Investigators Deliver Updates on Evolving Clinical Trials Evaluating ADCs in Lung Cancer

Melissa L. Johnson, MD

As antibody-drug conjugates (ADCs) continue to emerge in the lung cancer paradigm as invaluable therapeutic options for patients, several efforts have been made to improve on the benefits derived from this drug class, such as exploring combination regimens, developing new agents with novel targets, and examining different dose levels to ensure a balance between safety and efficacy.^1-3

In interviews with OncologyLive^®, investigators presented updates from the International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer. They examined the first-in-class B7-H3–directed ADC ifinatamab deruxtecan in patients with refractory small cell lung cancer (SCLC); different doses of fam-trastuzumab deruxtecan-nxki (Enhertu) in those with HER2-mutated non–small cell lung cancer (NSCLC); and the combination of datopotamab deruxtecan (Dato-DXd) with durvalumab (Imfinzi) and carboplatin vs pembrolizumab (Keytruda) and chemotherapy in patients with stage IIIB, IIIC, or IV metastatic NSCLC.

“We’re seeing for the first time [with ifinatamab deruxtecan] that ADCs work—not just in NSCLC, but also in SCLC,” Melissa L. Johnson, MD, said. “We often worry that so many of our breakthrough discoveries happen for patients with NSCLC, so it’s wonderful when things work for SCLC, too. I am optimistic about this agent in this group of patients.”

Johnson, who is the director of lung cancer research at Sarah Cannon Research Institute and chair of the Cancer Committee at TriStar Centennial Medical Center, both in Nashville, Tennessee, discussed ADCs in the lung cancer space along with Terufumi Kato, MD, the chief physician in the Department of Thoracic Oncology at Kanagawa Cancer Center in Yokohama, Japan, and Pasi A. Jänne, MD, PhD. Jänne is the director of the Lowe Center for Thoracic Oncology, director of the Belfer Center for Applied Cancer Science, director of the Chen-Huang Center for EGFR Mutant Lung Cancers, and a senior physician at Dana-Farber Cancer Institute in Boston, Massachusetts. He is also a professor of medicine at Harvard Medical School, Boston, and the 2021^® Giants of Cancer Care award winner in the lung cancer category.

Making Waves in SCLC

The First-in-Class B7-H3–Directed ADC

The novel ADC ifinatamab deruxtecan represents a possibility of filling an unmet need for patients with advanced solid tumors who have overexpression of the immune checkpoint B7-H3, which is associated with disease progression and lower survival rates, according to Johnson.¹

“There is an unmet need for patients in the second line and beyond who have received chemotherapy and immune therapy for SCLC,” she explained. “We know that checkpoint inhibitors don’t work as well for patients with SCLC and while there’s a lot of exciting ongoing [investigations of] novel agents, not everyone will be a candidate for the DLL3 bispecific [agent BI 764532], just as one example, so other targets and therapies are needed.”

A subgroup analysis of the phase 1/2 trial DS7300-A-J101 (NCT04145622) focusing on patients with SCLC (n = 21) demonstrated that those who received ifinatamab deruxtecan achieved a confirmed objective response rate (ORR) of 52.4% (95% CI, 29.8%-74.3%); 4.8% of responses were complete responses (CRs). The median time to response was 1.2 months (95% CI, 1.2-1.4) and the median duration of response was 5.9 months (95% CI, 2.8-7.5). Additionally, 2 patients remain on treatment.

“It’s important to know that ifinatamab deruxtecan is a drug that’s being developed for patients with SCLC, irrespective of B7-H3 expression,” Johnson added. “One of the findings from [the phase 1/2] trial is how well patients with SCLC did.”

In the dose-escalation portion of the study, patients with SCLC (n = 22) were treated at the following doses: 3.2 (n = 1), 6.4 (n = 1), 8.0 (n = 10), 12.0 (n = 8), and 16.0 (n = 2) mg/kg. Patients with other metastatic solid tumors also received doses of 0.8, 1.6, and 4.8 mg/kg, and as 4.8 mg/kg was determined to be the minimum effective dose, the patient with SCLC treated at 3.2 mg/kg was excluded from the efficacy analysis.

“Of the 21 patients who were evaluable for efficacy, all but 1 had some element of disease shrinkage, so this is a highly active agent in this subset [of patients],” Johnson noted. “We also looked at baseline tumor biopsies, looking for B7-H3 expression as an H score [histochemical score] and a composite score, including both membrane as well as cytosol B7-H3 expression; all the patients had some amount of B7-H3 expression although the amount of expression didn’t seem to correlate with clinical efficacy markers.”

When evaluating efficacy parameters by median B7-H3 level in patients (n = 17), the median B7-H3 membrane/cytosol H score at baseline was 115 (range, 10-190). Patients with B7-H3 parameters under the median, (n = 8; H score range, 10-105) experienced an ORR of 62.5% compared with 55.6% for those with parameters that were equal to the median or greater (n = 9; H score range, 115-190). The median progression-free survival (PFS) was 5.8 months (95% CI, 0.7-not applicable [NA]) vs 5.3 months (95% CI, 1.4-NA) and median overall survival (OS) was 12.2 months (95% CI, 5.8-NA) vs 6.9 months (95% CI, 2.8-NA), respectively.

