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The June issue of ONCOLOGY features a review on treatment-related cardiotoxicity for survivors of breast cancer, a case report on extranodal NK/T-cell lymphoma, and a Hot Topics article on AI use in NSCLC. 

June ONCOLOGY Publication

Taletrectinib is Suitable for First- and Second-Line ROS+ NSCLC

 taletrectinib’s (Ibtrozi) approval in 

-positive non–small cell lung cancer (NSCLC)

, CancerNetwork® spoke with Jorge Nieva, MD, about how this change in the landscape might affect his practice.

The FDA’s approval of taletrectinib was supported by results from the phase 2 TRUST-I (NCT04395677) and TRUST-II (NCT04919811) trials. As one of the investigators on the TRUST-II trial, Nieva, an associate professor of clinical medicine at the Keck School of Medicine of the University of Southern California, already had experience utilizing the agent.

He stated that this was going to become his go-to first-line drug in this indication, not just because he’s comfortable with it, but because it can also be used in the second-line setting following treatment with entrectinib (Rozlytek), repotrectinib (Augtyro), and crizotinib (Xalkori).

-positive NSCLC, Nieva expressed that he is glad for all the advancements that have been made, though there is still more work to be done, particularly in the aim for a cure.

This is going to be the go-to first-line drug in my practice. I had the opportunity to participate in the clinical trials with this agent. For all oncologists, the more you use a drug, the more you’re comfortable with managing its toxicity and the more comfortable you are with understanding what’s to come for our patient population and counseling them on what they can expect. It’s a drug that I’m very comfortable with, and it is a drug I’ll likely use primarily in the first-line setting.

For patients who were treated with other agents, if they had received entrectinib or some other agent in the past, then they certainly can use this drug in the second line. The good news for patients is that we now have choices, and we have very good drugs for 

disease, including taletrectinib, repotrectinib, and entrectinib, and even crizotinib is a good drug in many parts of the world where they may not have access to some of the newer agents. I’m very happy that we have choices for patients, and I’m very happy that we have such a wide variety of drugs, but we still need to do better, and we need to find better ways of using these agents because they’re still not cures for most patients. While these drugs can be helpful at debulking tumors, we still need to do a lot more work on making this a disease of the past for those patients who have it.

FDA approves taletrectinib for ROS1-positive non-small cell lung cancer. News release. FDA. June 11, 2025. Accessed June 23, 2025. https://tinyurl.com/yc4f379m

Nagasaka M, Ohe Y, Zhou C, et al. TRUST-II: a global phase II study of taletrectinib in 

-positive non-small-cell lung cancer and other solid tumors. 

(2), 123–135. doi:10.2217/fon-2022-1059

Videos

“It’s a drug that I’m very comfortable with, and it is a drug I’ll likely use primarily in the first-line setting,” stated Jorge Nieva, MD, on taletrectinib in non–small cell lung cancer. 

Taletrectinib is Suitable for First- and Second-Line ROS1+ NSCLC

Findings from WU-KONG1B (NCT03974022) support the accelerated approval of sunvozertinib for patients with locally advanced or metastatic non-small cell lung cancer harboring 

The FDA has granted accelerated approval to sunvozertinib (Zegfrovy) as a treatment for adults with locally advanced or metastatic non–small cell lung cancer (NSCLC) harboring 

exon 20 insertion mutations as detected with an FDA-approved test following progression on or after platinum-containing chemotherapy, according to a press release from the agency.

Additionally, the agency approved the Oncomine Dx Express Test as a companion diagnostic for the detection of 

exon 20 insertion mutations among those with NSCLC who may candidates to receive treatment with sunvozertinib.

The agency based its decision on data from the phase 1/2 WU-KONG1B trial (NCT03974022), in which investigators assessed sunvozertinib at 200 mg orally once daily among 85 patients with metastatic or locally advanced NSCLC harboring 

Topline data showed that confirmed overall response rate (ORR) was 46% (95% CI, 35%-57%). Additionally, the study treatment produced a median duration of response (DOR) of 11.1 months (95% CI, 8.2-not reached).

