Tarlatamab’s Impact on Platinum-Sensitive or -Refractory SCLC

Ticiana Leal, MD

Case: A 73-Year-Old Woman With Progressive Extensive-Stage Small Cell Lung Cancer

A 73-year-old woman presented with dyspnea on mild exertion, productive cough, chest pain, fatigue, anorexia, and a recent unintentional 18-lb weight loss.

Past Medical History

Hypertension, well controlled on candesartan and hydrochlorothiazide combination every day

45 pack-year smoking history and current smoker

Focused Physical Examination

1. ECOG performance status: 1
2. Dullness to percussion and diminished breath sounds on auscultation over the right, posterior lung field

Imaging Studies

1. Chest radiograph: 4.8 cm with opacification of posterior segment of right lower lobe on lateral view with volume loss; positive convex, unilateral, hilar lymphadenopathy with short axis diameter of 18 cm and widened mediastinum
2. Contrast chest CT: mass lesion with lobulated margins infiltrating the bronchial mucosa; evidence of necrosis and hemorrhage
3. ¹⁸F-fluorodeoxyglucose on PET/CT: avid fluorodeoxyglucose uptake in right lower lobe; ipsilateral hilar lymph node; contralateral mediastinal lymph node; a single hepatic lesion
4. Brain MRI: negative

Histopathology of transbronchial needle aspiration specimen: small, fusiform cells characterized by scant cytoplasm, finely granular nuclear chromatin, and absent nucleoli

Percutaneous image-guided liver biopsy: histopathology consistent with small cell lung cancer (SCLC)

Staging: T2bN3M1b–IVA extensive-stage (ES) SCLC

Primary Treatment

Carboplatin plus etoposide with durvalumab (Imfinzi) followed by maintenance durvalumab

The patient tolerated the regimen and achieved a partial response.

Nine Months After Completing Primary Systemic Therapy

The patient returned to her oncologist with complaints of increasing fatigue, anorexia, and recent onset of low-back pain

Follow-Up Imaging

Whole body ¹⁸F-fluorodeoxyglucose PET/CT demonstrated avid fluorodeoxyglucose uptake in L3 to L5 vertebrae and residual disease in the right lower lobe with no progression of liver metastasis.

Brain MRI: negative

Re-treatment With Platinum-Based Doublet Therapy

The patient initiated 4 cycles of carboplatin plus etoposide plus atezolizumab (Tecentriq) followed by atezolizumab maintenance every 3 weeks.

She achieved stable disease status.

Intermittent episodes of nausea were resolved with oral ondansetron.

Five Months Later

After the second maintenance dose of atezolizumab, the patient developed right upper quadrant pain, and jaundiced sclera, and reported an additional 15-lb weight loss.

Liver Function Tests

The patient’sα-fetoprotein was 450 ng/mL, aspartate aminotransferase was 135 U/L, and alanine aminotransferase was 94 U/L.

¹⁸F-fluorodeoxyglucose PET/CT: avid fluorodeoxyglucose uptake of numerous, hypodense hepatic nodules and erosion of ribs 6 to 8

Subsequent Systemic Therapy

The patient initiated a step-up dosing schedule with tarlatamab (Imdelltra) intravenous, including dexamethasone and normal saline before and after cycle 1, followed by subsequent, biweekly infusions.

Follow-Up Plan

The patient would be monitored for cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), and neurological toxicity during cycle 1, and thereafter for sustained therapeutic response, safety, and tolerability.

Complete blood count with differential and liver function levels prior to each tarlatamab dose, as clinically indicated

Brain MRI every 3 to 4 months during year 1, then every 6 months thereafter, as clinically indicated

Microscopic, photorealistic image of lung cancer cells - Generated with Adobe Firefly

Targeted Therapies in Oncology: Considering this case, how should survival benefits from subsequent therapies be balanced against adverse events (AEs) after progression on platinum-based therapy?

Ticiana Leal, MD: It is important to highlight that the strategy to rechallenge using platinum etoposide for patients who have had prior platinum etoposide with or without immunotherapy comes from many retrospective and case series that were done in the 1980s.¹

Subsequently, we did have a randomized phase 3 study [NCT02738346] that compared platinum etoposide rechallenge vs topotecan [Hycamtin] in patients who had prior platinum-based therapy, and the use of platinum sensitivity was 90 days or greater from prior platinum-based therapy.² What this showed was that the use of platinum etoposide as a rechallenge did meet the primary end point of progression-free survival [PFS]. It also showed an improvement from 2.7 months with topotecan to 4.7 months with the platinum combination. However, this study did not meet the overall survival [OS] benefit.

