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.

Two critical FDA approvals in 2024 included the tumor-agnostic ones of fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) and repotrectinib (Augtyro), the first of which changed the field for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who received prior systemic treatment and have no satisfactory alternative treatment options.

The latter targeted therapy provided another option for those with an 

 gene fusion who have experienced disease progression following treatment or have no satisfactory standard therapy and who have metastatic disease or disease where surgical resection is likely to result in severe morbidity.

We compiled "cheat sheets" for each approval, rounding up everything you need to know about the agents and their safety/efficacy in the many solid tumors they were examined in. Keep reading and see below for a PDF version of the sheet!

The FDA granted accelerated approval to T-DXd for the treatment of adult patients with unresectable or metastatic HER2-positive (immunohistochemistry 3+) solid tumors who have received prior systemic therapy and have no satisfactory alternative treatment options.

 This accelerated approval is based on the agent’s objective response rate and duration of response.

T-DXd is a HER2-directed antibody-drug conjugate; the antibody is a humanized anti-HER2 IgG1, and the small molecule DXd is a topoisomerase I inhibitor attached to the antibody via a cleavable linker.

5.4 mg/kg given as an intravenous infusion once every 3 weeks in a 21-day cycle until disease progression or unacceptable toxicity

DESTINY-PanTumor02 (NCT04482309), DESTINY-Lung01 (NCT03505710), and DESTINY-CRC02 (NCT04744831) were phase 2 trials conducted examining T-DXd in adults with previously treated unresectable or metastatic HER2-positive solid tumors.

Patients were excluded from the trials if they had:

A history of interstitial lung disease (ILD)/pneumonitis requiring treatment with steroids or ILD/pneumonitis at screening and clinically significant cardiac disease

An ECOG performance status of greater than 1

T-DXd has boxed warnings for ILD and pneumonitis, as well as embryo-fetal toxicity.

The FDA granted accelerated approval to repotrectinib for the treatment of patients 12 years or older with locally advanced or metastatic solid tumors harboring an 

 gene fusion or where surgical resection is likely to result in severe morbidity and who have progressed after treatment or have no satisfactory alternative therapy.

160 mg given orally once daily for 14 days, then increased to twice daily until disease progression or unacceptable toxicity

TRIDENT-1 (NCT03093116) was a multicenter, single-arm, open-label, phase 1/2 trial conducted in adults with locally advanced or metastatic 

 gene fusion–positive solid tumors examining repotrectinib.

Download the cheat sheets as a PDF below!

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed January 13, 2025. bit.ly/3UYSKqk

FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed January 13, 2025. bit.ly/4eGQtr4

FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed January 10, 2025. bit.ly/4gNsvMp

FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Updated August 16, 2019. Accessed January 10, 2025. bit.ly/3DPv1U1

Enhertu. Prescribing information. Daiichi Sankyo, Inc; 2024. Accessed January 13, 2025. bit.ly/42e1m12

Augtyro. Prescribing information. Bristol Myers Squibb; 2024. Accessed January 13, 2025. bit.ly/4aebIjo

Articles

In 2024, the FDA granted accelerated approvals for fam-trastuzumab deruxtecan-nxki (T-DXd) and repotrectinib, both offering new treatment options for specific solid tumors. T-DXd targets unresectable or metastatic HER2-positive tumors in adults who have exhausted other treatments, while repotrectinib is for patients 12 and older with NTRK gene fusion-positive tumors, especially when surgery poses severe risks. Both approvals are based on pivotal clinical trials demonstrating efficacy and safety, with T-DXd having specific warnings for interstitial lung disease and embryo-fetal toxicity.

All the data on the tumor-agnostic approvals of T-DXd and repotrectinib are featured in this article and it's downloadable PDF visual pages!

2024 Tumor-Agnostic Approval Cheat Sheet: T-DXd and Repotrectinib

High levels of social vulnerability, including in terms of education, transportation, and neighborhood resources, are associated with lower odds of enrollment in cancer clinical trials, according to findings from a multivariable analysis presented during the 2024 American Society of Clinical Oncology Annual Meeting.

“Unlike the reporting of [sex], race, and ethnicity for federally funded clinical trials, there is no mandate to collect and report social determinants of health,” Mariam F. Eskander, MD, MPH, the study’s senior author, wrote in an email to OncologyLive. “A major hurdle is simply collecting those data to understand [whether] a particular trial is enrolling a socioeconomically diverse population and what those barriers to enrollment might be. This is the first step and one of the major messages of this study––that we cannot fix what we do not measure. These social determinants data can be collected at the individual level or through a publicly available area-level index such as the Vizient Vulnerability Index [VVI].” 

Eskander is also a surgical oncologist in the Gastrointestinal/Hepatobiliary Oncology Program at Rutgers Cancer Institute and RWJBarnabas Health, as well as an assistant professor in the Department of Surgery, Division of Surgical Oncology, Section of Gastrointestinal Oncology, at the Rutgers Robert Wood Johnson Medical School in New Brunswick, New Jersey.

The investigators used the Vizient Clinical Database to determine the VVIs of subgroups within the study population. VVI is a novel index that aims to characterize social drivers of health at the census tract level. The Vizient Clinical Database contains inpatient and outpatient clinical claims data encompassing 98% of academic medical centers, more than 100 cancer hospitals, and more than 700 community hospitals in the US. The database captures information including patient demographics, billing data, clinical outcomes, social needs, and obstacles to care that may influence a person’s overall health.

The VVI is made up of 9 domains: clean environment, economic, education, social environment, transportation, housing, neighborhood resources, health care access, and public safety. The domains include 43 components that elucidate factors such as lower median income, unemployment, no college degree, lower rates of voting participation, and no car or public transportation access, among others.

International Classification of Diseases, Tenth Revision (ICD-10)

 codes to identify patients with breast, prostate, lung, colorectal, or pancreatic cancer; the first quartile of patients by VVI was deemed to be the least vulnerable, and the fourth quartile the most vulnerable. Investigators performed a cross-sectional analysis of diagnosis of cancer with a subsequent clinical trial code from 2022 to 2023 as well as a sensitivity analysis of clinical trial enrollment within 1 year of a new diagnosis of cancer in 2022. They also conducted a univariate analysis of clinical trial enrollment, multivariable analyses predicting clinical trial enrollment adjusted for demographic factors and comorbidities with separate models for overall VVI and the 9 VVI domains, and an interaction analysis of Black race and VVI.

