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Keeping investigators on the edge of their seats, new data from clinical trials evaluating the antibody-drug conjugates (ADCs) datopotamab deruxtecan (Dato-DXd) and fam-trastuzumab deruxtecan-nxki (T-DXd, Enhertu) continue to impress, with Dato-DXd earning acceptance from the FDA in February 2024 for a biologics license application (BLA) seeking approval of the agent for the treatment of patients with locally advanced or meta- static nonsquamous non–small cell lung cancer (NSCLC) following prior systemic therapy.

“These ADCs work well in patients with genomic alterations, [and] not just T-DXd but [with] Dato-DXd we’ve witnessed activity that we did not think would happen,” Benjamin P. Levy, MD, said in an episode of 

 Insights. “It’s an exciting time, it’s a complicated time, but being vigilant in [identifying] the right mutation, doing the right testing, giving the drug—at least right now at the time of disease progression—and moni- toring for toxicities like interstitial lung disease [ILD] are critical. That is going to improve the patient journey—it’s going to improve quality of life—and we’re going to begin again to move this field forward, not just with immunotherapies or targeted therapies, but also with ADCs.”

During the program, Levy, an associate professor of oncology and clinical director of medical oncology at Johns Hopkins Sidney Kimmel Cancer Center at Sibley Memorial Hospital in Washington, DC, detailed how these ADCs are shifting the HER2-mutated NSCLC treatment paradigm and he highlighted the efficacy seen in patients with brain metastases and squamous vs nonsquamous histology. Key adverse effects (AEs) for clinicians to monitor include stomatitis with Dato-DXd and ILD for not only T-DXd, but all ADCs as well, according to Levy.

“We’ve historically done a poor job drugging HER2 mutations in lung cancer. We’ve had tyrosine kinase inhibitors [TKIs] or monoclonal antibodies that have had underwhelming results when we’ve looked at them as a single agent or even in combination with chemotherapy. Fortunately, T-DXd [came along],” Levy said.

Data from the phase 2 DESTINY-Lung01 (NCT03505710) trial revealed that patients with HER2-overexpressing disease who received T-DXd 6.4 mg/kg (n=49) achieved an objective response rate (ORR) of 26.5% (95% CI, 15.0%- 41.1%); when stratified by HER2 expression by immunohistochemistry (IHC), patients with an IHC of 3+(n=10) experienced an ORR of 20.0% (95% CI, 2.5%-55.6%) compared with 28.2% (95% CI, 15.0%-44.9%) for those with an IHC of 2+(n=39). When patients were treated with T-DXd at 5.4 mg/kg (n=41), the confirmed ORR was 34.1% (95% CI, 20.1%-50.6%) and results varied for those with IHC 3+(n=17) and 2+(n=24) disease—the ORRs were 52.9% (95% CI, 27.8%-77.0%) vs 20.8% (95% CI, 7.1%-42.2%), respectively.

“What we learned from DESTINY-Lung01 is that overexpression doesn’t seem to predict response the way a HER2 mutation does,” Levy explained. “[Also], we need to remember that HER2 alterations come in many sizes, shapes, and forms. There’s HER2 overexpression, which is the most common alteration in lung cancer and is [identified] by IHC. There is also HER2 amplifi- cation, which can be [identified] by fluorescence in situ hybridization [FISH] or next-generation sequencing. [The third HER2 alteration is] theHER2 exon 20 insertion mutation and it’s import- ant [to note] that, for now, the HER2 exon 20 insertion mutation predicts efficacy for the ADC T-DXd—we need to make sure that patients we deliver this ADC to have that alteration. It’s not yet approved for HER2 overexpression or HER2 amplifications but is specifically approved for HER2 exon 20 insertions.”

When data from DESTINY-Lung01 was eval- uated in patients with HER2 mutations (n=91), most of whom had exon 20 insertions (86%), the confirmed ORR for patients treated with 6.4 mg/kg of T-DXd was 55% (95% CI, 44%-65%) and the median duration of response was 9.3 months (95% CI, 5.7-14.7).

“This changed the game for us. The challenge with this study was that although it showed the highest response rates we’ve ever seen in HER2-mutated lung cancer, unfortunately, the 6.4 mg/kg dose led to a high rate of ILD—26% of patients had ILD at the 6.4 mg/kg dose. That led to perhaps the more important phase 2 DESTINY-Lung02 [NCT04644237] study,” Levy said. “What we’ve learned from DESTINY-Lung02 is that the dose [of T-DXd] is 5.4 mg/kg, not 6.4 mg/kg. Now we have this approved and we’re using it in clinic.”

As the first ADC approved by the FDA in lung cancer and the first drug approved by the agency in HER2-mutant NSCLC, investigators are looking to determine T-DXd’s optimal place in the treatment paradigm for patients with HER2 mutations.

“For now, patients with this mutation should receive chemotherapy first. Currently, the drug is approved in the second line, so patients get chemotherapy first, and then once there’s disease progression, T-DXd 5.4 mg/kg in the second line [can be given]. We will have other studies coming out evaluating T-DXd vs chemotherapy in the first line because all of us believe that this drug should move first,” Levy said. “But for now, this drug is after disease progression on chemotherapy for patients with a HER2 mutation, not HER2 overexpression or HER2 amplification.”

Reinforcing the importance of genetic testing, Levy noted that finding HER2 mutations is key. HER2 dysregulations have been described as occurring in NSCLC as gene mutations (1%-4%), gene amplifications (2%-5%), and protein over-expression (2%-30%).

 However, as Levy explained, research has shown these should be regarded as 3 distinct subtypes of NSCLC.

He also noted that molecular testing in the advanced and early-stage settings is key as there are approvals in the adjuvant setting for targeted therapies. In addition to liquid biopsy, he stressed that tissue biopsy must be completed for patients with advanced nonsquamous NSCLC and that single-gene panels are not enough—RNA- and DNA-based testing should be performed, and clinicians should confirm that the assay they are using tests for both DNA and RNA. Ensuring an adequate sample is collected, whether it be by fine-needle aspiration or core biopsy, should also be top of mind, according to Levy.

“We know a couple of things from publications on liquid biopsies,” he explained. “Number one is there’s a high concordance rate—if you have the alteration in the blood, you’re going to have it in tissue because the DNA is the same. Number two is that if you have a positive result in the blood, you do not need to wait for the tissue to come back and you can move forward with executing a plan based on that alteration discovered in the plasma. The third thing is a negative result in plasma tells you nothing [because] if you don’t have anything in the plasma, you can still have it in the tissue. These are complementary.”

TROP2-Directed ADCs: a Class of Their Own 

Dato-DXd has emerged as another promising ADC in lung cancer, as the TROP2-directed agent was the first ADC to demonstrate a statistically significant improvement in progression-free survival (PFS) vs docetaxel for patients with previously treated, locally advanced or metastatic NSCLC. Data from the phase 3 TROPION-Lung01 (NCT04656652) trial showed that patients who received Dato-DXd (n=299) achieved a median PFS of 4.4 months (95% CI, 4.2-5.6) compared with 3.7 months (95% CI, 2.9-4.2) for those treated with docetaxel (n=305; HR, 0.75; 95% CI, 0.62-0.91; P=.004). The ORRs were 26.4% (95% CI, 21.5%-31.8%) vs 12.8% (95% CI, 9.3%- 17.1%), respectively.

“The phase 1 TROPION-PanTumor01 study [NCT03401385] told us a couple of things,” Levy explained. “[There were] encouraging response rates in a highly pretreated group of patients and we need to be mindful of stomati- tis. Fast forward to TROPION-Lung01—can we beat out docetaxel? We saw single-agent activity in TROPION-PanTumor01 as [the ORR] was 26% and there was durability of responses. The dose that was selected from that phase 1 study was 6 mg/kg. It made a lot of sense to look at Dato- DXd vs docetaxel in the second line given that docetaxel remains the standard of care and we need to do better.”