Although the B7-H3 combined membrane/cytosol H score did not correlate with survival outcomes, the correlative relationship between B7-H3 level and clinical efficacy will be evaluated further.

Regarding next steps, Johnson highlighted that “there are ongoing expansion cohorts, [including ones for patients with] squamous esophageal cancer, squamous NSCLC, and gastric cancer. The SCLC effort is being investigated in an ongoing phase 2 trial [NCT05280470] that enrolls patients with extensive-stage SCLC who have had 1 to 3 prior lines of therapy and evaluates ifinatamab deruxtecan in those patients.”

Safety With Ifinatamab Deruxtecan

Patients received treatment with ifinatamab deruxtecan for a median of 3.9 months (range, 0.03-12.5) and all experienced treatment-emergent adverse effects (TEAEs), with 36.4% experiencing a grade 3 or higher effect. TEAEs were associated with drug discontinuation (22.7%), dose delay (13.6%), and dose reduction (13.6%); 1 patient died from a TEAE. Of the 5 patients who discontinued treatment, reasons included grade 1 interstitial lung disease (ILD), grade 2 pneumonitis, grade 3 cardiac failure, grade 3 embolism, and grade 5 COVID-19 pneumonia; these patients were treated at the doses of 8.0 mg/kg, 8.0 mg/kg, 16.0 mg/kg, 8.0 mg/kg, and 12.0 mg/kg, respectively.²

“We’ve learned how to make this drug tolerable with prophylactic antiemetics that are now recommended in the ongoing ifinatamab deruxtecan trials,” Johnson explained.

The most common TEAEs occurring at any grade were nausea (59.1%), fatigue (50.0%), anemia (27.3%), vomiting (27.3%), decreased appetite (22.7%), pyrexia (18.2%), and constipation (18.2%). Grade 3 or higher events included nausea, anemia, decreased appetite, and constipation, all occurring in 1 patient each. A grade 1 or 2 pneumonitis or ILD event occurred in 3 patients.

“Ifinatamab deruxtecan has a bright future—not just in SCLC [based on] the cohort [from this trial] but also in prostate cancer and in squamous cancers of multiple histologies,” Johnson said. “It is also interesting that it continues to be an ADC for which we are questioning the need for a biomarker; ideally, it would be great if we could develop a biomarker for B7-H3 that would predict which patients should get this drug, but it does seem to have robust responses in an unselected group of patients. So, there’s more research that needs to be done about the importance of the B7-H3 H score or other biomarkers that might predict for activity. Evaluating this in a less pretreated group of patients is important, both in SCLC as well as in all the other tumor types mentioned.”

New NSCLC Updates

Evaluating Doses of Trastuzumab Deruxtecan

In the phase 2 DESTINY-Lung02 trial (NCT04644237), trastuzumab deruxtecan was evaluated at dose levels of 5.4 mg/kg and 6.4 mg/kg given every 3 weeks in patients with metastatic NSCLC harboring HER2 mutations who received at least 1 prior therapy. Both doses have demonstrated antitumor activity in a variety of cancer types, but the lower dose had not been evaluated in patients with previously treated HER2-mutated metastatic NSCLC.³

The primary analysis results of the blinded, randomized, noncomparative trial showed that at the data cutoff date of December 23, 2022, patients who received trastuzumab deruxtecan at 5.4 mg/kg (n = 102) achieved a confirmed ORR of 49.0% (95% CI, 39.0%-59.1%) with 1 of the 50 responders experiencing a CR. Patients who received the agent at the 6.4-mg/kg dose (n = 50) achieved a confirmed ORR of 56.0% (95% CI, 41.3%-70.0%) with 2 of the 28 responders experiencing a CR. The stable disease rates were 44.1% and 36.0% and the progressive disease rates were 3.9% and 4.0% in the 5.4-mg/kg group and the 6.4-mg/kg group, respectively.

“The response rate is similar to what we saw in [the phase 2 trial] DESTINY-Lung01 [NCT03505710], at approximately 50% in both arms,” Jänne explained. “The AE profile, however, is a little bit better in the lower-dose [arm]—there’s a lower incidence of overall AEs and a lower incidence of ILD in the 5.4-mg/kg dose [group]. The findings continue to support trastuzumab deruxtecan as an effective therapy for HER2-mutated lung cancer and support the 5.4-mg/kg dose as a correct balance of efficacy vs AEs; that is the approved dose in the United States for HER2-mutated lung cancer.”

Safety data demonstrated that in the 5.4-mg/kg group (n = 101) and the 6.4-mg/kg group (n = 50), patients experienced TEAEs that were any grade (96.0% vs 100.0%), grade 3 or higher (38.6% vs 58.0%), and serious (13.9% vs 24.0%), respectively. The most common grade 3 or higher TEAEs included neutropenia (18.8% vs 36.0%) and anemia (10.9% vs 16.0%), respectively.