The primary outcome of the study was participation in a clinical trial as measured by the 

 code Z-00.6 for “examination of participant in a clinical trial.”

Study authors identified 2,660,566 patients during the study period, 1.5% of whom were enrolled in a clinical trial; 28.6%, 26.3%, 22.8%, 12.8%, 9.5% of patients with breast, prostate, lung, colorectal, and pancreatic cancer, respectively, were enrolled in clinical trials. Young patients (< 55 years) were more likely to be enrolled in a clinical trial compared with older patients at respective rates of 19% vs 16% (

 < .0001), as were men (50%) vs women (46%; P < .0001), White patients (79%) vs other patients (78%; 

 < .0001), those with private insurance (33%) vs other (32%; 

 < .0001), those with metastatic (58%) vs nonmetastatic (25%) disease (

 < .0001), and those in the first VVI quartile (27%) vs the fourth VVI quartile (23%; 

Additional findings from the analysis revealed that being older than 75 years (adjusted OR, 0.61; 95% CI, 0.58-0.65; 

< .0001), female (adjusted OR, 0.97; 95% CI, 0.94-0.99; 

=.0352), Black (adjusted OR, 0.78; 95% CI, 0.75-0.81; P<.0001); having Medicaid (adjusted OR, 0.76; 95% CI, 0.73-0.80; P<.0001); or being diagnosed with cancer at a community hospital (adjusted OR, 0.30; 95% CI, 0.29-.031; P<.0001) was associated with decreased odds of clinical trial enrollment. Being classified in VVI quartile 2 (adjusted OR, 0.85; 95% CI, 0.83-0.88; P=.0002), VVI quartile 3 (adjusted OR, 0.85; 95% CI, 0.81-0.88; 

<.0001), or VVI quartile 4 (adjusted OR, 0.86; 95% CI, 0.81-0.91; 

=.0442) was also associated with decreased odds of clinical trial enrollment. In terms of the VVI domains, high vulnerability in terms of education (adjusted OR, 0.82; 95% CI, 0.78-0.86; 

<.0001), neighborhood resources (adjusted OR, 0.87; 95% CI, 0.83-0.91; 

<.0001), or transportation (adjusted OR, 0.89; 95% CI, 0.85-0.94; 

<.0001) was associated with decreased odds of clinical trial enrollment.

Being classified in the fourth VVI quartile decreased the odds of clinical trial enrollment for Black (OR, 0.80; 95% CI, 0.68-0.88; 

<.0001) and White patients (OR, 0.88; 95% CI, 0.89-0.96; 

=.0028). However, findings from an interaction analysis revealed that high social vulnerability decreased the enrollment odds more for Black patients than White patients (

“We found that living in a socially vulnerable census tract lowers the likelihood that a patient with lung, breast, prostate, colorectal, or pancreas cancer will enroll in a clinical trial,” Eskander said. “This applies to the entire cohort but impacts Black patients more than it does White patients, meaning a Black patient living in a socially vulnerable neighborhood is less likely to enroll in a clinical trial than a White patient from a socially vulnerable neighborhood. This is the most contemporary and nationally representative analysis of the association between social vulnerability and clinical trial enrollment and the first to explore the intersection of social vulnerability and race.”

Data from the sensitivity analysis showed that 1.0% of 1,820,247 total patients enrolled in a clinical trial within 1 year of diagnosis in 2022. Living in the most vulnerable census tract was associated with a 19% decrease in the odds of enrolling in a clinical trial, and high social vulnerability decreased the odds of enrollment more for Black patients than for White patients (

Eskander and her coauthors noted that their study was limited by challenges in quantifying patients who are eligible for clinical trials, heterogeneity of cancer types and disease biology, unmeasured confounding factors, and inaccurate/incomplete coding. Eskander noted that the next steps for this research are collecting social determinants of health data for all patients, taking action to bring clinical trial sites closer to socially vulnerable neighborhoods, investing in clinical trial education for patients and providers, and advocating for government funding to address social and financial barriers to clinical trial enrollment. The study authors will place an emphasis on educational, transportation, and neighborhood domain barriers.

“We are working to understand the role of social vulnerability in different populations and settings as well as tease out the underlying barriers that most impact clinical trial enrollment,” Eskander said. “We encourage institutions to look at their own data to assess barriers for socially vulnerable patients and design interventions at the system and individual level to meet community need.”

Perati SR, Mohayya SM, Shippey E, et al. Social vulnerability and clinical trial enrollment: the next frontier of health equity. 

. 2024;42(suppl 16):1508. doi:10.1200/JCO.2024.42.16_suppl.1508

High social vulnerability, encompassing factors like education, transportation, and neighborhood resources, correlates with reduced cancer clinical trial enrollment. The study highlights the absence of mandates to report social determinants of health in trials, emphasizing the need for data collection to address enrollment barriers. Using the Vizient Vulnerability Index, researchers found that social vulnerability impacts trial participation, particularly among Black patients. The study suggests enhancing trial accessibility, education, and government support to mitigate these barriers, with a focus on education, transportation, and neighborhood resources.

Oncology Business Management 

Lower odds of enrollment in cancer clinical trials could be associated with education, transportation, and neighborhood resources. 

Novel Index Identifies Social Vulnerability Barriers to Cancer Clinical Trial Enrollment

Several Bruton tyrosine kinase (BTK) degraders have emerged in early-phase studies and yielded high response rates in patients with chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), and the agents may be poised to fill an unmet need for patients who have experienced disease progression on BTK inhibitors.

With novel BTK degraders such as NX-5948 offering additional treatment modalities, the new class of drugs are looking to not only overcome BTK inhibitor resistance mutations, but also appear to penetrate the blood-brain barrier.

“[NX-5948] is different [from BTK inhibitors] in that it is a degrader and it leads to ubiquitination of the entire BTK enzyme and degradation of the entire enzyme. The preclinical hypothesis is that if you degrade the entire enzyme, then even if a patient has mutations in BTK—resistance mutations to covalent or noncovalent inhibitors—this would still potentially be an effective targeted agent in terms of a mechanism,” Nirav N. Shah, MD, MSHP, said in an interview with 

. Shah is an associate professor of medicine at the Medical College of Wisconsin at Froedtert Hospital in Milwaukee.