In addition to TROPION-PanTumor01 and TROPION-Lung01, the phase 1 TROPION-Lung02 (NCT04526691) and phase 2 TROPION-Lung05 (NCT04484142) studies were initiated to further evaluate Dato-DXd.6,7 The agent is exam- ined as monotherapy in TROPION-Lung05 and in combination with immunotherapy with or without platinum-based chemotherapy in TROPION-Lung02.

“These drugs [have] activity in the second line and we’ll see what happens if they get approved, but we’re going to start moving them up to the front line to see if they can replace platinum, even,” Levy said. “We’ll have to see how this plays out in the future, and how these TROP2 ADCs may work in patients [because] we don’t have the right biomarker yet. [Based on the data] from TROPION-PanTumor01 [and TROPION-Lung01], TROP2 overexpression doesn’t seem to matter—the higher the expression, it doesn’t seem to matter in its ability for that to predict response. As it stands now, we don’t have a biomarker for Dato-DXd and it may be an all-comer approach. TROP2 expression does not seem to predict efficacy from [these] studies.”

Breaking it Down by Histology: TROPION-LUNG01

Although benefit was observed in the intention- to-treat (ITT) population of TROPION-Lung01 with Dato-DXd vs docetaxel, the PFS benefit
was mainly driven by patients with nonsqua- mous histology. Among patients with and without actionable gene alterations, those with nonsqua- mous histology who received Dato-DXd (n=229) achieved a median PFS of 5.6 months (95%CI, 4.4-7.0) vs 3.7 months (95% CI, 2.9-4.2) for those given docetaxel (n=232; HR, 0.63; 95% CI, 0.51-0.78).

In the group of patients with squamous histology, those who received Dato-DXd (n=70) experienced a median PFS of 2.8 months (95% CI, 1.9-4.0) compared with 3.9 months (95% CI, 2.8-4.5) for patients treated with docetaxel (n=73; HR, 1.38; 95% CI, 0.94-2.02). Further, for patients without actionable genomic alterations and nonsquamous histology, benefit was also observed with Dato-DXd vs docetaxel (HR, 0.71; 95% CI, 0.56-0.91).

“When we look specifically at the patients with squamous disease, there didn’t seem to be a bene- fit at all. In fact, if you look at the Kaplan-Meier curves, [patients who received] docetaxel seemed to do better than those treated with Dato-DXd. This was a new signal and a new finding for us. When we looked at the OS in the ITT analysis, the HR was 0.90 and, once again, it seemed like when you broke down the HR by histology, the benefit was restricted to the patients with nonsquamous disease, not squamous. We still have a lot of work to do to try to understand this,” Levy said.

The interim OS findings favor the ADC over docetaxel, but OS data are still immature. However, the FDA accepted a BLA for Dato-DXd in patients with previously treated advanced nonsquamous NSCLC who received prior systemic therapy based on data from TROPION- Lung01, and the Prescription Drug User Fee Act date is set for the fourth quarter of 2024.

“Right now, the only second-line drug that we have approved is docetaxel and that is not good enough, we need to do better, and there are a lot of efforts to do so. Looking at these data, if there is an OS advantage [shown by] more mature data specifically in the nonsquamous patient population, it’s a no-brainer this drug will get approved. If there’s a trend in OS and a benefit and PFS in the nonsquamous population, I think it still will get approved and we’ll see if that happens,” Levy said.

Searching for Agents to Cross the Blood-Brain Barrier 

Patients with brain metastases enrolled in the phase 3 TROPION-Breast01 trial (NCT05104866) and DESTINY-Lung01 and DESTINY-Lung02 trials experienced benefit when treated with either Dato-DXd or T-DXd. In TROPION-Breast01, patients with previously treated, hormone receptor–positive/HER2-negative inoperable or metastatic breast cancer experienced benefit when treated with Dato-DXd (n=35) vs chemotherapy (n=23); the median PFS was 5.6 months (95% CI, 3.0-8.1) vs 4.4 months (95% CI, 1.4-5.7), respectively (HR, 0.73; 95% CI, 0.39-1.42).

In a pooled analyses of DESTINY-Lung01 and DESTINY-Lung02, the intracranial confirmed ORR (IC-cORR) was 50.0% (95% CI, 15.7%-84.3%) for patients who received T-DXd 5.4 mg/kg and underwent prior treatment (n=8) and was also 50.0% (95% CI, 11.8%-88.2%) for those who did not receive prior therapy (n=6). Among patients who received the 6.4 mg/kg dose of T-DXd, the IC-cORR was 21.4% (95% CI, 4.7%-50.8%) for patients who received prior therapy (n=14) and 37.5% (95% CI, 15.2%-64.6%) for those who did not (n=16).

Regarding this patient population with NSCLC from DESTINY-Lung01 and DESTINY-Lung02, Levy said that perhaps “this [data] can be viewed through the prism of a truly targeted therapy like a TKI where we don’t have to refer [patients] to radiation; maybe we can just give the drug and have confidence that the drug will cross the blood-brain barrier. This is remarkable, [but] we need more data—these are small numbers of patients, but very exciting.”

Balancing the Scales of Efficacy and Safety

Although ILD remains a common AE with T-DXd, stomatitis is an AE to watch with Dato-DXd, according to Levy (Figure 2).2,5 When discuss- ing TROPION-Lung01, he explained, “More than half of patients had stomatitis in the Dato-DXd arm. Most of these were grade 1 and 2 AEs, but we need to be mindful of that and how to treat, mitigate, and be proactive to prevent it from happening. If this drug gets approved, there are a lot of ways we may be able to do that—steroid mouth rinses may work for patients and ice chips during the infusion may work. We have our work cut out for us to try to understand how to mitigate these toxicities, but they can be done, and it can be manageable. Having participated in many of the trials with Dato-DXd, we have been able to get patients through [who have] done very well symp- tomatically from this standpoint of stomatitis.”

In TROPION-Lung01, any-grade stomatitis was observed in 47% of the patients in the Dato- DXd arm compared with 16% of patients in the docetaxel arm. Grade 3 stomatitis occurred in 6% vs 1% of patients, respectively. Additionally, grade 3 or higher treatment-related AEs (TRAEs) occurred in 25% of patients in the Dato-DXd arm vs 41% of patients in the docetaxel arm; 3 and 2 patients died due to TRAEs in the respective arms. TRAEs were associated with dose reduction (20% vs 29%), delay (17% vs 11%), and discontinua- tion (8% vs 12%) as well.

“It’s important to take 10 steps back and think about dose reductions, dose delays, and dose discontinuations—there were more dose reduc- tions and dose discontinuations in the docetaxel arm. Counterintuitively, there were more dose delays in the Dato-DXd arm. Bottom line is that it seemed like docetaxel was not as well tolerated as Dato-DXd, and that’s important to remem- ber,” Levy explained. “But this trial also did give us a nice snapshot of AEs that we need to be mindful of.”

Moreover, another notable AE that often accom- panies treatment with ADCs is ILD occurring during treatment with T-DXd. In DESTINY- Lung01, any-grade adjudicated drug-related ILD occurred in 20.4% of those given the 6.4-mg/kg dose, with 6.1% of patients experiencing a grade 5 event. Rates were lower in the 5.4-mg/kg dose group, at 4.9% and 2.4%, respectively.

“We need to be vigilant about monitoring for ILD with these ADCs. We see ILD with other ADCs such as TROP2-[directed] ADCs. Be mind- ful of that when you’re seeing these patients—you want to screen [as well as scan patients and] talk to them about some of the symptoms they may have that suggest ILD. If you suspect that, you want to work in a multidisciplinary way. If patients have ILD, you want to suspend the treat- ment and start steroids, [but with] a grade 1 ILD with an ADC the rule is to stop treatment with the ADC. We don’t necessarily stop immunotherapy with a grade 1 ILD, [however], so this is important. The bottom line is that we are witnessing a seismic therapeutic paradigm shift in all patients with lung cancer—clearly targeted therapies and immunotherapies have been a part of that story front and center, and now ADCs are doing the same,” Levy said. 