Based on warnings and precautions from the prescribing information, toxicities reported in patients who received sunvozertinib included interstitial lung disease or pneumonitis, adverse gastrointestinal reactions, adverse dermatologic reactions, ocular toxicity, and embryo-fetal toxicity.

The trial's primary end points included safety and tolerability in part A as well as ORR per blinded independent review committee assessment using RECIST v1.1 criteria.

 Secondary end points included DOR, disease control rate, and plasma concentration.

FDA previously granted priority review to sunvozertinib

 as a treatment for this patient population in January 2025.

FDA grants accelerated approval to sunvozertinib for metastatic non-small cell lung cancer with EGFR exon 20 insertion mutations. News release. FDA. July 2, 2025. Accessed July 2, 2025. https://tinyurl.com/4n4a75cb

Assessing an oral EGFR Inhibitor, sunvozertinib in patients who have advanced non-small cell lung cancer with EGFR or HER2 mutation (WU-KONG1). ClinicalTrials.gov. Updated February 28, 2025. Accessed July 2, 2025. https://tinyurl.com/bddrzrp3

U.S. FDA granted priority review to Dizal's sunvozertinib new drug application. News release. Dizal Pharmaceutical. January 7, 2025. Accessed July 2, 2025. https://tinyurl.com/59syffnb

Articles

Data from the phase 1/2 WU-KONG1 study support the accelerated approval of sunvozertinib in this population.

Sunvozertinib Earns FDA Accelerated Approval in EGFR Exon 20+ NSCLC

16 A Miami Hospital’s Infrastructure to Help Decrease Late-Stage Breast Cancer Diagnosis and Improve Health Equity

We previously demonstrated, using the National Cancer Database, that lower income and education levels are associated with a higher stage at diagnosis of breast cancer. Expanding on this work, we analyzed publicly available data in mortality rate, focusing on Homestead Hospital’s service area in Miami-Dade County where predominantly Hispanic and Black neighborhoods face significant socioeconomic challenges.

Using Miami-Dade Matters and US Census data, we evaluated the age-adjusted death rate in Miami-Dade County ZIP codes while analyzing hospital baseline data to identify opportunities to enhance screening rates. A ZIP code in Homestead Hospital’s service area has the county’s highest age-adjusted breast cancer mortality rate at 39.1 deaths per 100,000 females. In addition, the lowest percentage of high school graduates (65.5%), lowest percentage of bachelor’s degree (6.6%), highest percentage of health uninsurance (33.3%), and highest percentage of people living in poverty (32.6%) compared with the rest of Miami-Dade County. In Fiscal Year1 (FY1) 24, only 23% of Homestead Hospital’s screening mammograms were performed in Black, Hispanic, and multiracial women, despite these groups comprising 93% of the local female population. In FY1 24, there were a total of 4336 screening mammograms and diagnostic mammograms at Homestead Hospital. Of these, 16.5% (n = 716) needed additional work-up. While White had 77% of the total tests, they represented 19.6% of the tests that needed additional work-up. Minority demographic groups had 23% of the total tests but represented 80.4% of those in need of additional work-up.

Our findings highlight significant disparities in breast cancer screening and diagnostic follow-up among minority populations in Miami-Dade County. We are developing an infrastructure to improve screening rates and a safety net for our patient population to mitigate barriers for accessing care. We educated providers at a local federally qualified health center on identifying high-risk patients. We are integrating a prediagnostic Linkage Navigator to enhance diagnostic test completion by addressing barriers and ensuring seamless linkage. We are enhancing an existing electronic flagging alert system as a safeguard, building on lessons from infectious disease screening, to identify patients needing follow-up in real-time upon returning within the health system 

. We are developing a dashboard to track the impact of our interventions, displaying early data from our health system transformation to reduce late-stage breast cancer diagnoses in our community.