“For many of the B-cell malignancies, we’re running into [situations where patients treated with available] therapies have lost response,” Michael T. Tees, MD, MPH, a hematologist/oncologist at Colorado Blood Cancer Institute in Denver, added in an interview with 

. “For a while, the available agents weren’t able to keep up with those resistance mutations. BTK degraders target the similar pathway, but in a whole different context....Generally speaking, most of the BTK degraders that are under investigation are acting in a similar fashion, perhaps with increased activity in one pathway or the other.”

For example, NX-5948 induces specific protein degradation of wild-type and mutant forms of BTK by the cereblon E3 ligase, and the BTK degrader BGB-16673 induces BTK degradation by binding specifically to BTK and the E3 ligase.

As more than half of patients who experience disease progression on BTK inhibitors have covalent and noncovalent BTK inhibitor resistance mutations, and the population of patients who have disease refractory to both BCL2 and BTK inhibitors is increasing, BTK degraders represent a promising class of agents. NX-5948’s mechanism of action allows for the disruption of BTK scaffolding, and the agent can overcome BTK inhibitor treatment-emergent resistance mutations.

“Because you’re not necessarily binding at a specific site where a mutation can occur, this degrader may be able to overcome mutations that are present in patients who have [experienced disease progression on] other BTK drugs,” Shah noted.

Tees explained that “we are seeing signals of efficacy across several different molecules. The question is, are there certain degraders that work better than others for certain disease subtypes—for certain lymphoma subtypes? The other question is [regarding] the concept of this therapeutic intervention. Can it be [used] in other disease entities such as autoimmune diseases?” he asked. “I’m unsure if there are investigations that have started or if there are investigator-initiated trials across the country [in these diseases], but I believe that’s the next step.”

Examining Two of the Furthest Along BTK Degraders in Development: NX-5948 and BGB-16673

NX-5948 degraded wild-type and mutated BTK in patients with CLL/SLL, and findings from the phase 1a/b NX-5948-301 trial (NCT05131022) presented by Shah at the 2024 American Society of Hematology (ASH) Annual Meeting and Exposition revealed this patient population (n = 49) experienced an objective response rate (ORR) of 75.5% (95% CI, 61.1%-86.7%) at 8 weeks; a stable disease rate of 20.4% was also observed. The exploratory ORR analysis showed that at 16 weeks, patients (n = 38) experienced an ORR of 84.2% (95% CI, 68.7%-94.0%), and 10.5% experienced stable disease when treated with the oral agent. All responses in the trial were partial.

“It’s exciting to see [the] evolution of responses, and we looked at the mutational profile because these were all patients with relapsed/refractory CLL, so many of them harbored mutations in BTK, had high-risk mutations such as 

 mutations,” Shah said. “Independent of the mutational profile, we saw responses across the board, and when looking at blood samples of patients treated with the degrader, we saw that degradation of BTK occurred in approximately all patients independent of the mutations present at the time of enrollment in the trial.”

Responses achieved were also durable; 13 patients had a response ongoing for at least 6 months, and 5 patients remained on treatment following a year. The phase 1b dose expansion portion of NX-5948-301 is ongoing, and Shah noted that initiation of a pivotal trial is planned in 2025.

As NX-5948-301 also included patients with non-Hodgkin lymphoma, Waldenström macroglobulinemia, marginal zone lymphoma, diffuse large B-cell lymphoma, follicular lymphoma, and primary central nervous system (CNS) lymphoma/secondary CNS lymphoma, data are expected to be read out from those arms in the future.

The bivalent CNS-penetrating small molecule BGB-16673 is also under evaluation, and safety and efficacy data were presented at the 2024 ASH Annual Meeting and Exposition from the phase 1/2 CaDAnCe-101 trial (NCT05006716).

 Data revealed that patients with CLL/SLL (n = 49) experienced an ORR of 77.6% when treated with the agent across all dose levels. A notably high response rate was observed among patients treated at the 200-mg dose level (n = 16), who achieved an ORR of 93.8%. Additionally, high ORRs were seen in all biologic subsets examined, including in patients who previously received a covalent BTK inhibitor and BCL2 inhibitor (86.7%); received a covalent BTK inhibitor, noncovalent BTK inhibitor, and BCL2 inhibitor (58.3%); had a 17p deletion and/or 

mutation (74.2%); had a complex karyotype (73.3%); harbored 

Furthermore, the maximum tolerated dose of BGB-16673 was not reached in the population of patients with relapsed/refractory CLL/SLL; 1 dose-limiting toxicity of grade 3 maculopapular rash occurred at the 200-mg dose level, and the patient continued treatment following a 5-day hold.

Safety of BTK Degraders Appears Manageable

“[BTK degraders in general] look to be safe because they’re highly targeted against BTK,” Shah noted. “[However], these drugs are taken potentially for months or even years, and one thing we don’t have yet [are data on] the
cumulative incidence of toxicities. Are we going to see new things develop over time the longer a patient is [taking a BTK degrader]? We’re only going to get that information as we treat more patients and follow them longer.”

Patients treated with BGB-16673 did not experience any treatment-related treatment-emergent adverse effects (TEAEs) leading to death; however, TEAEs led to death in 3 of 60 patients who received the agent. Grade 3 or greater (55.0%) and serious (45.0%) TEAEs also occurred, with 11.7% of patients discontinuing BGB-16673 due to TEAEs. The most common any-grade TEAEs included fatigue (30.0%), contusion (28.3%), and neutropenia (25.0%).

“There are some signals that would suggest that the toxicity profile [of BTK degraders] is very similar to [that of] BTK inhibitors,” Tees said. “Perhaps there can be some hepatic insufficiency that we need to be looking out for and some hematologic toxicities like leukopenia or neutropenia.”

Among those with CLL/SLL treated with NX-5948 (n = 60), the TEAEs most frequently experienced were contusion (36.7%), fatigue (26.7%), and petechiae (26.7%).