Articles

Keeping investigators on the edge of their seats, new data from clinical trials evaluating ADCs continue to impress. 

Segmenting the Utility of ADCs in NSCLC: How These Agents Are Affecting Second-Line Standards

As the use of genomic testing becomes increasingly ubiquitous in cancer care across the United States, some patients are experiencing significant out-of-pocket costs due to their insurance coverage. These costs may be affecting oncologists’ decision to administer genetic testing, according to findings from a retrospective analysis published in 

Among oncologists who reported using multimarker tumor panels in the 2017 National Survey of Precision Medicine in Cancer Treatment (n = 1049), 47.3% responded that patients’ insurance coverage was very important regarding the clinician’s treatment decision to recommended genomic testing; 32.7% responded that it was somewhat important, and the remaining 20% said it was of little or no importance. Additionally, 56.9% reported that out-of-pocket costs were very important when deciding whether to recommend genomic testing, with 28.0% and 15.2% responding that they were somewhat important and of little or no importance, respectively.

Notably, 14.3% of clinicians who responded to the survey said they often did not order a multimarker panel test due to lack of patient health insurance coverage, with an additional 36.5% saying they sometimes do not do so and 49.2% reporting they rarely or never do not do so. Similarly, 16.5% of clinicians responded that they often did not order genomic testing due to a patient’s out-of-pocket costs, with 37.6% saying they sometimes do not do so and 45.9% responding that they rarely or never due so due to out-of-pocket costs.

“In cancer, genetic testing is often looking for specific genetic pathogenic variants in a patient’s blood, often inherited from a parent,” Susan D. Klugman, MD, director of reproductive and medical genetics, program director of medical genetics and genomics at Montefiore Einstein, and professor of obstetrics and gynecology and women’s health at Albert Einstein College of Medicine in Bronx, New York, said in an email to 

. “Genomic testing is typically used in reference to the molecular composition of the patient’s tumor. All tumors have genetic changes that allow them to grow. Both germline and somatic testing can be used to personalize care for individual patients, including surveillance, medication, and surgical management.”

To conduct their study, investigators identified practicing clinicians who participated in the 2017 National Survey of Precision Medicine in Cancer Treatment, which was sponsored by the National Cancer Institute, the National Human Genome Research Institute, and the American Cancer Society. The survey was nationally representative and genomic tests were defined as single-gene tests for chromosomal mutations and multimarker tumor panel testing for multiple genes assessed for mutations, alterations, or expression that may provide clinically actionable information. Only tests for tumor tissue were considered, not those used for germline or inherited cancer predisposition.

Overall, the survey cooperation rate was 38% and only clinicians who reported using multimarker tumor panel testing in the past 12 months were included in the retrospective analysis. The main outcomes of the study were clinician’s ratings of the importance of patient health insurance coverage and out-of-pocket costs for genomic testing in treatment recommendations. The secondary outcome was the clinician’s ratings of the importance of insurance coverage and out-of-pocket costs in decisions not to order a multimarker tumor panel.

The primary outcome was centered around a survey question which asked clinicians how important it was that a test be covered by patient’s insurance and how important patient out-of-pocket expenses for testing were in terms of their decision to use multimarker tumor panels to make treatment decisions over the past 12 months. The secondary outcome was based on a survey question which asked clinicians how often they decided not to order a multimarker panel for a patient with cancer over the past 12 months due to the test not being covered by a patient’s insurance or due to out-of-pocket costs that were too expensive for the patient.

At baseline, clinicians included in the retrospective study were mostly White (62.3%), men (66.6%), specialized in hematologic and solid tumors (64.8%), spent more than 75% of their time providing patient care (69.1%), had formal training in genomic testing (59.3%), and used next-generation sequencing (NGS) gene panel tests (90.4%). In terms of practice characteristics, the study included single specialty (43.5%), multispecialty (43.9%), and other (12.6%) types; 50.5% had a patient volume of 1 to 99 per month; and the remaining 49.5% had a volume of at least 100 per month. Internal policies or protocols for genomic tests (48.8%), electronic medical record alerts for genomic tests (17.9%), genomic and/or molecular tumor boards for genomic tests (38.1%), and at least 10% of patients being insured by Medicaid or self-pay/uninsured (73.9%) were all reported to varying degrees.

Additional findings from the study showed that clinicians who used NGS gene panel tests were more likely to respond that patient insurance status (OR, 2.00; 95% CI, 1.16-3.45) and out-of-pocket costs (OR, 2.12; 95% CI, 1.22-3.68) were important in treatment decisions related to genomic testing vs those who did not use NGS tests. Moreover, clinicians who worked in practices with at least 10% of patients insured by Medicaid or self-pay/uninsured were more likely to report insurance status (OR, 1.43; 95% CI, 1.09-1.89) and out-of-pocket costs (OR, 1.51; 95% CI, 1.13-2.01) as important factors in recommending genomic testing vs those who were at practices with less than 10% of patients of this insurance status. Clinicians working in practices with molecular tumor boards for genomic tests were less likely to report insurance status (OR, 0.63; 95% CI, 0.47- 0.85) and out-of-pocket costs (OR, 0.72; 95% CI, 0.53-0.97) as important factors in recommending genomic testing compared with those in practices without tumor boards.

Study authors concluded that “understanding oncologist perceptions of the importance of patient health insurance coverage and out-of-pocket costs and associated factors is central for developing and targeting interventions to ensure fully informed decision-making about cancer treatments.” They noted that clinician- and practice-level interventions that could address the negative impact from insurance status and out-ofpocket costs on the incidence of genomic testing include the continued gathering of general experience by clinicians, medical school curricula including training related to oncology care affordability, and increased oncology workforce diversity.

“The 2013 Supreme Court case, AMP vs Myriad Genetics, opened the door to other laboratories being able to offer 

testing and thus prices dropped dramatically,” Klugman noted in conclusion. “[Additionally], many labs have compassionate care programs [aimed at mitigating high prices].”

Yabroff KR, Sylvia Shi K, Zhao J, et al. Importance of patient health insurance coverage and out-of-pocket costs for genomic testing in oncologists’ treatment decisions. 

 Published online January 9, 2024. doi:10.1200/OP.23.00153

As genomic testing becomes ubiquitous in cancer care, some patients experience out-of-pocket costs that may affect oncologists’ genetic testing decisions. 

Patient Insurance Status and Out-of-Pocket Costs Affect Genomic Testing Frequency

The International Federation of Gynecology and Obstetrics (FIGO) system characterizes endometrial cancer by grade and stage. Surgery is the main treatment, with chemotherapy or radiation therapy based on stage, patient characteristics, and histology. Modern molecular analysis has further stratified endometrial carcinomas. Loss of mismatch repair (MMR) proteins (MLH1, MSH2, PMS1, or MSH6) results in high microsatellite instability (MSI-H), a hallmark of Lynch syndrome.

MMR deficient (dMMR) tumors may express PD-L1, which is the cell surface activator of the PD-1 receptor protein. When PD-1 receptors on the surface of T cells bind the PD-L1 ligand on the tumor cell, the tumor cell turns off the killing function of the T cell. However, the killing action of the T-cell–specific response can be reactivated by blocking the PD-L1 protein, or by preventing tumor cell binding at the PD-1 receptor. Immune checkpoint inhibitors (ICI), such as pembrolizumab (Keytruda) and dostarlimab-gxly (Jemperli), include high affinity, high specificity, and humanized monoclonal antibodies to the PD-1 receptor, preventing inactivation of the T cells.

Immunotherapy in Advanced-Stage Endometrial Cancer

According to research results published in several journals, approximately 48% of endometrial carcinomas display PD-L1 positivity, and approximately 25% to 31% are dMMR.