Surbhi Sidana, MD, Associate Professor of Medicine, Blood and Marrow Transplantation and Cellular Therapy, Clinical Research Group Coleader for BMT/Cell Therapy, Stanford Cancer Institute

Doris Hansen, MD, Assistant Member, Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center

Melissa Alsina, MD, Associate Professor, Department of Blood and Marrow Transplant, Head of Multiple Myeloma Transplant Program, Moffitt Cancer Center

Leyla Shune, MD, Associate Professor, Hematologic Malignancies and Cellular Therapeutics, University of Kansas Cancer Center

program, CancerNetwork® hosted a panel discussion surrounding a clinical comparison of the efficacy and safety of ciltacabtagene autoleucel (cilta-cel; Carvykti) and idecabtagene vicleucel (ide-cel; Abecma) in patients with relapsed/refractory multiple myeloma. The panel began with a discussion of findings from a retrospective comparative analysis of the agents published in the 

, followed by considerations for choosing between treatments.

 Furthermore, the panel ascertained risks and benefits associated with cilta-cel use in earlier lines of therapy and concluded by reviewing relevant data regarding the safety profile of ide-cel, particularly among multiple myeloma populations with central nervous system (CNS) involvement.

, associate professor of medicine for blood and marrow transplantation and cellular therapy and clinical research group coleader for bone marrow transplant/cell therapy at Stanford Cancer Institute. Panelists included 

, assistant member in the Department of Blood and Marrow Transplant and Cellular Immunotherapy at Moffitt Cancer Center; 

, associate professor in the Department of Blood and Marrow Transplant and head of the Multiple Myeloma Transplant Program at the Moffitt Cancer Center; and 

, associate professor of hematologic malignancies and cellular therapeutics at the University of Kansas Cancer Center.

Comparing Cilta-Cel and Ide-Cel Efficacy and Safety Data in R/R Multiple Myeloma

Given that there has been no clinical trial [comparing cilta-cel and ide-cel], this is the best study we have today that was published earlier this year in [the 

]. Can you speak to that, and what were the highlights of the findings?

This was a large multicenter analysis that included patients who were treated or had leukapheresis for standard-of-care ide-cel and cilta-cel, about 641 patients in total. Of those, 586 were infused. The attrition rate was mostly due to disease progression. We had 350 patients who received ide-cel and 236 who received cilta-cel.

We used inverse probability of treatment weighting to compare differences between products and balance any confounders between the 2 treatment arms, and we looked at outcomes in terms of safety, efficacy, and survival. What we found is that patients receiving cilta-cel had a higher incidence of certain toxicities. Particularly, they were more likely to experience severe cytokine release syndrome [CRS] infections as well as non–immune effector cell associated neurotoxicity syndrome [ICANS] neurologic toxicities. There was a trend for higher second primary malignancies, but the number was small, and certainly there is a survival bias in the cilta-cel cohort.

If we think about it from an efficacy perspective, patients receiving cilta-cel had better and deeper responses [with] a significantly improved progression-free and overall survival [OS], whether it be in the intention-to-treat [population] but also [in] the infused cohorts in the study.

Considerations for CAR T-Cell Therapy Use

What factors do you consider when recommending ide-cel vs cilta-cel?

 It is 2025, so patients are coming to me earlier and earlier. I know that our topic is for relapsed/refractory [populations], but people are coming to us for CAR [chimeric antigen receptor] T consideration much earlier [in treatment]. The first thing [to consider] is FDA level indication. Based on 

[the phase 3] CARTITUDE-4 trial (NCT04181827),

 cilta-cel is FDA approved for patients who have received 1 [prior] line of therapy and are lenalidomide [Revlimid] refractory.

 Somebody could come to me for CAR T evaluation at second line, and the only product I can offer them at that time is cilta-cel. Now beyond second-line CAR T consultation, we can [give] ide-cel based on the 

[phase 1b/2] CARTITUDE-1 trial (NCT03548207)

 In today's world, most CAR T is infused much earlier than the fifth line.