Additionally, TEAEs were associated with drug discontinuation (13.9% vs 20.0%), dose reduction (16.8% vs 32.0%), drug interruption (26.7% vs 48.0%), and death (1.0% vs 2.0%) in the lower-dose and higher-dose arms, respectively. The median treatment durations were similar, at 7.7 months (range, 0.7-20.8) in the 5.4-mg/kg group and 8.3 months (range, 0.7-20.3) in the 6.4-mg/kg group.

Adjudicated drug-related ILD occurred at any grade in 12.9% of patients in the 5.4-mg/kg arm compared with 28.0% of patients in the 6.4-mg/kg arm and occurred at grades 1 (4.0% vs 8.0%), 2 (6.9% vs 18.0%), 3 (1.0% vs 0.0%), and 5 (1.0% vs 2.0%).

Regarding next steps for the research, Jänne noted that “this trial was in patients who had received prior systemic therapy [and] there is an ongoing trial of trastuzumab deruxtecan vs combination chemotherapy plus immune checkpoint inhibition as first-line therapy for patients with stage IV HER2-mutated NSCLC. The efficacy is quite good and it’s what we are used to seeing for the targeted therapy patient population; the purpose of the [phase 3] DESTINY-Lung04 trial [NCT05048797] is to see whether it will be even higher or better than the standard of care in the first-line setting.”

A Phase 3 Trial Aims to Compare Combinations

In the interview with OncologyLive, Kato highlighted the phase 3 AVANZAR trial (NCT05687266), which is enrolling patients to receive Dato-DXd plus durvalumab and carboplatin as first-line treatment for stage IIIB, IIC, or IV NSCLC. The trial began enrollment in December 2022, and investigators anticipate participation at approximately 230 locations in 24 countries. They estimate that 1000 patients will be included in the trial, and they will be randomly assigned 1:1 to Dato-DXd plus durvalumab and carboplatin followed by Dato-DXd and durvalumab vs histology-specific chemotherapy and pembrolizumab.

“The purpose of the AVANZAR trial is to estimate the efficacy of chemotherapy plus Dato-DXd plus durvalumab,” Kato explained. “Usually, we use the chemotherapy plus immunotherapy [combination], especially [with] pembrolizumab; [we use the] KEYNOTE-189 [NCT02578680] regimen, carboplatin plus pemetrexed plus pembrolizumab, or the KEYNOTE-407 [NCT02775435] regimen, [which includes] carboplatin plus paclitaxel plus pembrolizumab. But in this trial, we [are] using durvalumab as a PD-L1 inhibitor and the chemotherapy is carboplatin plus pemetrexed or carboplatin plus paclitaxel. [It is a] newer [approach,] to use Dato-DXd and durvalumab for patients with NSCLC.”

The trial will enroll adult patients with metastatic NSCLC in addition to those with stage IIB or IIC NSCLC that is not amenable for surgical resection or definitive chemoradiation. Patients must lack sensitizing EGFR mutations as well as ALK and ROS1 rearrangements; they also must not have NTRK, BRAF, MET, or RET mutations or other actionable driver oncogenes for which there are approved and currently available therapies. Additional enrollment criteria state that patients must have an ECOG performance status of 0 or 1; adequate bone marrow and organ function; archival tumor tissue; and must not have received prior first-line chemotherapy or systemic therapy for stage IIIB, IIC, or IV NSCLC.

“So far, approximately 400 patients have already registered, and they are now going to trial,” Kato said. “The primary end point is PFS in the patients with high Trop-2 expression, but so far, any type of patient is included. Maybe soon, we will add the information of Trop-2 expression [and] then this trial will be more focused on the patients with Trop-2 high [expression].”

Dual primary end points will be PFS by blinded independent central review per RECIST 1.1 criteria and OS in patients who are TROP2 positive. Secondary end points will include PFS as well as OS in the intent-to-treat and TROP2-negative patient populations, among others. The estimated study completion date is May 2027.

“This regimen is very unique and popular for [my] institute, so the accrual speed is very high,” Kato concluded. “[I expect] soon this trial will achieve full registration, then the data will come up not so far [in the future]—this is kind of a fast trial.”

References

1. Johnson ML, Awad M, Koyama T, et al. Ifinatamab deruxtecan (I-DXd; DS-7300) in patients with refractory SCLC: a subgroup analysis of a phase 1/2 study. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract OA05.05.
2. Jänne PA, Goto Y, Kubo T, et al. Trastuzumab deruxtecan in patients with HER2-mutant metastatic non-small cell lung cancer: primary results of DESTINY-Lung02. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract MA13.10.
3. Aggarwal C, Cheema P, Arrieta O, et al. AVANZAR: phase III study of datopotamab deruxtecan (Dato-DXd) + durvalumab + carboplatin as 1L treatment of advanced/mNSCLC. Presented at: International Association for the Study of Lung Cancer 2023 World Conference on Lung Cancer; September 9-12, 2023; Singapore. Abstract P2.04-02.