 In those tumors, the PD-1 inhibitor pembrolizumab was initially studied in the multicohort phase 1 KEYNOTE-028 trial (NCT02054806).

 This study enrolled 24 patients with advanced-stage, progressive endometrial cancer. PD-L1 expression was determined by immunohistochemistry with 1% positivity in tumor and immune cells denoted as positive. The objective response rate (ORR) by RECIST v1.1 criteria was 13% (95% CI, 2.8%-33.6%) in response-evaluable patients (n = 23). Three patients had partial responses (PR), 3 had stable disease (SD), and 13 experienced progressive disease.

The phase 2 KEYNOTE-158 study (NCT02628067) investigated pembrolizumab in patients with dMMR or MSI-H advanced solid tumors, including endometrial cancer. Ninety patients with dMMR/MSI-H endometrial cancer were enrolled and received pembrolizumab monotherapy on a 3-week cycle for 35 cycles. Of these patients, 48% had received at least 2 prior lines of therapy, and 68% had received prior radiation. The efficacy analysis was conducted in 79 patients who had received at least 1 dose of pembrolizumab at least 26 weeks prior to data cutoff. An ORR of 48% (95% CI, 37%-60%) was observed, including 11 patients with complete responses, 27 with PRs, and 14 with SD.

 Treatment tolerance was fair, with grade 3 to 4 adverse effects (AEs) reported in 12% of patients in the safety population (n = 90).

Combining immunotherapy with chemotherapy was the next step. Results of 2 blockbuster trials were published simultaneously in 

 In a phase 3 study (NCT03914612), investigators combined pembrolizumab with carboplatin and paclitaxel in all endometrial carcinoma histologies except carcinosarcomas. The randomized, double-blind, placebo-controlled study enrolled 816 patients with stage III to IVB or recurrent endometrial carcinoma. The primary end point was progression-free survival (PFS) and patients were stratified by dMMR or pMMR (MMR proficient) status.

A significant PFS advantage was observed in the patients with dMMR disease who received pembrolizumab (n = 112) vs placebo (n = 113); the 12-month PFS rates were 74% vs 38%, respectively. The PFS HR was 0.30 (95% CI 0.19-0.48, 

 < .001) in favor of pembrolizumab in the dMMR cohort. Interestingly, in the pMMR cohort, the median PFS also favored pembrolizumab at 13.1 months (95% CI, 10.5-18.8) vs 8.7 months (95% CI, 8.4-10.7) in the placebo arm (HR 0.54; 95% CI, 0.41- 0.71; 

In the phase 3 RUBY trial (NCT03981796), dostarlimab was combined with carboplatin and paclitaxel. The study enrolled patients with recurrent or primary advanced endometrial cancer; carcinosarcomas and other histologies were allowed, and OS was assessed in addition to PFS.7 RUBY was a randomized, placebo-controlled, double-blind study of 494 patients; 23.9% had dMMR/MSI-H disease. In the dMMR/MSI-H cohort, PFS rate at 24 months favored the dostarlimab arm (n = 53) at 61.4% (95% CI, 46.3%-73.4%) vs 15.7% (95% CI, 7.2%-27.0%) in the placebo arm (n = 65; HR, 0.28; 95% CI, 0.16-0.50; 

 < .001). When patients with pMMR and dMMR disease were both included, the 24-month PFS rate still favored the dostarlimab arm (n = 245) at 36.1% (95% CI, 29.3%-42.9%) vs 18.1% (95% CI, 13.0%-23.9%) in the placebo arm (n = 249; HR, 0.64; 95% CI, 0.51-0.80; 

 OS rates assessed at 24 months mirrored the PFS rates, favoring dostarlimab at 71.3% (95% CI, 64.5%-77.1%) vs 56.0% (95% CI, 48.9%-62.5%) for placebo (HR, 0.64; 95% CI, 0.46-0.87; P = .0021). Therapy with dostarlimab or placebo was given every 6 weeks for up to 3 years.

Based on findings from the RUBY trial, the FDA approved dostarlimab in combination with carboplatin and paclitaxel followed by single-agent dostarlimab in advanced or recurrent dMMR or MSI-H endometrial carcinomas.

 Pembrolizumab had previously received FDA approval in March 2022 for use in recurrent endometrial carcinomas that were dMMR/MSI-H.

Immunotherapy in Recurrent Endometrial Cancer

The use of ICIs in pMMR/microsatellite stable (MSS) endometrial carcinomas has also been investigated in recurrent endometrial cancer. The VEGF angiogenesis pathway is an important target for the modulation of T-cell immune response through tyrosine kinase inhibitors such as lenvatinib (Lenvima). The combination of lenvatinib and pembrolizumab was superior to lenvatinib alone in preclinical models, leading to a phase 1b/2 KEYNOTE-146/Study 111 trial (NCT02501096) in advanced solid tumors.

This trial included 23 patients with endometrial carcinoma, with 48% percent receiving previous systemic therapy in the metastatic setting. Fifty-two percent of the endometrial cancers were PD-L1 positive. Findings from the phase 2 expansion portion demonstrated that the ORR among all patients in the endometrial cancer cohort was 52% (95% CI, 30.6%-73.2%). The median PFS was 9.7 months (95% CI, 4.2-not estimable [NE]). This trial did not specifically test for dMMR or MSI-H status but inferred a potential use in pMMR/MSS tumors from a previous observation that only 25% to 35% of endometrial cancers are dMMR/MSI-H.

Subsequent findings from the final primary efficacy analysis of the endometrial cancer cohort (n = 108) were stratified by MSI-H/dMMR (n = 11) or MSS/pMMR (n = 94) status. At the median follow-up of 18.7 months (95% CI, 13.1-20.3), the ORR was 63.6% (95% CI, 30.8%-89.1%) in patients with MSI-H tumors and 36.2% (95% CI, 26.5%- 46.7%) in those with MSS tumors. The combined group median duration of response was 21.2 months (95% CI, 7.6-NE), the median PFS was 7.4 months (95% CI, 5.3-8.7), and the median OS was 16.7 months (95% CI, 15-NE). The combination had a 66.9% rate of grade 3 or 4 AEs but displayed a generally manageable toxicity profile.

In the phase 3 KEYNOTE-775 trial (NCT03517449), patients with platinum-resistant endometrial cancer were randomly assigned to receive pembrolizumab plus lenvatinib or chemotherapy (doxorubicin or weekly paclitaxel). The 827 patients included 697 with pMMR/MSS disease and 130 with dMMR/MSI-H disease, equally divided between 2 arms. Both PFS and OS favored the combination of pembrolizumab and lenvatinib in the overall trial population; the median PFS was 7.2 months (95% CI, 5.7-7.6) vs 3.8 months (95% CI, 3.6-4.2), respectively (HR 0.56; 95% CI, 0.47-0.66; 

 < .001) and the median OS was 18.3 months (95% CI, 15.2-20.5) vs 11.4 months (95% CI, 10.5-12.9), respectively (HR, 0.62; 95% CI, 0.51-0.75; 

In the majority pMMR/MSS group, the results held with both PFS and OS favoring pembrolizumab plus lenvatinib over chemotherapy. pMMR PFS was 6.6 months (95% CI, 5.6-7.4) vs 3.8 months (95% CI, 3.6-5.0), respectively (HR, 0.60; 95% CI, 0.50-0.72; 

 < .001) and pMMR OS was 17.4 months (95% CI, 14.2-19.9) vs 12.0 months (95% CI, 10.8-13.3), respectively (HR, 0.68; 95% CI, 0.56-0.84; 

Based upon results of this trial, the FDA approved the combination of pembrolizumab and lenvatinib in patients with pMMR endometrial cancer with progressive disease who are not candidates for radiation or surgery.