If somebody comes to me in the clinic for CAR T consultation, if they are second line, the only [therapy I am considering is] cilta-cel. Let us assume it is the third or fourth line: How do I approach it? I start with small summaries of KarMMa-3 and CARTITUDE-4, and I present [those] to the patient. I say, “CAR T is an autologous T-cell product. It takes time to collect, engineer, and bring it back to our center for infusion.” I look at the [patient’s] disease tempo. If they have rapidly progressive disease that [needs treatment] right away, maybe CAR T is not the best therapy––maybe I may have to go to something else at that time. That is No. 1. No. 2 [is] the patients who are considered high-risk. If [a patient] is relapsing within 18 months of the initial therapy, these are functional, high-risk patients who will likely not benefit from additional chemotherapy, and I will channel them toward CAR T.

Which product should I choose? Recently, patients have chosen what they want because they are savvy. They are knowledgeable. They attend a lot of support groups. Their biggest focus is PFS [progression-free survival]—they want a prolonged PFS. Based on CARTITUDE-1 and CARTITUDE-4, we can tell cilta-cel has a prolonged PFS. Then based on our real-world data, [there] is a PFS and OS advantage with cilta-cel. However, there is [the risk of] delayed neurotoxicity. If a patient already has underlying parkinsonism or some neurogenic disease, I may be a bit [hesitant] to do CAR T at that time. I may go toward a bispecific T-cell engager, which has less non-ICANS toxicity.

[Another consideration] is patients who are frail. I give everybody a fair chance. Everybody goes through a frailty evaluation. Some patients are frail because the myeloma is active, so maybe after I collect and [conduct] bridging therapy, they can handle the CAR T better. These are some of the factors I think about. The biggest driver for patients is the PFS and OS advantage that cilta-cel has over ide-cel, and they are willing to even take on the risk of delayed neurotoxicity and secondary primary malignancy because they understand that myeloma is a lifelong illness, so they want the best advantage available to them.

Elucidating CAR T Benefit in Earlier Lines of Therapy

 Are you offering CAR T to every second-line patient, or are you choosing some patients over others? How are you approaching this, especially with the PFS and OS benefit that we have seen?

 [A patient] who is progressing early, who is functional, high-risk––that is a no-brainer. I would offer them CAR T, because [with] additional therapy, we have shown in trials that CAR T has superior PFS there and is always [advantageous]. Everyone else [must consider] access. Some people have no caregivers. They live far away from our center. Are they willing to relocate to come up here? I also worry about attrition.

I sit down with patients, and I tell them about the CAR T approval, the PFS advantage, and emphasize the toxicity, the time commitment, the time away from family and home, and being in Kansas City. Those are some of the factors I bring up to the patients, but I try to give it as an early intervention to people who are clearly high-risk, who I know will relapse quickly with second-line [therapy] and potentially die from multiple myeloma complications. Younger patients, functional, high-risk––high risk from the get-go––those [patients receive] second-line CAR T.

Assessing Ide-Cel Non-ICANS Toxicity Risk

 Some of the trade-offs [with CAR T-cell therapy] are the risk of potential early onset toxicity in the first month and later, perhaps the risk of non-ICANS toxicity, although it was low point, [2%] for parkinsonism and 5% for cranial nerve palsy in CARTITUDE-4. Then the trade-off between second primary malignancies, which is also the trade-off we have with transplant in early life. Yet the PFS and OS benefit is just so strong. How do you look at this in your practice?… How do you make these trade-offs?

 A patient in the second line has many other options. The safety part is even more important. I worry about delayed neurotoxicities because even though, No. 1, in the late relapsed setting, we thought, “Okay, these are only patients who have a high tumor burden that come to CAR T with bad disease.” We have learned from the data [that] giving cilta-cel early on is not the whole story.

You could have a patient who goes in with a low tumor burden and still develops these neurotoxicities. We have seen that in patients, for example, who get cilta-cel in the newly diagnosed setting in clinical trials and on second line. Evaluating the risk-benefit ratio in that patient population is even more important than in the late relapse.

It all depends on the patient whom you have in front of you. If you have a patient who has high-risk multiple myeloma based on how the disease has behaved [who experienced an] early relapse after first-line therapy, then we should [treat with cilta-cel]. But if I have a patient, for example, who has standard-risk myeloma by cytogenetics, the patient had already [received a transplant] 5 years ago, has been in remission for 5 years on [lenalidomide] maintenance…I would [likely] be more conservative with a patient like that.