In addition, in terms of toxicities, we did see slightly higher rates of neutropenia, febrile neutropenia, and thrombocytopenia with topotecan. However, there were no significant differences in terms of fatigue or anemia between the 2 groups. Thus, the platinum rechallenge is still in the NCCN [National Comprehensive Cancer Network] guidelines.³ I find that I am using less of the platinum rechallenge strategy as seen in this case study. The patient here did derive benefit, but less benefit the second time, and myelosuppression was still a significant issue.

You have to balance OS with toxicities, especially in patients with ES-SCLC who tend to have more medical comorbidities and rapid progression at relapse. There is a significant drop-off in terms of who is able to stay clinically well enough to tolerate a second-line therapy. Thus, we do have to balance toxicity with OS benefit, and with the new therapies available, I envision that we will be using less platinum rechallenge with patients who require subsequent lines of therapies, which is the vast majority of our patients.

For ES-SCLC, under what circumstances would you consider extending the cycles of chemoimmunotherapy from 4 to 6?

The basis of why we use chemoimmunotherapy comes from many trials, including the CASPIAN trial [phase 3; NCT03043872], which investigated the use of carboplatin or cisplatin and etoposide and durvalumab followed by durvalumab maintenance.⁴ The IMpower133 trial [phase 3; NCT02763579] also provided [evidence], investigating platinum etoposide with carboplatin/etoposide and atezolizumab followed by maintenance [therapy], favoring 4 cycles in the experimental arms.⁵ In my clinical practice I follow these studies’ design, noting the benefits and what they achieved utilizing 4 cycles of chemoimmunotherapy.

I find that I use 6 cycles less and less in clinical practice, as there are increasing toxicities with extending the platinum etoposide beyond 4 cycles. Thus, in clinical practice, I tend to stay with 4 cycles of the platinum etoposide in combination with the PD-L1 inhibitor and then continue with immunotherapy maintenance. This method helps balance out the benefit that the patient derives from the platinum etoposide and minimizes toxicities from the chemotherapy portion, which tends to be myelosuppression.

What other treatment options, in the absence of a clinical trial, would you consider as a second line or subsequent line of therapy and why?

This definition of platinum resistance in SCLC is based on clinical consensus. The NCCN guidelines define platinum sensitivity as a progression-free interval of 6 months or longer.³ There is an exception, however, for patients whose previous line of platinum etoposide treatment resulted in progression between 3 to 6 months.

As mentioned, the platinum rechallenge data from the phase 3 trial used 90 days or greater.² Thus, the greater the amount of time from prior exposure to platinum etoposide, the better the outcomes, but for the patients who have progression in less than 6 months of therapy, I tend to move on to the next line of therapy. Lurbinectedin [Zepzelca] is an option that we have used [at this stage]. We have FDA approval for that, and tarlatamab is our newest approval.^6,7 For patients who require a subsequent line of therapy, lurbinectedin or tarlatamab is my preferred strategy in this setting.

Would you change treatment sequencing for ES-SCLC after progression following a chemotherapy-free interval of more than 6 months?

Yes. For patients in my clinical practice who have initial benefit from platinum etoposide, atezolizumab, or durvalumab and then have progression longer than 6 months after prior platinum etoposide, I do tend to move on. I have used less and less of the platinum rechallenge strategy for the reasons that we talked about earlier. My go-to regimens tend to be lurbinectedin or tarlatamab, and we can talk about differences in why we would choose one vs the other, because we do not have a comparison of which agent is superior.

Regarding the lurbinectedin data, for the patients who have a chemotherapy-free interval longer than 6 months, there is more favorable PFS as well as OS for this patient population.⁸

An interesting finding from the extended follow-up of the phase 2 DeLLphi-301 study [NCT05060016], which evaluated tarlatamab, was that platinum sensitivity had no impact on patient outcomes.⁹ Thus, patients derive benefit from tarlatamab, whether or not they were considered platinum sensitive or platinum refractory. This is a bit of a paradigm shift, and it makes sense with the mechanism of action of tarlatamab that this would be the case. Tarlatamab is an option for patients who have progression after chemotherapy-free intervals longer than 6 months.

For patients who are not eligible for clinical trials and are platinum sensitive or platinum refractory, I would use lurbinectedin or tarlatamab. Consulting the NCCN guidelines is important.

Despite negative results from serial brain MRI, would you consider prophylactic cranial irradiation in this patient, and why or why not?

Prophylactic cranial irradiation [PCI] is an option for patients and has to be discussed with medical oncology, radiation oncology, and the patient. However, based on the data that we have, especially for patients who are candidates and adherent to serial brain MRI, I have not favored using PCI to minimize toxicities. These data are from a randomized phase 3 trial from Japan [UMIN000001755]; they showed that with either close monitoring or PCI there was no significant difference in OS.¹⁰ We will need additional data in a prospective fashion from the MAVERICK trial [phase 3; NCT04155034] that is ongoing.¹¹ As of now, I feel very comfortable withholding PCI for a patient with ES-SCLC who had serial brain MRI in order to minimize the neurocognitive toxicities that can occur.

