% CI, 79%-100%). The ORR and DCR were 27% and 95%, respectively.

Among patients with KRAS G12X–mutated PDAC treated at the RP2D (n = 22), the median PFS and OS were 8.8 months (95% CI, 8.5-NE) and NE (95% CI, NE-NE), respectively; notably, the 6-month OS rate was 100% (95% CI, 100%-100%). The ORR and DCR were 36% and 91%, respectively.

“We feel that the PFS data are remarkable,” Ignacio Garrido-Laguna, MD, PhD, MBA, said in an interview with 

. “The PFS in the second-line setting compares very positively with historical controls; in this setting, we typically see a [median] PFS in the range of 3 months.”

Garrido-Laguna is the director of the Phase 1 Program, coleader of the GI Oncology Multidisciplinary Disease Group, and a professor of oncology at the University of Utah Huntsman Cancer Institute in Salt Lake City. Garrido-Laguna presented the findings from the phase 1 study of daraxonrasib during ASCO GI.

Evaluable patients with KRAS G12X–mutated disease who received daraxonrasib at 160 mg to 300 mg daily (n = 60) experienced a reduction in KRAS G12X VAF of at least 50% at a rate of 93%; 48% of patients achieved a 100% decrease. Among evaluable patients with RAS-mutated disease (n = 73), these rates were 90% and 45%, respectively.

Among patients with PDAC in the safety population who received daraxonrasib at the RP2D (n = 76), 96% experienced any-grade TRAEs. Common any-grade TRAEs included rash (91%), diarrhea (53%), and nausea (38%). TRAEs leading to dose modification, interruption, or reduction, occurred at rates of 42%, 40%, and 25%, respectively. No patients discontinued treatment due to TRAEs.

“Based on [findings from] this study, there has been a randomized phase 3 trial, RASolute 302 [NCT06625320], that has been launched,” Garrido-Laguna said. “It is a global study that is enrolling patients [with PDAC] in the US. It started accrual in…2024, and it is going to include approximately 400 patients. It’s a very promising study based on these data, but we need to wait for completion of the study and follow up on outcomes from those patients. Patients are randomly assigned in the second line after disease progression with first-line chemotherapy to [receive] the multi-RAS inhibitor [daraxonrasib] or standard-of-care chemotherapy.”

Punekar SR, Velcheti V, Neel BG, Wong KK. The current state of the art and future trends in RAS-targeted cancer therapies. Nat Rev Clin Oncol. 2022;19(10):637-655. doi:10.1038/s41571- 022-00671-9

Nokin MJ, Mira A, Patrucco E, et al. RAS-ON inhibition overcomes clinical resistance to KRAS G12C-OFF covalent blockade. Nat Commun. 2024;15(1):7554. doi:10.1038/s41467-024-51828-2

Spira AI, Papadopoulos KP, Kim DW, et al. Preliminary safety, antitumor activity, and circulating tumor DNA (ctDNA) changes with RMC-9805, an oral, RAS(ON) G12D-selective tri-complex inhibitor in patients with KRAS G12D pancreatic ductal adenocarcinoma (PDAC) from a phase 1 study in advanced solid tumors. J Clin Oncol. 2025;43(suppl 4):724. doi:10.1200/ JCO.2025.43.4_suppl.724

Garrido-Laguna I, Wolpin BM, Park W, et al. Safety, efficacy, and on-treatment circulating tumor DNA (ctDNA) changes from a phase 1 study of RMC-6236, a RAS(ON) multi-selective, tricomplex inhibitor, in patients with RAS mutant pancreatic ductal adenocarcinoma (PDAC). J Clin Oncol. 2025;43(suppl 4):722. doi:10.1200/JCO.2025.43.4_suppl.722

Novel RAS(ON) inhibitors, zoldonrasib and daraxonrasib, are being developed to address resistance in solid tumors treated with existing RAS inhibitors. These inhibitors target the active, GTP-bound state of RAS, showing promise in overcoming resistance. Early clinical trials have demonstrated efficacy in pancreatic ductal adenocarcinoma (PDAC), with zoldonrasib achieving a 30% overall response rate and daraxonrasib showing a median progression-free survival of 8.5 months. Both drugs exhibited favorable safety profiles, with minimal treatment-related adverse effects leading to discontinuation.