Berek JS, Matias-Guiu X, Creutzberg C, et al; Endometrial Cancer Staging Subcommittee, FIGO Women’s Cancer Committee. FIGO staging of endometrial cancer: 2023. 

. 2023;162(2):383-394. doi:10.1002/ijgo.14923

Ott PA, Bang Y-J, Berton-Rigaud D, et al. Safety and antitumor activity of pembrolizumab in advanced programmed death ligand-1 positive endometrial cancer: results from the KEYNOTE-028 study. 

. 2017;35(22):2535-2541. doi:10.1200/JCO.2017.72.5952

Ryan NAJ, Glaire MA, Blake D, Cabrera-Dandy M, Evans DG, Crosbie EJ. The proportion of endometrial cancer associated with Lynch syndrome: a systematic review of the literature and meta-analysis. 

. 2019;21(10):2167-2180. doi:10.1038/s41436-019-0536-8

Bonneville R, Krook MA, Kautto EA, et al. Landscape of microsatellite instability across 39 cancer types. 

. 2017;2017:PO.17.00073. doi:10.1200/PO.17.00073

O’Malley DM, Bariani GM, Cassier PA, et al. Pembrolizumab in patients with microsatellite instability-high advanced endometrial cancer: results from the KEYNOTE-158 study. 

. 2022;40(7):752-761. doi:10.1200/JCO.21.01874

Eskander RN, Sill MW, Beffa L, et al. Pembrolizumab plus chemotherapy in advanced endometrial cancer. 

. 2023;388(23):2159-2170. doi:10.1056/NEJMoa2302312

Mirza MR, Chase DM, Slomovitz BM, et al; RUBY Investigators. Dostarlimab for primary advanced or recurrent endometrial cancer. 

. 2023;388(23):2145-2158. doi:10.1056/NEJMoa2216334

FDA grants regular approval to dostarlimab-gxly for dMMR endometrial cancer. FDA. February 9, 2023. Accessed January 31, 2024. 

FDA approves pembrolizumab for advanced endometrial carcinoma 2022. FDA. March 21, 2022. Accessed January 31, 2024. 

Taylor MH, Lee CH, Makker V, et al. Phase Ib/II trial of lenvatinib plus pembrolizumab in patients with advanced renal cell carcinoma, endometrial cancer, and other selected advanced solid tumors. 

. 2020;38(11):1154-1163. doi:10.1200/JCO.19.01598

Makker V, Taylor MH, Aghajanian C, et al. Lenvatinib plus pembrolizumab in patients with advanced endometrial cancer. 

. 2020;38(26):2981-2992. doi:10.1200/JCO.19.02627

Makker V, Colombo N, Casado Herráez A, et al; Study 309–KEYNOTE-775 Investigators. Lenvatinib plus pembrolizumab for advanced endometrial cancer. 

. 2022;386(5):437-448. doi:10.1056/NEJMoa2108330

FDA grants regular approval to pembrolizumab and lenvatinib for advanced endometrial carcinoma. FDA. Updated February 1, 2022. Accessed January 31, 2024. 

The incorporation of immune checkpoint inhibitors has altered the treatment paradigm for endometrial cancer.

Immune Checkpoint Inhibitors Revolutionize Endometrial Cancer Treatment

IL-15, a cytokine of the IL-2 family, is key in the development, proliferation, and activation of immune cells such as natural killer (NK) cells, making it an intriguing target, and the inflammatory cytokine has also been shown to stimulate the expression of immune checkpoint molecules, including PD-1 and PD-L1.

 A unique function of IL-15 is that it promotes the maintenance of not only NK cells but CD8+CD44hi memory T cells, thus providing a long-term immune response to pathogens (

The fusion protein SAR445877, which combines a human anti–PD-1 antibody with a mutated fusion of human IL-15 and human IL-15Rα Sushi domain, is currently one of many IL-15 targeted agents under evaluation in early phase studies.

When discussing the development of phase 1 studies to evaluate agents with different targets and mechanisms of action than previously seen, Martin E. Gutierrez, MD, told 

 that “phase 1 clinical trials tend to be rather complex. Historically, they were complex because of the intensity of pharmacokinetic [PK] and plasma volume analyses, but now [it’s because] we intend to introduce efficiency into the drug development [process], which we have, and the FDA has supported that. The complexity of the study design is also [something we] must pay attention to because there are multiple arms and multiple expansions.”

He added that “historically, what used to be a small 50- to 60-patient study has now become a few 100-patient study, interrogating multiple questions during the same protocol. What we do is incredibly important because, [through] this adaptative design, the time line on drug development can significantly improve over time, allowing patients access to these drugs faster.”

Gutierrez is the director of the Drug Discovery/Phase I Program and cochief of thoracic oncology at John Theurer Cancer Center, and a professor in the Department of Oncology at Hackensack Meridian School of Medicine in New Jersey. He is also an associate member of the Thoracic and Gastrointestinal Oncology Program, cochair of the Phase I Diseases Group, and cochair of the Protocol Review and Monitoring Committee at the Georgetown Lombardi Cancer Center in Washington, DC.

Targeting IL-15 With PD-1 in First-in-Human Study

SAR445877 is a fusion protein of high-affinity PD-1 antibody combined with a detuned IL-15. Gutierrez explained that the agent binds to “PD-1–expressing T cells and NK cells, [which] allows the activation of the CD8+ [T cells] and NK cells expressing PD-1 and IL-2/-15[Rβγ].”

“The uniqueness of the IL-15 component combined with PD-L1 is very important,” Gutierrez noted. “Secondly, we have seen some early signals already in some of the not necessarily inflamed tumors, which is very hypothesis generating. But again, we are still early in the process.”

Preclinical data revealed that SAR445877 exhibited increased cytotoxic immune cell recruitment to the tumor microenvironment as well as prolonged survival and tumor clearance, leading to a first-in-human phase 1/2 trial (NCT05584670).

 The study is currently enrolling patients with advanced unresectable or metastatic solid tumors to be treated with the anti–PD-1/IL-15 fusion protein in the dose-escalation portion, where the agent will be administered intravenously in 14-day cycles and the maximum tolerated dose (MTD) will be determined. Primary end points encompass safety as well as dose-limiting toxicities (DLTs) in the first 2 cycles.

“This is a typical phase 1 dose-escalation study with multiple histologies included. Most of what we consider, in some degree, [to be] inflamed tumors—such as lung cancer and melanoma—but also noninflamed tumor cells—such as microsatellite stable colorectal cancer—[are included]. There’s a wide variety of diseases that can be enrolled,” Gutierrez said.

Enrollment criteria for the trial varies for the escalation and expansion portions. Four cohorts will be open in the expansion, including cohort D, a biomarkers cohort in infiltrated tumor types.

 Patients with histologically or cytologically confirmed metastatic non–small cell lung cancer (cohort A), advanced unresectable or metastatic hepatocellular carcinoma (cohort B), and advanced unresectable or metastatic gastric cancer or gastroesophageal junction adenocarcinoma (cohort C) will also be enrolled. Those in cohort C must have a combined positive score of less than 1, nonmicrosatellite instability–high or mismatch repair–proficient disease, and tumors must be HER2/neu negative or positive with HER2/neu status determined locally. Those with HER2/neu-positive tumors must have experienced disease progression on HER2-targeted therapy.

The open-label, multicenter trial’s dose-expansion portion has a primary end point of objective response rate, with secondary end points of time to response, clinical benefit rate, progression-free survival, and safety. Both portions of the study are aiming to evaluate duration of response (DOR), PK, and incidence of antidrug antibodies.

“We’re still in the process of a dose escalation, so we will be finding the DLTs and defining the MTD. With any checkpoint inhibitors, immune-mediated adverse effects [AEs] are important, and we continue to watch them. Some of the bispecific [agents] also can have certain associated cytokine release syndrome, which we have to watch,” Gutierrez explained.