 Additionally, 1 case of grade 1 atrial fibrillation occurred in a patient who had prior atrial fibrillation, and 2 grade 5 AEs occurred but were deemed unrelated to NX-5948.

“So far, a very favorable safety profile has been seen. The way I look at safety is thinking about the grade 3 or higher toxicities that occurred in patients. Very low rates of grade 3 or higher toxicities [were observed with NX-5948 and] the most common one was neutropenia, [at 18.3%],” Shah said. “Consistent with that safety profile, only 1 patient in the CLL cohort discontinued the drug because of a TEAE.”

AC676 Is an Additional BTK Degrader to Watch

Another BTK degrader under examination is the novel agent AC676, which links a BTK ligand to the cereblon E3-ligase recruiting ligand.

 By doing so, AC676 brings BTK in proximity to cereblon, which induces subsequent ubiquitination and degradation of BTK. A phase 1 first-in-human study (NCT05780034) is currently enrolling adult patients with B-cell malignancies at 8 sites in the US to receive the agent; patients must have received at least 2 prior systemic therapies or have no other standard-of-care therapy options that provide significant clinical benefit.

According to Tees, “investigators will probably be advising that we open the inclusion [criteria] to look at patients who have CNS involvement of disease. It’s currently an exclusion [criterion], but there are some signals with other molecules [suggesting] that [BTK degraders can] cross the blood-brain barrier effectively and could be an exciting opportunity to provide an option for patients who may not have any given age or comorbidities.”

Like NX-5948 and BGB-16673, AC676 is also an oral drug.

 Investigations of the agents are going beyond CLL and SLL, but Tees noted that “the classic patient who derives benefits from BTK inhibitors [is one with] CLL/SLL, and thus it’s appearing that they derive benefits from BTK degraders.”

He added that “for a disease such as an indolent lymphoma, upon progression we may be limited [with] other therapeutic options, and this fulfills that unmet need if we see those not only positive safety signals but also efficacy signals…. Mantle cell lymphoma is a disease entity that we need to be investigating responses [to] BTK degraders [in] because we know that the BTK inhibitors have excellent efficacy, but oftentimes [patients] lose responses over time. Follicular lymphoma is a common indolent B-cell lymphoma, [and patients] tend not to have the most robust response to BTK inhibitors. The question is, do BTK degraders provide an opportunity for patients to derive benefit?”

Furthermore, Shah noted that “potentially, we hope that this may be a different modality to offer patients as an earlier line of treatment as well.”

“This is exciting and an advancement of science to target BTK in a way we haven’t done previously. We’re seeing efficacy at a high level, even in patients who have been previously treated with a BTK inhibitor,” Shah said.

Shah NN, Omer Z, Collins GP, et al. Efficacy and safety of the Bruton’s tyrosine kinase (BTK) degrader NX-5948 in patients with relapsed/refractory (R/R) chronic lymphocytic leukemia (CLL): updated results from an ongoing phase 1a/b study. 

. 2024;144(suppl 1):884. doi:10.1182/blood-2024-194839

Thompson MC, Parrondo RD, Frustaci AM, et al. Preliminary efficacy and safety of the Bruton tyrosine kinase degrader BGB-16673 in patients with relapsed or refractory chronic lymphocytic leukemia/small lymphocytic lymphoma: results from the phase 1 CaDAnCe-101 study. 

. 2024;144(suppl 1):885. doi:10.1182/blood-2024-199116

Tees MT, Bond DA, Khan N, et al. A phase 1 study of AC676, a novel BTK chimeric degrader, in patients with B-cell malignancies. 

. 2024;144(suppl 1):4422.1. doi:10.1182/blood-2024-194009

Emerging Bruton tyrosine kinase (BTK) degraders, such as NX-5948 and BGB-16673, show promise in treating chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL), particularly in patients with resistance to BTK inhibitors. These degraders target BTK through a novel mechanism, potentially overcoming resistance mutations and penetrating the blood-brain barrier. Early-phase trials demonstrate high response rates and manageable safety profiles. The ongoing development of BTK degraders, including AC676, may expand treatment options for various B-cell malignancies and potentially autoimmune diseases.

Nirav N. Shah, MD, MSHP, and Michael T. Tees, MD, MPH, detail BTK degraders such as NX-5948 under investigation in the CLL/SLL space.  

BTK Degraders May Be a Promising Approach in CLL/SLL for Patients With Disease Progression

As 8 regimens have received tumor-agnostic FDA approvals as of January 2025, and 2 came in 2024, biomarkers are becoming even more prevalent in care.

 Since the first tumor-agnostic approval occurred in 2017 with pembrolizumab’s (Keytruda) accelerated approval that was converted to full approval in 2023, much has been discovered about protein and gene profiles, but with that come several key questions predominately focused on testing strategies and the efficacy of these newly approved drugs in rare tumors.

“The question around genetic testing is a complicated one because it has a lot of factors that we need to consider,” Pedro Barata, MD, MSc, FACP, said in an interview with 

. “First, I talk about tumor testing or germline testing—somatic vs germline. With somatic testing you go after the tumor [and] the question then becomes are you testing the tissue or are you testing the circulating free DNA, which you hope will have a 100% representation with circulating tumor DNA, but [they] are not necessarily the same? From that point of view, the timing of collection, the wait time, and what tissue you are using are relevant. Is it very old tissue? Does it represent the tumor that’s now progressing on 1, 2, or 3 lines of therapy? Those questions are very important.”

Additionally, the efficacious targeted therapy fam-trastuzumab deruxtecan-nxki (T-DXd; Enhertu) represented a key approval in 2024 for adult patients with unresectable or metastatic HER2-positive (immunohistochemistry [IHC] 3+) solid tumors who received prior systemic treatment and have no satisfactory alternative treatment options.

 Although findings from 3 trials examining the drug in different tumor types supported the regulatory decision, data on the antibody-drug conjugate may still be lacking in certain tumor types, similar to what has been seen with other tumor-agnostic indications, according to experts.