Pathways

Study investigators are aiming to leverage therapy resistance, particularly in patients with solid tumors after receiving available RAS inhibitors.

RAS(ON) Inhibitors May Overcome Resistance to Traditional KRAS Inhibitors in Solid Tumors

The next-generation antibody-drug conjugate (ADC) ARX788 generated excitement when it received fast track designation from the FDA for patients with HER2-positive metastatic breast cancer and again when it yielded a significant improvement in progression-free survival (PFS) vs lapatinib (Tykerb) plus capecitabine and showed a trend toward overall survival (OS) improvement.

Differing from the topoisomerase I inhibitor payload of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu), ARX788 has an AS269 payload site specifically conjugated to the antibody.

 The drug is under investigation in the phase 2 ACE-Breast-03 trial (NCT04829604) in patients who previously received T-DXd.

“ARX788 is in active development, and phase 2 data [from the phase 2/3 ACE-Breast-02 study (CTR20201708) showed] it’s a highly active anti-HER2–directed therapy. It has a microtubule inhibitor payload and has [not only shown] activity against HER2-amplified disease but also HER2-low disease,” Joyce O’Shaughnessy, MD, said in an interview with 

In ACE-Breast-02, patients with metastatic or locally advanced HER2-positive disease who received prior therapy with trastuzumab (Herceptin) and a taxane achieved a median PFS of 11.33 months (95% CI, 8.44- 13.83) by blinded independent central review when treated with ARX788 (n = 221) vs 8.25 months (95% CI, 6.93-8.71) among those given lapatinib plus capecitabine (n = 220; HR, 0.64; 95% CI, 0.49-0.82; stratified log-rank 

At 18.6% maturity, with a median follow-up of 14.23 months, the preliminary OS analysis revealed that the median OS was not reached (NR; 95% CI, NR-NR) in the ARX788 arm vs NR (95% CI, 23.59-NR) in the chemotherapy arm (HR, 0.71; 95% CI, 0.46-1.10). 

Keeping a Close Eye on Ocular Toxicities and ILD

“[ARX788] has good tolerability, [although] it can cause interstitial lung disease [ILD], so we have to be aware of that as we are for T-DXd. It’s been able to help patients [in a] late-line [setting]. It’s a very exciting, active, and safe [agent],” O’Shaughnessy said.

In ACE-Breast-02, 6 patients (2.7%) experienced fatal treatment-related adverse effects (TRAEs), which included ILD (n=3), pneumonitis (n=1), and respiratory failure (n = 2); 1 patient with ILD and 1 patient with respiratory failure also had a lung infection. 

Additionally, treatment-emergent AEs (TEAEs) in the investigative vs control arm led to dose reduction (23.6% vs 37.7%), dose interruption (67.3% vs 50.7%), treatment discontinuation (6.8% vs 1.9%), and death (5.0% vs 3.7%). The most common grade 3 or higher TRAEs were blurred vision (12.3% vs 0.0%), dry eye (9.1% vs 0.0%), keratopathy (5.9% vs 0.0%), and ILD (5.9% vs 0.0%), respectively. 

“For dry eye, the over-the-counter refresh moisturizing eye drops [are] recommended. One drop [can be given] 3 to 4 times a day [to] preventively avoid the eyes getting dried out,” O’Shaughnessy said. “Sometimes patients must have a dose reduction, and that tends to help. It’s rare for patients to have inflammation of the cornea or anything like that from dry eyes getting bad. We will send the patient to an ophthalmologist if they need to go, but most do fine with the eye drops and then a dose reduction if they need one.”

Certain newer ADCs are no exception to having ocular AEs, as the toxicities remain prevalent with the drug class. Data from the phase 3 TULIP trial (NCT03262935) showed that despite a statistically significant improvement in PFS observed with the ADC vic-trastuzumab duocarmazine (SYD985; n = 291) vs physician’s choice of therapy (n = 146), 78.1% of patients treated with the ADC experienced ocular AEs.

Treatment discontinuation rates in the study were 35.4% vs 5.8%, respectively, and 20.8% of patients discontinued trastuzumab duocarmazine due to ocular toxicities. The recovery rates of grade 3 or higher keratitis, conjunctivitis, and dry eye were 80.5%, 94%, and 58% in the investigative arm, respectively. 

