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New Tx for Relapsed SCLC
What’s New in the Treatment of Relapsed SCLC

Released: January 22, 2024

Mark A. Socinski
Mark A. Socinski, MD
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Key Takeaways
  • Chemotherapy plus immunotherapy is the standard of care for newly diagnosed ES-SCLC, but patients inevitably experience disease progression and require further therapy; however, the relapsed setting remains an area of unmet need.
  • Two novel agents recently have demonstrated promising antitumor activity in relapsed ES-SCLC: tarlatamab, a DLL3-targeted T-cell engager, and ifinatamab deruxtecan, a B7-H3–directed antibody–drug conjugate.
  • Studies evaluating these agents enrolled a highly selected patient population with good performance status not wholly representative of the larger population of patients with relapsed ES-SCLC, so we will need to see the results of ongoing randomized, controlled trials to determine the impact that tarlatamab and I-DXd will have on the treatment paradigm for ES-SCLC.

Extensive-stage small-cell lung cancer (ES-SCLC) remains a disease of poor prognosis with an unmet need for new therapies. The first-line standard-of-care therapy for ES-SCLC is immunotherapy plus chemotherapy, but almost all patients will experience disease progression—the majority within 6 months. Currently, only 2 agents—topotecan and lurbinectedin—are approved by the FDA for use in the second-line setting for ES-SCLC, and there are no third-line approvals. In this commentary, I consider data from recent clinical oncology meetings on 2 novel investigational therapies showing promise in relapsed ES-SCLC: tarlatamab, a bispecific T-cell engager (BiTE), and ifinatamab deruxtecan, an antibody–drug conjugate (ADC).

Tarlatamab
Tarlatamab is a DLL3-directed BiTE immunotherapy that binds to CD3 on T-cells and DLL3 on small-cell lung cancer (SCLC) cells, thereby leading to T-cell–mediated cancer cell lysis. DLL3 is an inhibitory ligand of Notch signaling implicated in oncogenesis, which is overexpressed at the cell surface in approximately 85% of SCLC tumors. In the phase I DeLLphi-300 study, tarlatamab demonstrated promising antitumor activity and manageable safety in 107 patients with relapsed/refractory SCLC after ≤1 line of prior therapy.

At ESMO 2023, Paz Arez and colleagues presented results from the multipart phase II DeLLphi-301 study evaluating tarlatamab in patients with advanced SCLC after ≤2 lines of prior therapy. In part 1, patients were randomly assigned to receive tarlatamab 10 mg (n = 88) or 100 mg (n = 88) every 2 weeks. Once 30 patients per dose level demonstrated an objective response, the 10-mg dose was selected for part 2 and administered to 12 patients. Part 3, the reduced inpatient monitoring period, focused on 34 patients receiving tarlatamab 10 mg. Step-up dosing (ie, 1 mg on Day 1 followed by full dose on Days 8 and 15 in cycle 1) was used throughout the study. Patients had received a median of 2 prior therapies (up to 8), with the majority having received prior anti–PD-1/PD-L1 treatment.

With a median follow-up of approximately 10 months, the objective response rate (ORR) with tarlatamab 10 mg (n = 100) and 100 mg (n = 88) was 40% and 32%, respectively, and the disease control rate was 70% and 63%, respectively, with the majority showing some degree of benefit. The median time to response was 1.4 months, and the mean duration of response was not reached. Among those receiving tarlatamab 10 mg, 3 patients showed a significant reduction in tumor volume, and all have ongoing partial response at 42-48 weeks of treatment. Median progression-free survival (PFS) was 4.9 months with tarlatamab 10 mg vs 3.9 months with tarlatamab 100 mg, so there does not seem to be an advantage with the higher dose level. Overall survival (OS) data were immature. This is quite impressive for third-line treatment, as many patients with advanced SCLC do not make it to this line of therapy.

Treatment-emergent adverse events (TEAEs) of any grade were reported in nearly all patients, with upwards of 93% being attributed to tarlatamab. Grade ≥3 TEAEs were reported in approximately 60% of patients, with 15% to 33% being related to tarlatamab. Cytokine-release syndrome (CRS) was reported in more than 50% of patients, but instances of grade ≥3 CRS were not common. A toxicity such as CRS may require hospitalization to manage, so if tarlatamab becomes available in the clinic, we will need to keep in mind that an elevated level of supportive care may be needed. Finally, immune effector cell–associated neurotoxicity syndrome was infrequent and mostly observed with the 100-mg dose. Despite the given toxicities, the discontinuation rate for tarlatamab was relatively low (9%-14% for the 10-mg dose).