“More broadly, there are many rare cancers where they’re never going to have a large enough population of patients to be able to run a large, randomized clinical trial looking at the outcome of [a drug like T-DXd in] a rare sarcoma, [for example],” Stephanie L. Graff, MD, said in an interview with 

. “To know that if a tumor has HER2 expression it potentially benefits [from the drug] opens up therapeutic options for patients and given the magnitude of benefit we’ve seen with T-DXd in trial after trial, it’s very powerful to see these tissue-agnostic approvals coming through.”

Barata also noted that care teams are in the process of adapting and figuring out optimal workflows with the arrival of more pan-tumor approvals. “For germline [testing], do you have a genetic counselor, or do you have to do the pretest counseling, and then what do you do with the positive results? Do you have a genetic counselor there, or do you have to provide a remote genetic counseling service? All those are relevant, important questions that the care teams are struggling to figure out the right answer to, and my guess is the right answer is not the same for all the care teams out there.”

The agents currently holding tumor-agnostic FDA approval indications are:

Larotrectinib (Vitrakvi), entrectinib (Rozlytrek), and repotrectinib (Augtyro)

 gene fusion who have experienced disease progression following treatment or have no satisfactory standard therapy and who have metastatic disease or disease where surgical resection is likely to result in severe morbidity

Adult and pediatric patients with unresectable or metastatic microsatellite instability–high (MSI-H) or mismatch repair–deficient (dMMR) solid tumors who have experienced disease progression following prior treatment and have no satisfactory alternative treatment options

Adults with dMMR recurrent or advanced solid tumors, as determined by an FDA-approved test, who have experienced disease progression on or following prior treatment and who have no satisfactory alternative treatment options

Dabrafenib (Tafinlar) plus trametinib (Mekinist)

Adult and pediatric patients 6 years or older with unresectable or metastatic solid tumors and a 

V600E mutation who have experienced disease progression following prior treatment and have no satisfactory alternative treatment options

Dabrafenib plus trametinib is not indicated for patients with colorectal cancer (CRC).

Dabrafenib is not indicated for patients with 

Adults with locally advanced or metastatic solid tumors and a 

 gene fusion who have experienced disease progression on or following prior systemic treatment or who have no satisfactory alternative treatment options

Adults with unresectable or metastatic HER2-positive (IHC3+) solid tumors who have received prior systemic treatment and have no satisfactory alternative treatment options

Putting T-DXd’s Tumor Agnostic Approval Under the Microscope

-mutated non–small cell lung cancer [NSCLC] with a response rate of approximately 50%, so that’s been a standard of care [SOC]. This tumor-agnostic approval for HER2-positive IHC 3+ [tumors] has changed our SOC in that we’re performing HER2 IHC [testing] on all our patients with NSCLC [and are] now looking for that in addition to broad genomic profiling next-generation sequencing,” Jonathan Wesley Riess, MD, MS, said in an interview with 

 on the significance of T-DXd’s approval in lung cancer.

In the phase 2 DESTINY-Lung01 study (NCT03505710), which was one of the trials with data supporting the pan-tumor approval of T-DXd, patients (n = 17) with NSCLC and HER2 IHC 3+ expression achieved an objective response rate (ORR) of 52.9% (95% CI, 27.8%-77.0%), with a median duration of response (DOR) of 6.9 months (range, 4.0-11.7+).

Kaplan-Meier estimates of overall survival (OS) from the phase 2 DESTINY-PanTumor02 trial (NCT04482309)—results of which also supported the approval of T-DXd—showed the median OS in patients with HER2 IHC 3+ expression as follows in the cohorts examined: 26.0 months (95% CI, 18.9-not reached [NR]) in the endometrial cancer group (n = 13); NR (95% CI, 3.9-NR) in the cervical cancer arm (n = 8); 20.0 months (95% CI, 3.8-NR) in the ovarian cancer cohort (n = 11); 13.4 months (95% CI, 6.7-19.8) in the bladder cancer group (n = 16); 24.3 months (95% CI, 11.1-NR) in the other tumors arm (n = 9); 12.4 months (95% CI, 2.8-NR) in the biliary tract cancer arm; (n = 16) and 12.4 months (95% CI, 8.8-NR) in the pancreatic cancer cohort (n = 2).

“HER2 is being used a little differently [in gynecologic cancers] than for breast cancer, but in general, the medical oncologists in the community setting have more experience than most gynecologic oncologists because in the grand scheme of HER2-directed therapies, we’re pretty late to the game; breast cancer and other cancers have been using these [Her2 targeted drugs] for a long time,” Katherine Kurnit, MD, MPH, said in an interview with 

Additionally, higher ORRs were seen in patients with HER2 IHC 3+ expression than in the all-comers population of DESTINY-PanTumor02, excluding the pancreatic cancer cohort. Rates were as follows in the HER2 IHC 3+ populations for endometrial (84.6%), cervical (75.0%), ovarian (63.6%), bladder (56.3%), other (44.4%), and biliary tract (56.3%) cancers. No patients with HER2 IHC 3+ expression in the pancreatic cancer cohort experienced a response (

“The only thing to keep in mind [with gynecologic cancers] is we had to have a discussion with our pathologists about which HER2 scoring system to use and [if we] needed to take the time to do reflex fluorescence in situ hybridization [(FISH) testing, which] we decided that we don’t [need] in most cases. We’re not using [T-DXd] in the frontline setting, [and] the trial didn’t require ISH positivity for the 2+ [population],” Kurnit noted. “First, not making more work or cost than you need to [is important, as is] making sure that the pathologists know which scoring systems to use for HER2. Making sure you’re catching all the patients and not being needlessly exclusive [is also key]. For some of the other biomarkers, it’s hard. Some of these are send-out [tests, and] some of them we don’t have easy access to, so thinking about how much tissue you have and how to prioritize it [is critical] for us and probably for a lot of community groups.”

Furthermore, data from the phase 2 DESTINY-CRC02 trial (NCT04744831), the third study with results supporting the regulatory decision on T-DXd, showed that patients with CRC and HER2 IHC expression (n = 64) experienced an ORR of 46.9% (95% CI, 34.3%-59.8%); the median DOR was 5.5 months (range, 1.3+to 9.7+).