“[The drug] unfortunately did not lead to FDA approval, because although it had some improvement over standard chemotherapy plus trastuzumab regarding PFS, it had eye toxicity and ILD and some deaths from [pneumonitis]. [Therefore], it did not receive regulatory approval because of the toxicity, so that’s not going to [move] further in development,” O’Shaughnessy noted.

The role of ADCs continues to evolve in the HER2-positive space, and data are expected soon from the phase 3 DESTINY-Breast05 trial (NCT04622319) examining T-DXd vs ado-trastuzumab emtansine (T-DM1; Kadcyla), which O’Shaughnessy noted could change standard of care.

 To dive deeper into the evolving paradigm, join O’Shaughnessy as she chairs the 24th Annual International Congress on the Future of Breast Cancer® (IBC) occurring on the east coast in New York, New York, from July 11 to 12, 2025.

For additional crucial conversations on the study and new data surrounding this drug class, the conference will also be occurring on the west coast in San Diego, California, from July 18 to 19, 2025, where Sara Hurvitz, MD, FACP, will join O’Shaughnessy as cochair.

“By the time we get to IBC East/West...[for] HER2-positive breast cancer in the curative setting, we may have the DESTINY-Breast05 data. It may be that T-DXd is going to be better than T-DM1 in patients who have residual disease after preoperative chemotherapy and trastuzumab/ pertuzumab [Perjeta]. That would be a major change. Then we’ll hopefully see first-line T-DXd [data] in the phase 3 DESTINY-Breast09 trial [NCT04784715]—that could be absolutely practice changing as well [if results are positive]. There may be a lot to talk about at the IBC conferences with HER2-positive breast cancer.”

ARX788, a next-generation antibody-drug conjugate (ADC), has shown promise in treating HER2-positive metastatic breast cancer, demonstrating improved progression-free survival compared to lapatinib plus capecitabine. It features a microtubule inhibitor payload and is effective against both HER2-amplified and HER2-low disease. However, ARX788 is associated with ocular toxicities and interstitial lung disease (ILD). The evolving role of ADCs in HER2-positive breast cancer is highlighted by ongoing trials, such as DESTINY-Breast05, which may influence future treatment standards.

The next-generation ADC ARX788 is under investigation in the phase 2 ACE-Breast-03 trial of patients with T-DXd–pretreated HER2-positive breast cancer.

New ADCs Aim to Strengthen the HER2+ Breast Cancer Paradigm and Join T-DXd and T-DM1

The management of advanced biliary tract cancer (BTC) hit a turning point in 2024 with the first approvals of targeted therapies fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and zanidatamab-hrii (Ziihera) for patients with HER2 positivity. However, the 5-year overall survival (OS) rate for patients with advanced BTC remains at less than 5%, underscoring the need for additional effective treatment options for these patients.

“These are very aggressive cancers with median OS of approximately 12 months,” Haley Ellis, MD, said. “However, in recent years, we’re moving the needle forward in a positive way with the incorporation of immunotherapy and targeted therapies for a growing number of genomic alterations. BTCs stand as a benchmark for precision medicine in gastrointestinal [GI] cancers, and we’ve seen some impressive survival data in some of these biomarker-driven tumors. [Although] this is still a challenging cancer with lots of room to improve, this rapidly evolving treatment landscape offers patients a lot of hope.” 

During the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI) in January, an OncLive Peer Exchange

 featured insights from expert investigators in the field of BTC. They discussed the importance of early molecular testing, recent updates in the frontline setting, and the significance of targeted therapies moving into the second line and beyond.

New Standard Set By Targeted Agents In Frontline BTC

The panelists began their discussion by explaining the importance of early biomarker testing in informing treatment decisions in advanced BTC. They highlighted findings from an international real-world analysis of targeted therapy matched with molecularly actionable alterations in patients with advanced BTC following at least 30 days of palliative systemic treatment. The most common alterations included somatic BRCA1/2 mutations (n = 106), FGFR2 fusions (n = 61), HER2 amplification (n = 65), and IDH1 mutations (n = 38). Investigators used a Kaplan-Meier analysis to estimate OS from the start of frontline palliative systemic therapy until death or last follow-up. 

