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

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.1 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.1,2

“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 OncologyLive. “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.3 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 OncologyLive. “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: 1, 3-9

• Larotrectinib (Vitrakvi), entrectinib (Rozlytrek), and repotrectinib (Augtyro)4-6
  • All are approved for patients with an NTRK 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
• Pembrolizumab2
  • 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
• Dostarlimab-gxly (Jemperli)7
  • 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)8
  • Adult and pediatric patients 6 years or older with unresectable or metastatic solid tumors and a BRAF 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 BRAF wild-type solid tumors.
• Selpercatinib (Retevmo)9
  • Adults with locally advanced or metastatic solid tumors and a RET gene fusion who have experienced disease progression on or following prior systemic treatment or who have no satisfactory alternative treatment options
• T-DXd3
  • 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

“T-DXd has already been approved for HER2-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 OncologyLive 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+).3

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).10

“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 OncologyLive.

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 (FIGURE).10

“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+).3

“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.”

A Deep Dive Into Repotrectinib

When examining the efficacy of repotrectinib by tumor type in 40 patients with tyrosine kinase inhibitor (TKI)–naive NTRK 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).11 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 NTRK 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 ROS1 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).6,11

“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.”

References

1. Tumor-agnostic drugs. American Cancer Society. Updated June 20, 2024. Accessed January 10, 2025. bit.ly/4fRNg8r
2. 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
3. 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
4. FDA approves larotrectinib for solid tumors with NTRK gene fusions. FDA. Updated December 14, 2018. Accessed January 10, 2025. bit.ly/4gNsvMp
5. FDA approves entrectinib for NTRK solid tumors and ROS-1 NSCLC. FDA. Updated August 16, 2019. Accessed January 10, 2025. bit.ly/3DPv1U1
6. 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
7. FDA grants accelerated approval to dostarlimab-gxly for dMMR advanced solid tumors. FDA. Updated July 18, 2023. Accessed January 10, 2025. bit.ly/3Ps1n9Y
8. 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
9. FDA approves selpercatinib for locally advanced or metastatic RET fusion-positive solid tumors. FDA. September 21, 2022. Accessed January 10, 2025. bit.ly/4abeNAu
10. 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. J Clin Oncol. 2024;42(1):47-58. doi:10.1200/JCO.23.02005
11. Augtyro. Prescribing information. Bristol Myers Squibb; 2024. Accessed January 13, 2025. bit.ly/4aebIjo