“We’re getting to an era where, at least in the US, we’re able to sequence all the patients with unresectable or metastatic malignancies who come to see us, specifically those with solid tumors,” Barata said. “It opens the door to precision oncology, whether you talk about specific markers to predict response to immunotherapy or specific targets to predict the efficacy of targeted approaches; that has revolutionized treatment with the care we’re providing to patients. For the most part, [these therapies] are still being used in the refractory setting beyond frontline regimens. There are a few exceptions to that: I’m thinking of lung cancer, for example, where you go after EGFR, ROS or ALK [targets]. But [when] you start talking beyond that, you start seeing [that] biomarker-based approaches [are] moving early on and sparing the patient from the toxicity of chemotherapy and sometimes the lack of efficacy of chemotherapy with [a] far more effective therapy.”

When examining the efficacy of repotrectinib by tumor type in 40 patients with tyrosine kinase inhibitor (TKI)–naive 

fusion–positive cancers, the ORR was 62% (95% CI, 38%-82%) in NSCLC (n = 21); 100% (95% CI, 48%-100%) in thyroid cancer (n = 5); 100% (95% CI, 29%-100%) in salivary gland cancer (n = 3); and 33% (95% CI, 0.8%-91%) in soft tissue sarcoma (n = 3).

 Additionally, both patients with breast cancer experienced progressive disease (PD), as did 1 patient with cholangiocarcinoma. A patient with secretory carcinoma and a patient with a peripheral nerve sheath tumor each achieved a partial response (PR), and patients with glioblastoma (n = 1), CRC (n = 1), and other tumors (n = 2) experienced stable disease (SD).

“For repotrectinib, the efficacy data are striking, [with a] median progression-free survival [PFS] of approximately 3 years in the first-line [setting for patients with NSCLC and] 9.0 months in the second line and prior ROS1 [TKI–treated population],” Riess said. “High response rates [were also seen,] so it’s now my first-line treatment of choice for patients with NSCLC.”

Additionally, when examining responses to repotrectinib in 48 patients with TKI-pretreated 

fusion–positive cancers, the ORR was 43% (95% CI, 18%-71%) in NSCLC (n = 14); 88% (95% CI, 47%-100%) in salivary gland cancer (n = 8); 17% (95% CI, 0.4%-64%) in soft tissue sarcoma (n = 6); 50% (95% CI, 7%-93%) in thyroid cancer (n = 4); and 33.3% (95% CI, 0.8%-91%) in glioblastoma (n = 3). The 1 patient with breast cancer achieved a PR, and both patients with peripheral nerve sheath tumors as well as both with neuroendocrine tumors achieved PRs. Patients with cholangiocarcinoma (n = 2) experienced a PR and PD, those with CRC (n = 2) had a PR and SD, and those with other tumors (n = 2) experienced SD and PD. Finally, both patients with pancreatic cancer had PD.

“Repotrectinib has its own set of adverse effects [AEs], but it looks to be exceptionally effective, particularly as a first-line treatment for patients with 

 fusion–[positive] NSCLC. That’s the biggest decider for me,” Riess said. “Like anything, you weigh risks/benefits [and] what the clinical benefit is. Here, it’s a robust PFS [benefit and the] risk is it could have a bit more AEs than crizotinib [Xalkori], for example, but patients can manage, and [repotrectinib] can be quite effective.”

Furthermore, data from the phase 1/2 TRIDENT-1 study (NCT03093116) that supported repotrectinib’s pan-tumor FDA approval showed that all patients in the TKI-naive group (n = 40) experienced an ORR of 58% (95% CI, 41%-73%) with a median DOR that was not estimable (NE) (95% CI, NE-NE). The ORR was 50% (95% CI, 35%-65%) in the TKI-pretreated group (n = 48), and patients experienced a median DOR of 9.9 months (95% CI, 7.4-13.0).

“As you approach a patient with metastatic carcinoma who has numerous lines of therapy available to them, making sure that you’ve gone to something like the National Comprehensive Cancer Network guidelines or American Society of Clinical Oncology guidelines and looked at that list of available biomarkers that can help inform treatment decisions and that you’ve done all of the appropriate testing [is key],” Graff said. “[It’s also crucial to] be able to quickly access those checklists that exist in most of our national guidelines and make sure that the patient has been screened for every single biomarker that could potentially inform your treatment choice, and then you [should be] looking at things like the strength of that biomarker.”

When asked how to treat a patient who could qualify for a biomarker approval when there are not a lot of data for their tumor type, Barata said, “As an academic doctor, my easy answer is we’ll have to develop that data. That happened with immunotherapy—when pembrolizumab was approved based on MSI-H [status] initially, we had microsatellite instability being tested in tissue even before it was able to be tested in liquid biopsy. We didn’t have that in prostate cancer, so we had to develop those data. When we don’t have much data, usually those therapies are not prioritized over the SOC and are saved [for] the settings where there are more limited options.”

Tumor-agnostic drugs. American Cancer Society. Updated June 20, 2024. Accessed January 10, 2025. bit.ly/4fRNg8r

FDA converts to full approval indication for Keytruda (pembrolizumab) for certain adult and pediatric patients with advanced microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR) solid tumors. News release. Merck. March 29, 2023. Accessed January 10, 2025. bit.ly/428y4AQ

FDA grants accelerated approval to fam-trastuzumab deruxtecan-nxki for unresectable or metastatic HER2-positive solid tumors. FDA. April 5, 2024. Accessed January 10, 2025. bit.ly/3UYSKqk

FDA grants accelerated approval to repotrectinib for adult and pediatric patients with NTRK gene fusion-positive solid tumors. FDA. June 13, 2024. Accessed January 10, 2025. bit.ly/4eGQtr4

FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated July 18, 2023. Accessed January 10, 2025. bit.ly/3Ps1n9Y

FDA grants accelerated approval to dabrafenib in combination with trametinib for unresectable or metastatic solid tumors with BRAF V600E mutation. FDA. Updated June 23, 2022. Accessed January 10, 2025. bit.ly/42acfAP

FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. September 21, 2022. Accessed January 10, 2025. bit.ly/4abeNAu

Meric-Bernstam F, Makker V, Oaknin A, et al. Efficacy and safety of trastuzumab deruxtecan in patients with HER2-expressing solid tumors: primary results from the DESTINY-PanTumor02 phase II trial. 

