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2022 WCLC Highlights

CME

Independent Conference Coverage of the IASLC 2022 World Conference on Lung Cancer

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: October 25, 2022

Expiration: October 24, 2023

Wade T. Iams
Wade T. Iams, MD, MSCI
Heather Wakelee
Heather Wakelee, MD
CME/CE Information

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Tarlatamab: Background

Heather Wakelee, MD:
Switching gears, we will highlight 1 study in small-cell lung cancer, which is aggressive with limited treatment options available after first-line chemoimmunotherapy.

The Notch ligand DLL3 is commonly expressed on SCLC cells. Tarlatamab is a bispecific antibody that targets DLL3 on tumor cells and CD3 on T‑cells, which on binding to both targets, brings T-cells in close proximity to DLL3-expressing tumor cells to enhance the immune response against the tumor cells.16

An interim analysis of the phase I dose exploration data from DeLLphi-300 included preliminary efficacy and showed an acceptable safety profile for tarlatamab among patients with SCLC.17 The analysis from WCLC 2022 includes updated data from the dose exploration phase and new data for the dose expansion phase of the DeLLphi-300 study.18

DeLLphi-300: Phase I Study of Tarlatamab in Patients With Relapsed/Refractory SCLC

Heather Wakelee, MD:
DeLLphi-300 was a first-in-human, nonrandomized phase I dose escalation and expansion study that assessed the bispecific antibody tarlatamab in patients with relapsed/refractory SCLC that progressed or recurred following ≥1 previous platinum-based chemotherapy regimen. The trial enrolled just more than 100 patients and the median follow-up time for this analysis was 8.5 months.

The primary objectives were safety, maximum tolerated dose, and recommended phase II dose. The secondary objectives included pharmacokinetics and preliminary antitumor activity, and additional exploratory objectives included evaluation of the immunogenicity of tarlatamab and assessing biomarker expression.18

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DeLLphi-300: Baseline Characteristics

Heather Wakelee, MD:
The baseline characteristics were similar to what we would expect in this patient population. The median age was 64 years, and 88% were current or former smokers. Almost one third of patients had ≥3 previous lines of therapy, representing a very heavily pretreated patient population, and many of them had known liver (51%) or brain (27%) metastases.18

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DeLLphi-300: Treatment-Related AEs

Heather Wakelee, MD:
Treatment-related adverse events occurred in 92% of patients and 31% were grade ≥3. Some immune‑type reactions were reported, including pyrexia and fatigue, which is expected from this class of drugs.18 Cytokine release syndrome was reported in 53% of patients receiving tarlatamab and neurologic events occurred in 50% of patients. These adverse events are common with bispecific antibodies, but they are something to be mindful of when using this class of therapy.

After tarlatamab therapy was initiated, 4 patients (4%) discontinued due to treatment-related adverse events, including encephalopathy in 1 patient, neurotoxicity in 1 patient, and pneumonitis in 2 patients (including 1 with grade 5 pneumonitis).

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DeLLphi-300: Response

Heather Wakelee, MD:
The confirmed ORR with tarlatamab was 23%, although 37% of patients had target tumor shrinkage of ≥30%.18 These response data included patients across multiple doses and some were quite low, so it is encouraging to see responses and the higher doses may result in better response rates.

It is important to keep in mind that these patients have already had responses to first‑line therapy but are now either refractory or have relapsed to 1 or more lines of therapy. There are still patients who respond to standard chemotherapy in this population, so a 23% response rate is not necessarily dramatically higher than expected. There were 2 patients in this trial who achieved a CR, which is striking and something to further explore as to what made them unique. There also were not as many patients who had progressive disease as we might see with standard chemotherapy, so there are some encouraging results, particularly at the higher doses.

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DeLLphi-300: Response

Heather Wakelee, MD:
There are some patients who are experiencing a long DoR, including 11 of the 24 patients with a confirmed response continuing on therapy at cutoff. The median time to response was 1.8 months and the median DoR was 13 months.18

The DoR in this trial is very promising in this patient population because, historically, patients with SCLC do achieve responses but they are often short-lived in the second and third lines of therapy. If these data are confirmed, a 20% to 30% response rate with a DoR that is over a year would be a welcome new treatment option for our patients with relapsed/refractory SCLC.

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DeLLphi-300: Conclusions

Heather Wakelee, MD:
The dose exploration and preliminary dose-expansion data from the DeLLphi-300 trial with tarlatamab, a DLL3-CD3 bispecific antibody, reported promising antitumor activity, with a 23% response rate and median DoR of 13 months in relapsed/refractory SCLC. There were also no surprising adverse events reported, although cytokine release syndrome is always something to watch carefully and know how to manage appropriately in an infusion center. There weren’t a lot of treatment discontinuations, so they are going to be doing a phase II study of tarlatamab in patients with relapsed/refractory SCLC who’ve had at least 2 previous lines of therapy.

Wade T. Iams, MD, MSCI:
I think these data are promising, particularly the median DoR in responders of 13 months, which is impressive in relapsed/refractory SCLC. The reported ORR is comparable to the response rates for standard therapies for patients with relapsed SCLC.

A question that Dr. Wakelee alluded to was whether we can use biomarkers to select which patients will respond best to this treatment approach. Responders may be patients with high DLL3 expression or patients with the emerging SCLC immunogenic phenotype called SCLC‑I.19 Whether we can do a better job of selecting patients with SCLC for specific therapies is one of the major questions in the field moving forward.

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