Ifinatamab Deruxtecan (I-DXd)
I-DXd, originally known as DS7300, is a B7-H3 (CD276)–directed ADC composed of a humanized, anti–B7-H3 IgG1 monoclonal antibody and the topoisomerase I inhibitor payload DXd. B7-H3 is an immune checkpoint inhibitor protein that is commonly overexpressed in a range of cancer types and is associated with disease progression and a poor prognosis. At WCLC 2023, Johnson and colleagues presented a subgroup analysis of 21 patients with SCLC from the multicohort dose-escalation/dose-expansion phase I/II DS7300-A-J101 study who received I-DXd at a dose of at least 6.4 mg/kg up to 16.0 mg/kg every 3 weeks.

With a median follow-up of 11.7 months, I-DXd achieved an ORR of 52.4%, with a complete response rate of 4.8%. The median time to response was 1.2 months, and the median duration of response was 5.9 months, with 2 patients still receiving treatment at the time of the analysis. Although this population was heavily pretreated (median prior systemic regimens: 2; range: 1-7), all but 1 patient (who had stable disease) experienced a decrease in target lesion size. The median PFS and OS were 5.6 and 12.2 months, respectively. With the caveat that these early-phase data in a highly selected population with good performance status (0-1) that may not be wholly representative of a typical patient with ES-SCLC, the data show clear antitumor activity of I-DXd in relapsed ES-SCLC.

The safety analysis included 22 patients with ES-SCLC who received any dose of I-DXd (3.2 mg/kg to 16.0 mg/kg). These patients received a median of 6.5 cycles (range: 1.0-18.0), with a median duration of treatment of 3.9 months (range: 0.03-12.5). TEAEs were reported in all patients, with 8 patients (36.4%) experiencing grade ≥3 TEAEs. Treatment discontinuations due to TEAEs occurred in 5 patients (22.7%; 1 each for interstitial lung disease, pneumonitis, cardiac failure, embolism, and COVID-19). Although this is a small cohort, the discontinuation rate is slightly higher than that of drugs currently approved by the FDA. Nausea (n = 13; 59.1%) and fatigue (n = 11; 50.0%) were the most common any-grade AEs, along with smaller incidences of other chemotherapy-related AEs, such as myelosuppression. Of note, prophylactic premedication for nausea/vomiting and infusion-related reactions was not permitted during cycle 1, so I imagine the safety profile of I-DXd will improve with better supportive care. 

Real-world Considerations
Although these new strategies, with new targets, clearly have activity in ES-SCLC, it is important to remember that these studies were conducted in the best-of-the-best patients with ES-SCLC—patients who reach third-line treatment and have a good performance status are not representative of average patients—so these data, which look pretty good, should be interpreted in the context of a highly selected population. There was no control arm in either of these trials, making it difficult to judge how truly active these agents are and whether the activity is more reflective of patient selection. In the real-world setting, there are significant drop-offs in the percentage of patients who even receive second- and third-line treatment. Furthermore, the typical patient with relapsed ES-SCLC is in their 70s, are men, and have comorbidities due to the link between SCLC and smoking. The concern with this population is a higher risk for treatment-related toxicities. Although I remain optimistic any time I see the potential for a better option for relapsed SCLC, I also am a bit cautious regarding how much activity these agents really have—and at the end of the day, whether they will have an impact on the standard of care.

Where Do We Go From Here?
Although promising, what impact tarlatamab and I-DXd will have on the overall care of relapsed SCLC ultimately will be determined by the results of subsequent randomized phase II and III trials, 2 of which to consider enrolling patients on are listed here:  

  • IDeate-1 (NCT05280470): phase II study evaluating I-DXd in patients with ES- SCLC following 1-3 prior lines of therapy
  • DeLLphi-304 (NCT05740566): randomized phase III study evaluating tarlatamab 10 mg vs standard-of-care chemotherapy in relapsed SCLC after 1 platinum-based regime

There is also work to be done on biomarker strategies to select patients most likely to benefit from treatment with these agents. Despite being antibody-based therapies where you might assume target expression would be important to their activity, in these small studies, responses to tarlatamab were observed regardless of DLL3 expression, and tarlatamab efficacy did not correlate with B7-H3 expression.

During my career, I have seen many drugs fail in second-line SCLC, and even our available second-line options leave something to be desired, so I hope something will come along that will make a real difference to our patients with ES-SCLC.

Your Thoughts?
Have you enrolled any of your patients with relapsed SCLC on trials evaluating tarlatamab or I-DXd? Answer the polling question and join the discussion by leaving a comment below.

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