. 2024;42(1):47-58. doi:10.1200/JCO.23.02005

The increasing prevalence of tumor-agnostic FDA approvals highlights the growing importance of biomarkers in cancer care. Since pembrolizumab's initial approval in 2017, numerous regimens have been approved, raising questions about testing strategies and drug efficacy in rare tumors. The approval of fam-trastuzumab deruxtecan-nxki for HER2-positive tumors exemplifies the challenges and opportunities in this field. Care teams are adapting to these changes, considering factors like genetic counseling and testing logistics. The efficacy of drugs like repotrectinib and T-DXd in various cancers underscores the potential of precision oncology.

Clinicians parse through the impacts of tumor-agnostic FDA approvals, examining T-DXd and repotrectinib's 2024 approvals in particular. 

Tumor-Agnostic Approvals of T-DXd and Repotrectinib Carry the Field Forward

The treatment landscape of chronic lymphocytic leukemia (CLL) has expanded rapidly in recent years, with data emerging using triplet, doublet, and monotherapy approaches. In the frontline setting, the Bruton tyrosine kinase (BTK) inhibitor zanubrutinib (Brukinsa) has emerged as a viable treatment option both as monotherapy and as a combination component. For patients with relapsed/refractory disease, the chimeric antigen receptor (CAR) T-cell agent lisocabtagene maraleucel (liso-cel; Breyanzi) has received FDA approval, and novel BTK degraders such as NX-5948 and BGB-16673 have shown promise in early-phase clinical trials.

 Peer Exchange filmed at the 2024 American Society of Hematology (ASH) Meeting and Exposition, expert investigators in hematology discussed exciting findings from several clinical trial updates in CLL presented during the meeting.

“The past decade has been a revolution in CLL treatment, particularly for our older [patients with CLL],” 

, said. “For many of them, we have the available tools to prolong life to what their natural life span would be otherwise. The patients I still worry the most about are my younger patients; if they’re in their early 50s, we don’t know what happens over 20 or 30 years with these targeted therapies. That’s a group where additional research is needed. I’m also optimistic about modalities such as bispecific antibodies; if we use them in smart ways earlier in the treatment course, there may be curative potential there. We shouldn’t shy away from developing curative strategies for younger patients with CLL.”

Triplet and Doublet Regimens Offer Deep Responses in Frontline CLL

The most recent agent to gain FDA approval in CLL is zanubrutinib.

 In January 2023, the agent earned an indication from the FDA for the treatment of patients with CLL or small lymphocytic lymphoma (SLL). The regulatory decision was supported by findings from the phase 3 SEQUOIA (NCT03336333) trial, which compared zanubrutinib with bendamustine plus rituximab (Rituxan) in patients with previously untreated CLL or SLL.

At a median follow-up of 61.2 months, updated findings from SEQUOIA demon- strated that the median progression-free survival (PFS) among patients who received zanubrutinib (n = 241) was not reached (NR) compared with 44.1 months (95% CI, 38.4- 55.6) in the bendamustine plus rituximab arm (n = 238; HR, 0.29; 95% CI, 0.21-0.40; P < .0001). The 54-month PFS rates were 80.1% (95% CI, 74.3%-84.7%) and 44.6% (95% CI, 37.6%-51.3%), and the 60-month rates were 75.8% (95% CI, 69.0%-81.3%) and 40.1% (95% CI, 32.7%-47.3%), respectively. The estimated 54-month overall survival (OS) rates were 87.7% (95% CI, 82.7%-91.3%) and 86.0% (95% CI, 80.6%-90.0%), and the 60-month rates were 85.8% (95% CI, 80.6%-89.7%) and 85.0% (95% CI, 79.5%-89.2%), respectively.

“The interesting aspect of SEQUOIA is not the comparator arm or even the comparison between the drugs: It’s what happened to the zanubrutinib-treated patients and their toxicity profiles over time,” 

, said. “Those data are compelling, and I have already converted to using zanubrutinib in the vast majority of my patients based on the toxicity data. [There were] continuing low rates of atrial fibrillation. It confirms a lot of the previous observations that we had with the drug, both about its excellent efficacy and the relatively high-quality safety profile.”

In a phase 2 trial (NCT03824483), investigators examined zanubrutinib as a combination component with obinutuzumab (Gazyva) and venetoclax (Venclexta; BOVen) in patients with treatment-naive CLL or SLL.

 The primary end point was minimal residual disease (MRD) negativity rate. The threshold for undetectable MRD (uMRD) was 10

At a median follow-up of 57 months (range, 4-63+), data from the trial demonstrated that patients who received the triplet and were included in the 8-month analysis (n = 49) achieved an 8-month MRD4 negativity rate of 77.6% (1 patient was confirmed positive). The best and end-of-treatment MRD4 negativity rates by peripheral blood and bone marrow analysis were 96% and 92%, respectively, in the total population (n = 50). The median MRD4-free survival was 34 months (95% CI, 23-NR), with 92% of patients reaching this threshold.

“These patients are remaining in a very deep remission, and, on average, they only had [approximately] 10 months of treatment,” Hoffmann said. “They get 10 months of treatment and then 2 years of ongoing, extremely deep MRD remissions, which is a remarkable outcome for a targeted therapy combination that is well tolerated and avoids chemotherapy. That’s extremely exciting, [but] my question with a lot of these triplets is about toxicity. When you add the third drug, you get increased toxicity, and it doesn’t bear out perfectly well in the reported abstracts.”

Another triplet regimen is being evaluated in a separate phase 2 trial (NCT05536349). Investigators are examining pirtobrutinib (Jaypirca) plus venetoclax and obinutuzumab as first-line therapy for patients with CLL or SLL.

 The primary end point is uMRD rate; secondary objectives included overall response rate (ORR), PFS, OS, and safety and tolerability.

At a median follow-up of 11.9 months (range, 2.0-21.4), among patients who completed 7 cycles of treatment (n = 66), the peripheral blood uMRD rate at a threshold of less than 10

 (uMRD6) was 79%, with 93% achieving uMRD4 at this time point. Patients who completed 13 cycles of treatment (n = 41) achieved an uMRD4 rate of 100% and an uMRD6 rate of 85%.

“The responses are early, this is less than a year [of follow-up], but the data look very exciting. There are high response rates in both bone marrow and peripheral blood, with a 10

, said. “With this triplet, there’s more neutropenia and thrombocytopenia, but very high levels of response.”