N-803 (Anktiva) is a mutant IL-15–based immunostimulatory fusion protein complex that promotes proliferation and activation of NK cells and CD8+ T cells, but not regulatory T cells.

 The QUILT studies have evaluated the first-in-class IL-15 superagonist in several tumor types, with phase 3 studies active in bladder and lung cancers.

In October 2023, the FDA accepted the resubmission of the biologics license application (BLA) seeking the approval of N-803 in combination with BCG for the treatment of patients with BCG-unresponsive, non–muscle-invasive bladder cancer (NMIBC) with carcinoma in situ with or without Ta or T1 disease. The target action date under the Prescription Drug User Fee Act for the resubmitted BLA is set for April 23, 2024.

In the May 2023 complete response letter issued by the FDA to the initial N-803 BLA, it was noted the BLA could not be approved in its current form due to deficiencies related to the prelicense inspection of the manufacturer’s (ImmunityBio, Inc) third-party contract manufacturing organizations. The FDA also provided recommendations regarding additional Chemistry Manufacturing and Controls issues and assays that must be resolved.

Data from the phase 2/3 QUILT-3.032 trial (NCT03022825) which showed clinically meaningful efficacy results supported the N-803 BLA and the final results of the trial were presented at the 2022 American Society of Clinical Oncology Annual Meeting. The complete response rate among patients with BCG-unresponsive NMIBC with carcinoma in situ treated with BCG plus N-803 (n = 82) was 71% (95% CI, 59.6%-80.3%), and the median DOR was 26.6 months (95% CI, 9.9-not reached).

The safety profile of the combination was tolerable, and investigators noted it was comparable to BCG alone; there were no treatment-related grade 4 or 5 AEs or immune-related serious AEs. Further, 1% of patients experienced treatment-related serious AEs, and treatment-related discontinuation occurred in 2% of patients.

Additional IL-15 targeted agents under investigation include SOT201, NKTR-255, and NIZ985, among others (

). SOT201, an immunocytokine fusing a proprietary IL-15 superagonist to an anti–PD-1 antibody, which its manufacturer notes is to directly target T cells, is under investigation in a phase 1 study (NCT06163391). The trial evaluating one of the first IL-15/PD-1–targeting immunocytokines is currently enrolling adult patients with advanced unresectable or metastatic solid tumors.

Additionally, NKTR-255, a novel polyethylene glycol conjugate of recombinant human IL-15, demonstrated promising preclinical activity, supporting the first-in-human phase 1 trial (NCT04136756) of the agent in patients with relapsed or refractory hematologic malignancies.

Finally, NIZ985, which is a recombinant heterodimer of IL-15 and IL-15Rα, was well tolerated as a single agent and in combination with spartalizumab in dose-escalation (n = 47 and n = 20, respectively) and dose-expansion (n = 36, overall) portions of a phase 1/1b trial (NCT02452268). No DLTs occurred, and the recommended dose for expansion was determined as 1 µg/kg 3 times per week. In the doublet arm, 5% of patients achieved a partial response which included 3 patients with melanoma, pancreatic cancer, and gastric cancer. In the monotherapy arm, 30% of patients experienced stable disease, which was the best response.

“Immunotherapy, specifically PD-1 and PD-L1 checkpoint inhibitors, has transformed the oncology treatment landscape. But even with the excellent responses, some of them have [demonstrated] in certain histologies and diseases we treat that there is still a large percentage of patients who will relapse or are refractory to [immunotherapy],” Gutierrez said. “Bispecific antibodies such as [SAR445877, which targets IL-15 among others], will fill that unmet need in the population.”

Cai M, Huang X, Huang X, Ju D, Zhu YZ, Ye L. Research progress of interleukin-15 in cancer immunotherapy. 

. 2023;14:1184703. doi:10.3389/fphar.2023.1184703

Awad RM, De Vlaeminck Y, Meeus F, et al. In vitro modelling of local gene therapy with IL-15/IL-15Rα and a PD-L1 antagonist in melanoma reveals an interplay between NK cells and CD4+ T cells. 

. 2023;13(1):18995. doi:10.1038/s41598-023-45948-w

Waldmann TA. The shared and contrasting roles of IL2 and IL15 in the life and death of normal and neoplastic lymphocytes: implications for cancer therapy. 

. 2015;3(3):219-227. doi:10.1158/2326-6066.CIR-15-0009

Bernardo M, Zhang Y, Lu D, et al. Preclinical characterization of SAR445877, an anti-PD-1 antibody-IL-15 mutein fusion protein with robust anti-tumor efficacy as monotherapy and in combination with PD-L1 blockade. 

. 2023;83(suppl 7):2972. doi:10.1158/1538-7445.AM2023-2972

Gutierrez M, Garralda E, Calvo E, et al. A phase 1/2, open label, first-in-human, dose escalation and expansion study of SAR445877 administered as monotherapy in adults with advanced solid tumors.

. 2023;11(suppl 1):779. doi:10.1136/jitc-2023-SITC2023.0779

A first-in-human, dose escalation and dose expansion study of SAR445877 in adult participants with advanced solid tumors. ClinicalTrials.gov. Updated February 26, 2024. Accessed February 26, 2024. https://clinicaltrials.gov/study/NCT05584670

Gutierrez M, Garralda E, Calvo E, et al. A phase I/II, open label, first-in-human, dose escalation and expansion study of SAR445877 administered as monotherapy in adults with advanced solid tumors. 

. 2023;34(suppl 2):S646-S647. doi:10.1016/j.annonc.2023.09.2213

Chamie K, Chang SS, Gonzalgo M, et al. Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC). 

. 2022;40(suppl 16):4508. doi:10.1200/JCO.2022.40.16_suppl.4508

ImmunityBio pipeline. ImmunityBio. Accessed February 26, 2024. https://immunitybio.com/pipeline/

FDA accepts ImmunityBio’s BLA resubmission as complete and sets new PDUFA date. News release. ImmunityBio. October 26, 2023. Accessed February 26, 2024. bit.ly/3UU2fbf

Form 8-K. United States Securities and Exchange Commission. May 9, 2023. Accessed February 26, 2023. bit.ly/4bTX2GG

IL-15 superagonist SOT201 immunocytokine. Sotio. Accessed February 26, 2024. bit.ly/3OZo85k

A study to assess safety and efficacy of SOT201 in patients with advanced/metastatic cancer. Updated December 11, 2023. Accessed February 26, 2024. https://classic.clinicaltrials.gov/ct2/show/NCT06163391

Miyazaki T, Maiti M, Hennessy M, et al. NKTR-255, a novel polymer-conjugated rhIL-15 with potent antitumor efficacy. 

. 2021;9(5):e002024. doi:10.1136/jitc-2020-002024

Leidner R, Conlon K, McNeel DG, et al. First-in-human phase I/Ib study of NIZ985, a recombinant heterodimer of IL-15 and IL-15Rα, as a single agent and in combination with spartalizumab in patients with advanced and metastatic solid tumors. 

. 2023;11(10):e007725. doi:10.1136/jitc-2023-007725

Pathways

A deep dive into IL-15 targeted agents including N-803, those in the pipeline, and the fusion protein SAR445877 which Martin E. Gutierrez, MD, sheds light on.

All Eyes Are on IL-15 in Early Phase Studies 

Hepatocellular carcinoma (HCC) is the sixth most common malignancy and the fourth leading cause of global cancer-related mortality.

 Despite its prevalence, many patients historically have faced a poor prognosis and a lack of effective treatment options beyond surgery. However, that is beginning to change with the development of new therapeutic approaches.

During a recent OncLive Peer Exchange, a panel of oncologists discussed updated findings from key clinical trials presented during the 2024 American Society of Clinical Oncology Gastrointestinal Cancers Symposium (ASCO GI), which was held in January. They highlighted key data across the spectrum of HCC management, the use of frontline systemic treatment for advanced HCC, and sequencing considerations in the second line and beyond.

