Ifinatamab Deruxtecan Demonstrates Robust Efficacy, Acceptable Safety in SCLC

The antibody-drug conjugate (ADC) ifinatamab deruxtecan (I-DXd; DS-7300) was well tolerated and elicited durable activity in patients with heavily pretreated small cell lung cancer (SCLC), suggesting that its continued development may address the lack of effective therapeutics in the second line and beyond for this disease, according to Melissa L. Johnson, MD.

Findings from a subgroup analysis of patients with refractory SCLC in a phase 1/2 trial (NCT04145622) were presented at the 2023 IASLC World Conference on Lung Cancer. The objective response rate (ORR) achieved with I-DXd was 52.4% (95% CI, 29.8%-74.3%) in evaluable patients who received the agent at a dose of 6.4 mg/kg or higher (n = 21); this consisted of a complete response rate of 4.8% and partial response (PR) rate of 47.6%. 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. The progression-free survival and overall survival with the agent was 5.6 months (95% CI, 3.9-8.1) and 12.2 months (95% CI, 6.4-not applicable), respectively. The toxicity profile of the agent aligned with what has previously been reported with the agent, with no new signals observed.

“For the first time, we’re seeing that ADCs work—not just in NSCLC, but also in SCLC,” said Johnson, who is the director of Lung Cancer Research at Sarah Cannon Research Institute, as well as the chair of the Oncology Department, member of the Medical Executive Committee at TriStar Centennial Medical Center in Nashville, Tennessee. “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.”

I-DXd is under further exploration in patients with extensive-stage SCLC following 1 to 3 prior lines of therapy as part of the ongoing phase 2 IDeate-1/DS7300-127 trial (NCT05280470).

In an interview with OncLive^®, Johnson spotlighted the early-phase investigation of I-DXd in advanced solid tumors, discussed the efficacy and safety of the agent in patients with SCLC, and emphasized how results from this subgroup analysis support its continued investigation in SCLC and beyond.

OncLive: What unmet needs exist for patients with SCLC, and how might the development of I-DXd help address them?

Johnson: It’s important to know that I-DXd is being developed for patients with SCLC, irrespective of B7H3 expression. The subgroup analysis that I presented is part of an ongoing phase 1/2 study that enrolled [patients with] advanced solid tumors unselected for B7H3-expressing cancer. One of the findings from that trial is how well patients with SCLC [responded to I-DXd]. The subgroup includes 22 patients with SCLC who were treated as part of that phase 1 study.

There is an unmet need for patients in the second line and beyond who have received chemotherapy and immunotherapy for their disease. We know that checkpoint inhibitors don’t work as well for patients with SCLC. Although there’s a lot of exciting novel agents [in development in SCLC], not everyone will be a candidate for [agents like] DLL3-targeted bispecifics. [Therefore,] other targets and therapies are needed.

Please expand on the mechanism of action of I-DXd.

I-DXd is an ADC. We’re increasingly aware that there are 3 components to these drugs: the IgG monoclonal antibody portion, in this case, directed against B7H3; a proprietary linker; and a deruxtecan payload, which is an exatecan derivative. The linker combines the monoclonal antibody to the payload. When I-DXd is administered, it binds to B7H3 in the tumor or in the stroma. Once it binds, the payload diffuses into the nucleus, binds to the DNA, and causes selected tumor cell death. These ADCs all work in a similar fashion. The advantage [of ADCs] over standard chemotherapy is the reduced systemic exposure. We believe that these drugs are better tolerated as a result.

Could you provide some background on the phase 1/2 trial? Which tumor types were included on the study, and what preliminary results were reported from the phase 1 portion?

Patients with advanced solid tumors were enrolled in this phase 1/2, multicenter, ongoing, first-in-human trial, and 10 tumor types were included. [These] included SCLC, squamous cancers of the lung and esophagus, and prostate cancer. We’ve now presented [data from] the dose-escalation portion, in which doses from 3.2 mg/kg all the way up to 16 mg/kg have been investigated, and 12 mg/kg has been identified as the dose to be further studied in the expansion [portion]. There are ongoing expansion cohorts of [patients with] esophageal squamous cancer, non–small cell lung cancer [NSCLC], and gastric cancer.

[For] the SCLC [population, I-DXd] is being investigated in a phase 2 trial, DS7300-127, that enrolls patients with extensive-stage SCLC who’ve had 1 to 3 prior lines of therapy. That [trial is supported by] the results from the 22 patients in the [phase 1] cohort.

What efficacy and safety findings from the phase 1 SCLC cohort were presented at this year’s WCLC?

Of the 22 patients with SCLC included in this analysis, 52%, or 11, had a PR when treated with I-DXd. A waterfall plot shows that all but 1 of the 21 patients evaluable for efficacy had some element of disease shrinkage. This [indicates that I-DXd] is a highly active agent in this subset. We also looked at baseline tumor biopsies, looking for B7H3 expression as a composite H score, including both membrane and cytosol B7H3 expression. All the patients had some amount of B7H3 expression, although the amount of expression didn’t seem to correlate with clinical efficacy markers. This is an exciting opportunity in SCLC, [as] we always need more [research in this space. I-DXd] is well tolerated and there were no new safety signals, which is reassuring. We’ve learned how to make this drug tolerable with prophylactic antiemetics that are now recommended in the ongoing I-DXd trials.

Are any next steps planned for this research?

I-DXd has a bright future—not just in SCLC, but also in prostate cancer and squamous cancers of multiple histologies. It is also interesting that [I-DXd] continues to be an ADC for which we are questioning the need for a biomarker. It would be great if we could develop a biomarker for B7H3 that would [identify which] patients should get this drug, but [I-DXd] does seem to have robust responses in an unselected patient population. There’s more research that needs to be done [to understand] the importance of the B7H3 H-score or other biomarkers that might predict activity. Evaluating this in a less-pretreated group of patients is important, both in SCLC and the other tumor types.

What other research were you excited to see presented at the IASLC 2023 World Conference on Lung Cancer?

The I-DXd abstract is a part of a cool session talking about ADCs in general, called “The Next Tsunami.” I [was] excited to hear those data. There are several emerging ADCs in the lung cancer space. Whether those drugs are going to find their place in the refractory setting after chemotherapy and immuno-oncology or be able to move up into the front line, is a hot area of investigation. There are a lot of questions about that, so this is an important session. I’m also excited about the [phase 3] FLAURA2 [NCT04035486] data. We’d heard that it was a positive trial and so we saw how positive and to what degree the [results] inform or change clinical practice.

Reference

Johnson M, 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: 2023 IASLC World Conference on Lung Cancer; September 9-12, 2023; Singapore, Republic of Singapore. Abstract OA05.05.