Beyond triplet therapy, the phase 3 AMPLIFY trial (NCT03836261) is exam- ining acalabrutinib (Calquence) plus venetoclax with or without obinutuzumab vs chemoimmunotherapy in frontline CLL.

 The primary end point is PFS per blinded independent central review (BICR). Secondary end points include uMRD4 rate and OS.

“AMPLIFY compared acalabrutinib plus venetoclax [with or without obinutuzumab] given in a time-limited fashion [over] 14 cycles vs chemoimmunotherapy with investigator’s choice of fludarabine, cyclophosphamide, and rituximab, or bendamustine plus rituximab,” 

, said. “The findings show, not surprisingly, a big advantage for the novel agents over chemoimmunotherapy.”

Findings from the interim analysis of AMPLIFY showed that the median BICR-assessed PFS among patients who received acalabrutinib plus venetoclax (n = 291) or acalabrutinib plus venetoclax and obinutuzumab (n = 286) was NR vs 47.6 months for those treated with chemoimmunotherapy (n = 290). The HR for acalabrutinib plus venetoclax vs chemoimmunotherapy was 0.65 (95% CI, 0.49-0.87; 

 < .0001) for acalabrutinib plus venetoclax and obinutuzumab vs the control arm. The uMRD4 rates were 26.8%, 66.4%, and 51.0% in the doublet, triplet, and control arms, respectively, at the time of the key secondary end point analysis in the intent-to-treat population.

“The comfort of doing a time-limited [treatment] with a BTK-based therapy [is that it] gives us more options with the triplet,” 

, noted. “I’m skeptical about routinely adding a bispecific monoclonal antibody to the combination. You may deepen the response, but you are paying a price for that—the infections are not trivial. On the AMPLIFY trial, [there were] issues with serious infectious complications [from] the bispecific [antibody]. What I tend to do is bide my time in the first few cycles for those patients [who] seem to be dragging and not really having a response; sometimes they have bad hemolytic anemia that might give you another edge in terms of adding the antibody. [However,] I do not routinely add a triplet in the first line.”

CAR T, Combinations, and Novel Agents Emerge in Relapsed/Refractory CLL

During the ASH meeting, investigators presented results of a real-world treatment sequencing analysis that examined 16 of the most frequently utilized treatment sequences in patients with relapsed/refractory CLL/SLL in community-based settings.

The unadjusted median OS results were as follows: For patients who received BTK inhibitor monotherapy and then CD20 antibody monotherapy, 63 months (95% CI, 55-74); BTK inhibitor monotherapy then BCL2 inhibitor monotherapy, 81 months (95% CI, 74-not estimable [NE]); chemoimmunotherapy then chemoimmunotherapy, 72 months (95% CI, 58-NE); CD20 antibody monotherapy then BTK inhibitor monotherapy, 82 months (95% CI, 68-NE); and CD20 antibody monotherapy then chemoimmunotherapy 93 months (95% CI, 54-NE). The median OS was NE for all other sequences that were examined.

“In reality, what we’re deciding on in the first and second line are BTK inhibitor vs BCL2 inhibitor data,” Alencar commented. “In general, if [a patient] is on a covalent BTK inhibitor and has issues with tolerability, they may switch over to a different agent and still maintain the response with different toxicities. On the other hand, if patients progress on a BTK inhibitor, it’s unlikely that a similar class BTK inhibitor will rescue that patient. For a patient who started a BTK inhibitor in the first line, what is the switchover? In general, it’s going to be a BCL2 inhibitor–based approach.”

Also presented at ASH were results from a phase 2 study (NCT05168930) examining the combination of zanubrutinib and venetoclax for the treatment of patients with relapsed/refractory CLL.

 At a median follow-up of 8 months, the ORR in the overall population (n = 26) was 95%, with a complete response (CR) rate of 17%. Patients who were BTK and BCL2 inhibitor naive (n = 13) achieved an ORR of 91%; those who received a prior BTK and/or BCL2 inhibitor and stopped therapy for reasons other than disease progression (n = 12) and those who experienced disease progression on a BTK inhibitor without a 

 C481 mutation (n = 1) all achieved ORRs of 100%. Six patients reached the end-of-treatment time point, with 1 achieving uMRD4.

Following BTK and BCL2 inhibitor exposure, treatment with CAR T-cell agents represents a potential option for patients with relapsed/ refractory CLL. In the phase 1/2 TRANSCEND CLL 004 trial (NCT03331198), liso-cel is being examined in patients with relapsed/refractory CLL/ SLL, including those who experienced disease progression on a BTK inhibitor and venetoclax.

The treatment landscape for chronic lymphocytic leukemia (CLL) has evolved significantly, with new therapies such as zanubrutinib and lisocabtagene maraleucel gaining prominence. Zanubrutinib has shown efficacy in both monotherapy and combination regimens, while lisocabtagene maraleucel offers a novel option for relapsed/refractory cases. Triplet and doublet regimens are providing deep responses, though concerns about toxicity remain. Emerging therapies, including BTK degraders and CAR T-cell agents, are promising for relapsed/refractory CLL. The focus is on optimizing treatment strategies, particularly for younger patients, and improving minimal residual disease (MRD) management.

During an OncLive Peer Exchange at the 2024 ASH Meeting, expert investigators in hematology discussed findings from several clinical trial updates in CLL.

Vol. 26/No. 2 | Oncology Live®

2024 Tumor-Agnostic Approval Cheat Sheet: T-DXd and Repotrectinib

Novel Index Identifies Social Vulnerability Barriers to Cancer Clinical Trial Enrollment

BTK Degraders May Be a Promising Approach in CLL/SLL for Patients With Disease Progression

Tumor-Agnostic Approvals of T-DXd and Repotrectinib Carry the Field Forward

Combination Regimens Expand CLL Treatment Paradigm

Prognostic vs Predictive Factors in Oncology Carry Differing Intent but May Have Complementary Clinical Utility

Targeting Menin: A New Frontier in Treating Refractory Leukemias

Zanidatamab Proves Efficacious in Pretreated Biliary Tract Cancer With Potential to Move to the Frontline