The panel started by reviewing updates on initial treatment options for patients with HCC. For patients with HCC who are eligible for embolization, the standard of care is transarterial chemoembolization (TACE). However, the median progression-free survival (PFS) for patients following TACE is only 7 to 8 months, underscoring the need for more effective therapies for patients with embolization-eligible HCC. Additionally, due to the heterogeneity of HCC in terms of tumor burden, liver function, and comorbidities, the efficacy of TACE can vary greatly.

During ASCO GI, investigators presented findings from the phase 3 EMERALD-1 trial (NCT03778957), which evaluated TACE plus durvalumab (Imfinzi) with or without bevacizumab (Avastin) in patients with embolization- eligible, unresectable HCC. Patients were randomly assigned 1:1:1 to receive durvalumab, bevacizumab, and TACE (n = 204); durvalumab plus TACE (n = 207); or placebo plus TACE (n = 205). The primary end point was PFS for the durvalumab, bevacizumab, and TACE arm vs the placebo plus TACE arm. Secondary end points included PFS for durvalumab plus TACE vs TACE alone, overall survival (OS), objective response rate (ORR), time to progression (TTP), and safety.

“[These data from] ASCO GI showed us that there is probably a new era in terms of multimodality approaches and integrating our liver-directed approaches with systemic therapy as it gets better and better,” Rachna T. Shroff, MD, MS, FASCO, said. “The short story is that there were not necessarily any positive trials in this space leading up to EMERALD-1 and that’s why it made such a splash.”

At the final PFS analysis, the median PFS was 15.0 months (95% CI, 11.1-18.9) in the durvalumab, bevacizumab, and TACE arm vs 8.2 months (95% CI, 6.9-11.1) with placebo plus TACE (HR, 0.77; 95% CI, 0.61-0.98; 

 = .032). The 12- and 18-month PFS rates were 55.5% and 43.1% with durvalumab and bevacizumab vs 39.8% and 28.3%, respectively, with TACE alone. 

Additionally, the median TTP was 22.0 months (95% CI, 16.6-24.9) vs 10.0 months (95% CI, 7.1-13.6) in the durvalumab and bevacizumab arm vs the placebo arm, respectively (HR, 0.63; EL-95% CI, 0.48-0.82). The confirmed ORR was 43.6% vs 29.6%, respectively (OR, 1.87; 95% CI, 1.24- 2.84), including complete response (CR) rates of 3.0% vs 2.5%. 

However, the durvalumab plus TACE arm did not display a significant benefit in terms of PFS vs the placebo arm; the median PFS was 10.0 months (95% CI, 9.0-12.7) compared with 8.2 months (95% CI, 6.9-11.1), respectively (HR, 0.94; 95% CI, 0.75-1.19; P = .638). The median TTP in the durvalumab plus TACE arm was 11.5 months (95% CI, 9.2-13.9), and the confirmed ORR was 41.0% with a 1.5% CR rate.

“This [trial] is potentially practice-changing, [however], we’re not sure how to extrapolate this with institutions that tend to use more transarterial radioembolization [TARE] than TACE in terms of how we can combine the systemic approach with that approach,” Jun Gong, MD, said. “[Additionally], the durvalumab plus TACE arm didn’t do better than placebo plus TACE, which raises the [question of] whether there is a VEGF benefit. There have been a lot of negative trials with VEGF inhibition plus local regional therapy, so I wonder if the addition of VEGF inhibition is important for modulating the immunotherapy component with local regional therapy and that’s why this combination did better.” 

Study authors concluded that EMERALD-1 met its primary end point and noted that it was the first global phase 3 trial to display a significant and clinically meaningful PFS benefit with immunotherapy plus TACE in this population of patients with HCC. They concluded that the regimen could potentially represent a new standard of care in unresectable HCC eligible for embolization.

“We also are waiting to see a lot more details in relation to the tumor burden of these patients— what was it exactly and is there a specific subgroup that had more benefit than others, [etc]. It’s also unclear if we would get the same outcome if we did TACE followed [immediately] by systemic therapy rather than delayed systemic therapy. But as a proof of concept, that an effective immunotherapy combination could be combined with liver-directed therapy and potentially could be beneficial, that’s what we’ve learned from EMERALD-1. How we incorporate it into practice is going to have to evolve with more data,” Anthony B. El-Khoueiry, MD, added. 

The panel also briefly discussed findings from the phase 2 REPLACEMENT study (jRCTs071200051), which were presented during the 2023 ASCO Annual Meeting. 

REPLACEMENT was a trial in Japan that evaluated the combination of atezolizumab (Tecentriq) plus bevacizumab in patients with intermediate-stage HCC who were eligible for TACE. The primary end point was PFS; secondary end points included ORR, OS, duration of response, and safety.

At the August 15, 2022, data cutoff, patients who received the combination (n = 74) had achieved a median PFS of 9.1 months (95% CI, 7.1-10.2) with a 6-month PFS rate of 66.8% (95% CI, 54.7%-76.4%) and a median OS of not reached (NR; 95% CI, NR-NR) with a 6-month OS rate of 94.5% (95% CI, 86.0%-97.9%). The ORR by HCC mRECIST was 45.9% (95% CI, 34.3%-57.9%), including a CR rate of 16.2%. 

“[Investigators] used an existing control group of patients who received TACE [with] propensity matching for those patients,” Michael Morse, MD, MHS, FACP, said. “It was interesting in that if you do that comparison, PFS was better with systemic therapy and the response rate was better. The OS hadn’t been reached with this early data, but it certainly suggests that patients who are not ideal candidates for local regional therapy like TACE certainly could benefit quite a bit from the systemic therapy with atezolizumab plus bevacizumab.”

Frontline Systemic Therapy for Advanced HCC 

The panelists opened their conversation on frontline therapy in the advanced setting by discussing the regimen most recently approved by the FDA, tremelimumab (Imjudo) plus durvalumab. The combination was approved for the treatment of adult patients with unresectable HCC on October 21, 2022.

The approval was supported by findings from the phase 3 HIMALAYA trial (NCT03298451), which compared the safety and efficacy of the STRIDE regimen (single tremelimumab regular interval durvalumab) with sorafenib (Nexavar) in patients with unresectable HCC who had no prior systemic therapies. The primary end point was OS; secondary end points included PFS, TTP, ORR, and safety.

Updated findings from HIMALAYA, which were presented during the European Society for Medical Oncology Asia Congress 2023 in December, showed that at a median follow-up of 49.12 months (95% CI, 46.95-50.17) in the STRIDE arm (n = 393) and 47.31 months (95% CI, 45.08- 49.15) in the sorafenib arm (n = 389), treatment with STRIDE led to a 22% reduction in the risk of death compared with sorafenib (HR, 0.78; 95% CI, 0.67-0.92). The 36-month OS rates were 30.7% (95% CI, 26.1%-35.3%) vs 19.8% (95% CI, 15.9%- 24.1%), respectively, and the 48-month OS rates were 25.2% (95% CI, 20.8%-29.7%) vs 15.1% (95% CI, 11.5%-19.2%), respectively. 

The panelists then discussed the current role of atezolizumab plus bevacizumab, which is considered the standard of care in frontline unresectable HCC. On May 29, 2020, atezolizumab plus bevacizumab was approved by the FDA for the frontline treatment of patients with unresectable or metastatic HCC based on findings from the phase 3 IMbrave150 trial (NCT03434379).

IMbrave150 randomly assigned patients 2:1 to receive atezolizumab plus bevacizumab (n = 336) or sorafenib (n = 165); the coprimary end points were OS and PFS. The median OS was NR in the combination arm compared with 13.2 months (95% CI, 10.4-not estimable) in the sorafenib arm (HR, 0.58; 95% CI, 0.42-0.79; P = .0006). The estimated median PFS was 6.8 months (95% CI, 5.8-8.3) vs 4.3 months (95% CI, 4.0-5.6), respectively (HR, 0.59; 95% CI, 0.47-0.76; P < .0001). 