If there is no clonal evolution, I might treat that patient with another second-line therapy and see how they behave and then [treat with] CAR T. I do not think we have any data to say that if I do the CAR T at that first relapse, it is going to be different than if I do it at second relapse. And if a patient has standard risk and not a patient who is clinically high-risk, doing a second-line therapy would be okay. We still have [effective therapies]. A regimen like [carfilzomib (Kyprolis), pomalidomide (Pomalyst), and dexamethasone] or [carfilzomib, daratumumab (Darzalex), and dexamethasone] is an effective regimen that we can still use in that setting.

 Can you talk a bit about the incidence of these delayed neurotoxicities and other toxicities that were seen in [a retrospective analysis published in 

 This was a large cohort across our institutions looking at outcomes of cilta-cel in the standard-of-care setting. We did see that the rates of severe CRS and severe ICANS were low, less than 5% as expected. When we go back to the non-ICANS neurologic toxicities, we saw that the rate overall was about 10%. We did see parkinsonism rate was a bit lower than what we saw in CARTITUDE-1, which was about 6%, so in a way, that was perhaps encouraging. This was the first cohort of patients where we might have been more selective; we might have been debulking them well, and then we did as I mentioned: cranial nerve palsies, particularly Bell palsy, [which] was most common. About 55% resolved those toxicities.

Nonrelapse mortality was about 10% and was mostly driven by infection. When these patients go back into the community, we must communicate with these providers in terms of how do we best support these patients, whether that be with prophylactic antibiotics, and currently, I would say probably most of us are doing primary prophylaxis with intravenous immunoglobulin [IVIg] for at least 3 to 6 months following CAR T-cell therapy. Vaccinations post treatment have been important, but optimizing ways in terms of supportive care to help improve outcomes and mitigate toxicity for these patients is important.

There is some emerging evidence about using CAR T in patients with CNS myeloma. How do you address this in your clinical practice? And what do data show?

 The European group presented their data at [the 2024 American Society of Hematology Annual Meeting].

 They had 10 patients with proven CNS involvement, and they gave them ide-cel, and they had 70% complete response rates and a PFS of 10 months, which is like ide-cel without CNS involvement. That was encouraging.

In my practice, if somebody has CNS myeloma, I collect for CAR T and then I do synesthetic therapy because we have shown in [another retrospective analysis that] those who are responding are those who do the best. We immediately institute intrathecal chemotherapy to try and get a handle on that. And then we move on to CAR T. More people will receive CAR T with real-world data supporting us.

Hansen DK, Peres LC, Dima D, et al. Comparison of standard-of-care idecabtagene vicleucel and ciltacabtagene autoleucel in relapsed/refractory multiple myeloma 

. 2024;43(13):1597-1609. doi:10.1200/JCO-24-01730

San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. 

 2023;389(4):335-347. doi:10.1056/NEJMoa2303379

FDA approves ciltacabtagene autoleucel for relapsed or refractory multiple myeloma. FDA. February 28, 2022. Accessed June 24, 2025. https://tinyurl.com/yy2em5zv

Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. 

. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614

Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. 

 2023;41(suppl 16):8009. doi:10.1200/JCO.2023.41.16_suppl.8009

Sidana S, Patel KK, Peres LC, et al. Safety and efficacy of standard-of-care ciltacabtagene autoleucel for relapsed/refractory multiple myeloma. 

. 2025;145(1):85-97. doi:10.1182/blood.2024025945

Maulhardt M, Berning P, Hanoun C, et al. Efficacy of idecabtagene vicleucel (ide-cel) in patients with relapsed/refractory multiple myeloma and prior central nervous system manifestation: a retrospective real-world analysis. 

 2024;144(suppl 1):4759. doi:10.1182/blood-2024-202467

The expert panel discussed the efficacy observed with cilta-cel in patients with relapsed/refractory multiple myeloma. 

Comparing CAR T Safety, Efficacy in Relapsed/Refractory Multiple Myeloma

Upon successful completion of this activity, you should be better prepared to:

 and other genetic alterations in diagnosis and management.