Findings from the analysis demonstrated that matched patients (n = 135) achieved a median OS of 21.4 months (95% CI, 18.4-27.9). Comparatively, patients in the unmatched group (n = 231) and those without actionable alterations (n = 566) experienced a median OS of 14.6 months (95% CI, 12.8-17.6) and 17.2 months (95% CI, 15.5-19.0), respectively. 

“Unfortunately, due to the rarity of the disease, there is not much [community] knowledge [in terms of] when we need to do biomarker testing. Tissue [supply] is always an issue [because] we have few cells to perform sequencing. In our practice, we [perform] both liquid biopsy and solid tumor next-generation sequencing [NGS] at the same time at the time of diagnosis,” Amit Mahipal, MD, said. “[The findings from this analysis] are very interesting; matched therapy is making a difference, and patients are living longer compared with unmatched [treatment]. It proves that we need to check for these actionable alterations and, when we do find them, [use] those therapies that could act on [those alterations].”

In the frontline setting of unresectable or metastatic BTC, durvalumab (Imfinzi) in combination with gemcitabine and cisplatin is a standard-of-care (SOC) option. The regimen was approved in September 2022 for treating adults with locally advanced or metastatic disease; the approval was supported by findings from the phase 3 TOPAZ-1 trial (NCT03875235).

 TOPAZ-1 compared durvalumab plus gemcitabine and cisplatin vs placebo with gemcitabine and cisplatin in patients with unresectable locally advanced or metastatic BTC. 

Updated findings from TOPAZ-1 presented at the European Society for Medical Oncology Gastrointestinal Cancers Congress 2024 showed that at a median follow-up of 41.3 months (95% CI, 39.3-44.1) patients in the durvalumab arm (n = 341) achieved a median OS of 12.9 months (95% CI, 11.6-14.1) compared with 11.3 months (95% CI, 10.1-12.5) in the placebo arm (n = 344; HR, 0.74; 95% CI, 0.63-0.87).

The 36-month OS rates were 14.6% and 6.9%, respectively. 

“TOPAZ-1 was a landmark study,” Ellis commented. “There is a notable tail effect on the survival curve, suggesting that there are durable responses in a subset of patients. There’s a huge ongoing effort to identify [which patients] are benefiting more. The toxicity was manageable. In general, there were no unexpected safety signals. For many of us in clinical practice in BTC, TOPAZ-1 has established the new SOC for first-line treatment.” 

During ASCO GI, investigators presented findings from an exploratory analysis of clinically actionable alterations in TOPAZ-1 as a potential method to help guide treatment decisions.

 The findings showed that patients experienced an OS benefit with the addition of durvalumab to gemcitabine and cisplatin across all genetic mutation and wildtype subgroups examined, except for mutations in ARID1A and ERBB2. The most pronounced benefits were seen in patients with ARID1A (HR, 0.68; 95% CI, 0.56-0.81), KRAS (HR, 0.71; 95% CI, 0.59-0.85), and IDH1 wild-type (HR, 0.70; 95% CI, 0.59-0.84) disease. Progression-free survival (PFS) data also favored the durvalumab arm across all subgroups except for mutations in ARID1A, IDH1, and ERBB2.

Another FDA-approved first-line option for patients with advanced BTC is pembrolizumab (Keytruda) in combination with gemcitabine and cisplatin. In October 2023, the regimen was approved by the FDA for the treatment of patients with locally advanced unresectable or metastatic BTC.

 The approval was supported by findings from the phase 3 KEYNOTE-966 trial (NCT04003636), which compared pembrolizumab with placebo, both in combination with gemcitabine and cisplatin. 

Updated findings from KEYNOTE-966 presented during the 2024 ASCO Annual Meeting showed that at a median follow-up of 36.6 months (range, 29.2-49.4), patients who received pembrolizumab (n = 533) achieved a median OS of 12.7 months (95% CI, 11.5-13.6) compared with 10.9 months (95% CI, 9.9-11.6) in the placebo arm (n = 536).

 The median PFS was 6.5 months (95% CI, 5.7-6.9) vs 5.6 months (95% CI, 4.9-6.5), respectively. 