“I believe both of those regimens are viable in the frontline space considering the different populations that went on both studies, which might [also] explain why we’ve seen different median OS between the two studies,” Anwaar Saeed, MD, said. “But in real-world practice, the patients that I would avoid using durvalumab/ tremelimumab in would be those [who] have issues with getting a timely esophagogastroduodenoscopy [EGD] to rule out high-risk viruses, variceal bleeding, and other issues. That’s a big issue in busy clinical practices in the community as well as in some of the larger cancer centers where the endoscopy suites are busy with a high volume of patients. [We know] getting a timely EGD for a patient who needs to start therapy is important.” 

During ASCO GI, investigators presented findings from a retrospective observational study that examined 374 patients who initiated first-line therapy with atezolizumab plus bevacizumab between January 2019 and August 2022 within the US Oncology Network. The median real-world OS was 13.2 months (95% CI, 9.5-15.9) and the median real-world PFS was 6.4 months (95% CI, 5.1-7.7). The estimated 6- and 12-month real-world PFS rates were 52.2% (95% CI, 46.7%-57.5%) and 33.4% (95% CI, 27.8%-39.1%), respectively, and the estimated 6- and 12-month real-world OS rates were 68.6% (95% CI, 63.2%-73.3%) and 53.5% (95% CI, 47.4%-59.2%).

Findings from an exploratory subgroup analysis revealed that patients with Child-Pugh class A (n = 229), B (n = 91), or C (n = 12) disease had a median real-world PFS of 7.3 months (95% CI, 5.4-9.4), 5.7 months (95% CI, 3.1-7.0), and 4.5 months (95% CI, 1.3-9.2), respectively. The median real-world OS in these groups was 16.5 months (95% CI, 12.6-NR), 7.5 months (95% CI, 4.7-9.9), and 4.5 months (95% CI, 1.3-NR), respectively. Investigators noted that outcomes with atezolizumab plus bevacizumab did not differ significantly across etiology and race/ ethnicity subgroups. “In community oncology settings, first-line atezolizumab plus bevacizumab demonstrates effectiveness in diverse patient cohorts, including those with impaired liver function, nonviral liver disease, and racial/ ethnic minorities,” they conclude. 

“For now, the National Comprehensive Cancer Network guidelines place a category 1 [recommendation] for atezolizumab plus bevacizumab [for patients] with Child-Pugh A disease,” Gong said. “This is where the [real-]world evidence really shares some more insight into [outcomes in] the real world. For the most part, the retrospective real-world studies have mirrored the trial data in terms of efficacy and safety, but [this analysis also] provided more insight into [one-fourth] to one-third of the study population that was Child-Pugh B. The OS, not surprisingly, was a little bit inferior to [that of] the Child- Pugh A population. There have been some mixed results [in terms of adverse effects (AEs)], where the AEs may be comparable to [those seen in] the Child-Pugh A population. But this is where some more granularity [could be beneficial]. [Indicating] whether they’re including those with Child-Pugh B 7 vs 8 vs 9 could really separate out who gets the more toxic results with this combination.” 

Added El-Khoueiry, “A prospective trial into Child-Pugh B 7 and 8 populations is launching imminently with atezolizumab plus bevacizumab to provide data in the space. There’s also a trial launching into the Child-Pugh B space with durvalumab and tremelimumab. This is very important that we will have prospective, phase 2 data with these regimens in that space. So currently, we’re using [the combination] cautiously [in the Child-Pugh B population]; we all extrapolate to different extents.”

Options in Second-Line Advanced HCC and Beyond

After treatment with standard-of-care atezolizumab plus bevacizumab, there is no globally established subsequent therapy for patients with unresectable HCC who experience failure with this regimen.8 However, there are multiple regimens under clinical evaluation that have been showing promise for patients with advanced HCC in the second line and beyond. 

During ASCO GI, investigators presented updated findings from the phase 2 REGONEXT study (NCT05134532), which evaluated the safety and efficacy of second-line treatment with the kinase inhibitor regorafenib (Stivarga) in patients with unresectable HCC. Eligible patients had received at least 2 prior cycles of atezolizumab plus bevacizumab, have Child-Pugh A disease, and have an ECOG performance status of 1 or 0. The primary end point was PFS; secondary end points included ORR, OS, and safety. 

At the August 15, 2023, data cutoff, the median PFS among patients who received regorafenib (n = 40) was 3.5 months (95% CI, 3.0-4.0) and the median OS was 9.7 months (95% CI, 8.3-11.1), including a 6-month OS rate of 55.0%. Additionally, the ORR was 10.0% and the disease control rate was 82.5%. Study authors concluded that regorafenib was an effective second-line atezolizumab plus bevacizumab. Results from REGONEXT were consistent with those in the pivotal phase 3 RESORCE trial (NCT01774344), which evaluated the efficacy and safety of regorafenib in patients who had progressed on sorafenib. Based on the results, in April 2017, the FDA approved regorafenib in patients with HCC who previously received sorafenib.

In the phase 3 CELESTIAL trial (NCT01908426), patients were randomly assigned 2:1 to receive either the tyrosine kinase inhibitor cabozantinib (Cabometyx; n = 470) or placebo (n = 237). Eligible patients had received prior treatment with sorafenib and experienced disease progression after at least 1 line of treatment for HCC. Patients were permitted to have received up to 2 previous systemic regimens for advanced HCC. The primary end point was OS; secondary end points included PFS and ORR.

Data from CELESTIAL, which were published in The New England Journal of Medicine in 2018, showed that patients treated with cabozantinib achieved a median OS of 10.2 months (95% CI, 9.1-12.0) vs 8.0 months (95% CI, 6.8-9.4) in patients who received placebo (HR, 0.76; 95% CI, 0.63-0.92; P = .005). Additionally, the median PFS was 5.2 months (95% CI, 4.0-5.5) vs 1.9 months (95% CI, 1.9-1.9), respectively (HR, 0.44; 95% CI, 0.36-0.52; P < .001). 

The FDA approved cabozantinib on January 14, 2019, for patients with HCC who had previously undergone treatment with sorafenib. The approval was supported by findings from CELESTIAL.

 “It’s certainly an exciting time in the HCC space, we’ve gone from just 1 drug [that was available] for a long time, sorafenib, until about 2017, when nivolumab opened the door to immunotherapy in the space. Since then, the field has really exploded,” El-Khoueiry commented. 

“Combinations are really exciting,” Anne Covey, MD, said. “TACE has been the standard local regional therapy worldwide but, at least in this country, it’s shifting toward radioembolization. Two exciting studies for me are going to be [the phase 2] ROWAN trial [NCT05063565], looking at radioembolization plus durvalumab and tremelimumab, and [the phase 2] EMERALD-Y90 trial [NCT06040099], which is going to look at radioembolization with durvalumab and bevacizumab. I’m very excited to see what the future holds.”

Brown ZJ, Tsilimigras DI, Ruff SM, et al. Management of hepatocellular carcinoma: a review. JAMA Surg. 2023;158(4):410-420. doi:10.1001/jamasurg.2022.7989 

Experts discuss updated findings from key clinical trials in hepatocellular carcinoma presented during the 2024 Gastrointestinal Cancers Symposium. 

Vol. 25 No. 5 | Oncology Live®

Segmenting the Utility of ADCs in NSCLC: How These Agents Are Affecting Second-Line Standards

Patient Insurance Status and Out-of-Pocket Costs Affect Genomic Testing Frequency

Immune Checkpoint Inhibitors Revolutionize Endometrial Cancer Treatment

All Eyes Are on IL-15 in Early Phase Studies

ASCO GI Updates Provide Window Into Evolving HCC Treatment Paradigm

Is It Time to Address the Fiscal Reality of the Cancer Care Model and Consider Alternatives?