• Discuss current guidelines and treatment recommendations for the management of patients with advanced pancreatic cancer.

• Analyze clinical trial data to inform the selection of emerging therapeutic agents for advanced pancreatic cancer.

• Apply strategies to optimize molecular testing algorithms using diverse testing modalities in advanced pancreatic cancer.

, LLC, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

, LLC, designates this enduring material for a maximum of 0.25 

™. Physicians should claim only the credit commensurate with the extent of their participation in the activity.

This activity is supported by an educational grant from Partner Therapeutics, Inc.

This activity may or may not discuss investigational, unapproved, or off-label use of drugs. Learners are advised to consult prescribing information for any products discussed. The information provided in this activity is for accredited continuing education purposes only and is not meant to substitute for the independent clinical judgment of a health care professional relative to diagnostic, treatment, or management options for a specific patient’s medical condition. The opinions expressed in the content are solely those of the individual faculty members and do not reflect those of PER

 or any company that provided commercial support for this activity.

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YOU MAY IMMEDIATELY DOWNLOAD YOUR CERTIFICATE.

To date, 32 genes have been identified as frequently mutated in pancreatic ductal adenocarcinoma (PDAC).

 However, less than 10% of patients are eligible for an FDA-approved targeted therapy, highlighting the need for the development of novel therapeutics.

 Here are 3 things you should know about molecular testing and personalized strategies in pancreatic cancer.

1 RNA testing is critical to identify actionable gene fusions in PDAC.

NCCN guidelines recommend tumor molecular profiling in cases of metastatic PDAC.

 RNA-based next-generation sequencing (NGS) is preferred to DNA-based NGS for detecting fusions in genes like 

. These fusions are enriched in the 5% to 10% of patients with 

 wild-type PDAC, a molecular profile more often found in patients younger than 50 years.

 NGS using tumor tissue is preferred to blood-based assays, according to NCCN guidelines.

 Liquid biopsy can be performed concurrently with tissue testing or used when adequate tissue is unavailable.

RNA-based NGS can detect structural variants of gene fusions, which may inform the potential efficacy of targeted therapies.

 Since RNA sequencing encompasses only exons after splicing, this technique can overcome the technical challenges of excessive sequencing or misaligned reads when DNA-based NGS is used on genes with long or repetitive introns (

 In a heterogeneous tumor in which the gene fusion is present only in some cells, RNA-based NGS can detect the alteration if it is highly expressed.

FIGURE 1.RNA-based NGS May Overcome Limitations of DNA-Based Testing

2 The first NRG1-targeted therapy is approved for advanced or metastatic PDAC.

 fusions are found in approximately 1% of solid tumors, most commonly in patients with mucinous adenocarcinoma of the lung and 

 These altered proteins consist of the EGF-like domain of NRG1 attached to the transmembrane domain of various fusion partners. This construct enables constitutive binding and activation of the HER3 receptor, activating RAS and the MAPK and PI3K signaling pathways.

Zenocutuzumab is a HER2×HER3 bispecific antibody that inhibits NRG1 binding.

 In the phase 1/2 eNRGy trial (NCT02912949), zenocutuzumab demonstrated an overall response rate (ORR) of 30% (95% CI, 23%-37%) in 158 patients of all tumor types with 

 The response rate in 33 patients with PDAC was 42.4% (95% CI, 25.5%-60.8%), including 1 complete response and 13 partial responses (

 The median progression-free survival in the overall population was 6.8 months (95% CI, 5.5-9.1 months).

 The most common treatment-related adverse events (TRAEs) were diarrhea (18%), fatigue (12%), and nausea (11%). Infusion-related reactions occurred in 14% of patients. Based on results from the eNRGy study, zenocutuzumab received accelerated approval from the FDA as a second-line systemic therapy to treat advanced, unresectable, or metastatic PDAC harboring an 

FIGURE 2. Response to an NRG1 Inhibitor in Pancreatic Adenocarcinoma

3 Ongoing investigations are evaluating numerous other emerging targets of interest.

 wild-type PDAC tumors harbor other genetic alterations, including 

 Erdafitinib demonstrated an ORR of 30% (95% CI, 24%-36%) in patients of different tumor types harboring 

 alterations in the single-arm, phase 2 RAGNAR trial (NCT04083976).