“Looking at both [TOPAZ-1 and KEYNOTE-966], it seems that [patients with] intrahepatic cholangiocarcinoma seemed to benefit more with the addition of immunotherapy compared with other subtypes, and [those with] gallbladder cancer do not tend to benefit as much with addition of immunotherapy,” Mahipal said. “These [subset findings] are hypothesis-generating; we should not change our treatment practice, but it’s interesting how the 2 studies are aligned.”

Targeted Therapeutics Move Into Pretreated BTC With a Focus on HER2

The panelists transitioned their discussion into the management of BTC in the second line and beyond by initially highlighting findings from a retrospective study presented during ASCO GI that aimed to characterize clinical and molecular outcomes associated with HER2 positivity in BTC.

 Patients were defined as being HER2 positive when they had an immunohistochemistry (IHC) of 3+ or 2+ in situ hybridization positive or by next-generation sequencing. 

Findings from the analysis showed that 25.1% of patients with BTC included in the analysis (n = 310) were HER2 positive. The median OS for patients with HER2-positive disease was 13.7 months compared with 17.1 months for patients with HER2-negative disease (P = .084). Patients with HER2-positive disease who received an anti-HER2 agent experienced a median OS of 18.2 months, comparable to that of patients with HER2-negative disease (HR, 0.95; 95% CI, 0.71-1.27). Comparatively, patients with HER2-positive disease who did not receive a HER2-targeted agent experienced a median OS of 8.1 months. 

One HER2-directed agent that has shown efficacy in BTC is the antibody-drug conjugate (ADC) T-DXd. T-DXd was examined in the phase 2 DESTINYPanTumor02 trial (NCT04482309) in patients with HER2-expressing solid tumors, including BTC.

The primary end point was investigator-assessed overall response rate (ORR) per RECIST 1.1. Secondary end points included duration of response, disease control rate (DCR), PFS, OS, and safety. 

Data from DESTINY-PanTumor02 showed that patients with BTC who received T-DXd (n = 41) experienced a confirmed ORR of 22.0% (95% CI, 10.6%-37.6%); notably, the ORR among patients with a HER2 IHC of 3+ (n = 16) was 56.3% (95% CI, 29.9%-80.2%). The median PFS was 4.6 months (95% CI, 3.1-6.0) in the overall BTC cohort and 7.4 months (95% CI, 2.8-12.5) in the HER2 IHC 3+ subgroup. The respective median OS values were 7.0 months (95% CI, 4.6-10.2) and 12.4 months (95% CI, 2.8-not reached). 

Findings from DESTINY-PanTumor02 partially supported the April 2024 FDA pan-tumor approval of T-DXd for adult patients with unresectable or metastatic HER2-positive (IHC 3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options.

In 2024, targeted therapies fam-trastuzumab deruxtecan-nxki and zanidatamab-hrii were approved for HER2-positive advanced biliary tract cancer (BTC), marking a significant advancement. Despite this, the 5-year overall survival rate remains below 5%, highlighting the need for more effective treatments. Recent studies emphasize the importance of early molecular testing and the role of targeted therapies in improving outcomes. Notable trials like TOPAZ-1 and KEYNOTE-966 have established new standards of care, while emerging therapies like T-DXd and zanidatamab show promise in pretreated BTC, particularly for HER2-positive cases.

During the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium, an OncLive Peer Exchange® featured insights from expert investigators in the field of BTC.

Vol. 26 No. 4 | Oncology Live®

Targeted CAR T-Cell Therapies Show Early Efficacy in Solid Tumors With Focus on Mitigating Toxicity

Inflation Reduction Act Leads to Seesaw Effect Between Oncologic Drug Savings and Development

Personalizing Lung Cancer Treatment Reduces Toxicity and Improves Cure Rates

RAS(ON) Inhibitors May Overcome Resistance to Traditional KRAS Inhibitors in Solid Tumors

New ADCs Aim to Strengthen the HER2+ Breast Cancer Paradigm and Join T-DXd and T-DM1

Targeted Treatments Shift the Paradigm of Advanced BTC

"Halfway Technology": Is It Time to Seriously Discuss Transitioning From the Current Focus of Cancer Research?

Ensartinib Looks to Find a Place in ALK+ NSCLC Paradigm Alongside Approved TKIs

Tips for Tomorrow: What 4 Experts Wish They Knew Earlier About ADCs