Combination dabrafenib and trametinib produced an ORR of 38% (95% CI, 22.9%-54.9%) in patients with solid tumors, lymphomas, or multiple myeloma whose tumors harbored a 

 V600 mutation in the single-arm NCI-MATCH trial subprotocol H (NCT02465060).

 Of the 27 evaluable patients, the 1 patient with PDAC achieved stable disease. Combined use of dabrafenib and trametinib received accelerated approval to treat patients with unresectable or metastatic solid tumors, including PDAC, that harbor 

 V600E mutations and who have progressed following prior treatment.

Selpercatinib yielded an ORR of 43.9% (95% CI, 28.5%-60.3%) in patients with 

 fusion-positive non-lung and non-thyroid solid tumors in the phase 1/2 LIBRETTO-001 basket trial (NCT03157128).

 The ORR was 44% in patients with PDAC. Selpercatinib received accelerated approval to treat adults with locally advanced or metastatic solid tumors, including PDAC, that harbor a

gene fusion and who have progressed following prior treatment.

The HER2-targeting antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (T-DXd) has not provided as much benefit in patients with PDAC. In the phase 2 DESTINY-PanTumor02 trial (NCT04482309) in patients with solid tumors overexpressing HER2 (immunohistochemistry [IHC], 3+ or 2+), the ORR was 37.1% (95% CI, 31.3%-43.2%) across all cohorts, but only 4.0% (95% CI, 0.1%-20.4%) in those with PDAC.

 Further investigation would be required to determine why this disease type is particularly resistant to T-DXd, but this agent is still approved for HER2 IHC 3+ PDAC under the tissue agnostic approval.

 Y220C mutation is the target of the first-in-class p53 reactivator PC14586.

 In the phase 1 portion of the phase 1/2 PYNNACLE trial (NCT04585750) at the highest dose of PC14586, the ORR was 46.2%. In 6 patients with PDAC, 4 achieved stable disease, and 1 achieved an unconfirmed partial response.

Claudin18.2 (CLDN18.2) is an emerging actionable target in many cancers, including PDAC.

 Therapeutics with various mechanisms of action are under investigation to exploit this target. IBI389 is a CLDN18.2×CD3 bispecific antibody evaluated in a phase 1 study (NCT05164458) in 64 previously-treated patients with CLDN18.2-positive PDAC.

 The ORR was 30.4% (95% CI, 13.2%-52.9%), and the disease control rate was 69.6% (95% CI, 47.1%-86.8%). TRAEs of grade 3 or greater were reported in 54.7% of patients. Treatment was discontinued in 4.7% of patients due to TRAEs. Cytokine release syndrome is an AE of particular concern with IBI389, with grade 1 or 2 events occurring in 51.6% of patients.

Zolbetuximab is an anti-CLDN18.2 monoclonal antibody being tested against several tumor types and will be assessed in combination with gemcitabine/nab-paclitaxel (GN) vs GN alone as first-line therapy in patients with metastatic pancreatic cancer in a phase 2 study (NCT03816163).

 The primary end point is overall survival.

4. Singhi AD, George B, Greenbowe JR, et al. Real-time targeted genome profile analysis of pancreatic ductal adenocarcinomas identifies genetic alterations that might be targeted with existing drugs or used as biomarkers. 

. 2019;156(8):2242-2253.e4. doi:10.1053/j.gastro.2019.02.037

6. Davies KD, Aisner DL. Wake up and smell the fusions: single-modality molecular testing misses drivers. 

. 2019;25(15):4586-4588. doi:10.1158/1078-0432.Ccr-19-1361

9. Schram AM, Goto K, Kim DW, et al. Efficacy of zenocutuzumab in NRG1 fusion-positive cancer. 

. 2025;392(6):566-576. doi:10.1056/NEJMoa2405008

1 A patient is referred to you with a new diagnosis of metastatic
pancreatic ductal adenocarcinoma (PDAC) with multiple liver
metastases. The patient is asymptomatic and has an ECOG perform-
ance status of 0. Which of the following would be the next best step?

 Germline testing for inheritable pathogenic mutations

 Germline testing and somatic tissue testing

 Initiate systemic treatment without further testing

2 Blockade of which of the following molecules is an active
treatment approach in tumors with 

3 A patient with metastatic PDAC is referred to you after disease
progression on FOLFIRINOX. No somatic testing was performed at the time of diagnosis. On further investigation, the tumor has no evidence
of 

fusion. Which of the following therapies would you choose at this time?

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The recommended dose for intravenously administered linvoseltamab includes step-up doses at 5 mg, 25 mg, and 200 mg, followed by 200 mg weekly for 10 doses, and 200 mg biweekly thereafter.

The FDA has granted linvoseltamab-gcpt (Lynozyfic) accelerated approval as treatment for adult patients with relapsed/refractory multiple myeloma who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody, according to a news release from the agency.

Data supporting the FDA decision came from the 

phase 1/2 LINKER-MM1 (NCT03761108) trial.

 Efficacy findings revealed that the objective response rate (ORR) by blinded independent review committee (BICR) among 80 patients with relapsed/refractory multiple myeloma previously treated with at least 3 prior lines of therapy was 70% (95% CI, 59%-80%). After a median follow-up of 11.3 months among responders to treatment, the estimated 9- and 12-month duration of response (DOR) rates were 89% (95% CI, 77%-95%) and 72% (95% CI, 54%-84%) respectively.

Any-grade cytokine release syndrome (CRS) occurred in 46% of patients. Neurologic toxicities, including immune effector cell-associated neurotoxicity syndrome (ICANS), occurred at a frequency of 54%. The prescribing information includes a boxed warning for life-threatening CRS and neurologic toxicities, with linvoseltamab only available through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), called the Lynozyfic REMS.

The recommended dose for intravenously administered linvoseltamab includes step-up doses at 5 mg, 25 mg, and 200 mg, followed by 200 mg weekly for 10 doses, and 200 mg biweekly thereafter. Patients who have achieved and maintained a very good partial response or better at or after week 24 and received a minimum of seventeen 200 mg doses, the dosing frequency is decreased to 200 mg every 4 weeks.

linvoseltamab a complete response letter (CRL) 

in relapsed/refractory multiple myeloma after an issue was indicated from a third-party manufacturing site.

biologics license application (BLA) resubmission was accepted

 for linvoseltamab by the FDA in the same indication in February 2025.

In an interview with CancerNetwork® regrading the CRL, Surbhi Sidana, MD, associate professor and hematologist in the Department of Medicine, Division of Blood and Marrow Transplantation and Cellular Therapy at Stanford University School of Medicine, said, "In the big picture, CRLs are usually certain deficiencies that are noted by the FDA. In this case, it was at a manufacturing plant that was a third-party facility. Overall, the linvoseltamab program– yes, they have to address this. Yes, this might delay things for a certain period for FDA approval. In the big picture, I don’t think this impacts how I look at the data that is publicly available, the approval chances long-term for linvoseltamab, and how we might use it in the future. This is my read on the data that is publicly available."

FDA grants accelerated approval to linvoseltamab-gcpt for relapsed or refractory multiple myeloma. News release. FDA. July 2, 2025. Accessed July 2, 2025. https://tinyurl.com/5b9eb3kj

Regeneron provides update on biologics license application for linvoseltamab. News release. Regeneron Pharmaceuticals, Inc. August 20, 2024. Accessed July 2, 2025. https://tinyurl.com/2u2pvw82

Linvoseltamab BLA accepted for FDA review for the treatment of relapsed/refractory multiple myeloma. News release. Regeneron Pharmaceuticals. February 11, 2025. Accessed July 2, 2025. https://tinyurl.com/y7hjbdub

Data supporting the FDA decision came from the phase 1/2 LINKER-MM1 trial.