Please discuss the mechanisms of action of tarlatamab and its treatment potential as a subsequent therapy for SCLC that has progressed after platinum-based chemotherapy.

[Investigators in] the DeLLphi-301 study evaluated the efficacy, safety, tolerability, and pharmacokinetics of tarlatamab in patients with relapsed or refractory SCLC after 2 or more prior lines of therapy.⁹Tarlatamab is a bispecific T-cell engager that targets DLL3 on the SCLC cells and targets CD3 on the T cells. Essentially what this does is enhance cytotoxicity and has the effect of T-cell–mediated tumor lysis and regression.

This bispecific T-cell engager targeting DLL3 was considered very promising because notch signaling is a regulator of neuroendocrine differentiation in SCLC and upregulation of DLL3 is associated with SCLC progression. DLL3 is highly expressed on the surface of SCLC cells from 85% to 94% of cases. This was considered a very promising strategy. Another important factor is that this is independent of major histocompatibility complex-I, which sometimes can be altered in SCLC and drive resistance.

The initial development of these DLL3-targeting therapies occurred through the development of antibody-drug conjugates [ADCs] with rovalpituzumab tesirine, which unfortunately failed. However, the target was still considered promising enough to continue development with the unique mechanism of action for tarlatamab as a bispecific T-cell engager.

In the phase 1 study, we saw early-on promising activity, with not only promising response rates but also promising outcomes in terms of OS and duration of response [DOR] in a very heavily pretreated population.¹² This led to the phase 2 study of the DeLLphi-301 study evaluating 2 doses of tarlatamab at 10 mg and 100 mg, using a stepwise dosing approach to minimize AEs.⁹ What was observed in the DeLLphi-301 study was promising response rates of 32% to 40% in patients across both doses who were heavily pretreated with greater than 2 or more prior lines of therapy.

These responses were quite meaningful, and I will focus on the patients in the 10-mg cohort, which was the cohort chosen for further development and ultimately led to the FDA approval.⁷ Although a response rate of 40% is quite clinically meaningful, it does not necessarily correlate with the outcomes that we need, such as PFS, or OS.

This was demonstrated in a study conducted by Afshin Dowlati, MD, et al.¹³

The DeLLphi-301 data showed promising DOR and OS rates. In the median follow-up of 20.7 months, the median OS was 15.2 months, which is very promising in this patient population.

What is the future treatment potential of tarlatamab in combination therapy for previously treated advanced SCLC after 2 or more prior lines of therapy?

The DeLLphi-303 phase 1b study [NCT05361395] combined tarlatamab with durvalumab, or atezolizumab in the maintenance setting after induction therapy with chemoimmunotherapy.¹⁴ This study showed a favorable safety profile with the combination. Importantly, the study also showed promising OS rates with this combination. Thus, moving tarlatamab earlier in the maintenance setting, or perhaps in combination with chemoimmunotherapy, is going to be exciting to witness.

Based on the promising results of the DeLLphi-303 study, the combination of tarlatamab with durvalumab is being evaluated in the ongoing, randomized phase 3 DeLLphi-305 study.¹⁵

Please discuss the mechanism of action of B7-H3 and its treatment potential as a subsequent therapy for SCLC.

Ifinatamab deruxtecan [I-DXd; DS-7300 is an ADC that targets B7-H3, which is a transmembrane protein expressed in many solid tumors and highly expressed in SCLC. B7-H3 has also been associated with poor prognosis and lack of response to standard therapy.

A 1/2 phase trial [NCT04145622] showed very promising response rates with an objective response rate of 52%, a median DOR of 5.9 months, and a median OS of 12.2 months.¹⁶ This benefit was irrespective of B7-H3 expression. There are still a lot of questions about whether using B7-H3 as a target will be successful because benefit is observed irrespective of B7-H3 expression.

Adjusting the biomarker is still of interest, but I do not believe it is ready to be used in clinical practice, and furthermore, in terms of testing, PD-L1 has not been successful as a biomarker predictive of response for these therapies.

What treatment synergies might you expect from a combination of MK-6070, the trispecific T-cell engager, and I-DXd?

MK-6070 is demonstrating a safety profile consistent with the mechanism of action of T-cell engagers, and, in addition, there is an early signal of efficacy shown in the phase 1 study [NCT04471727] currently being conducted.¹⁷

It is interesting to combine T-cell engagers with either immunotherapy or with I-DXd, given that they do not have overlapping mechanisms of action or toxicities. However, the studies will have to show where combination therapies will fit, balancing benefits and toxicities as well.

Combining therapies in the maintenance setting strategy is also interesting because when patients with SCLC initially present, they may be highly symptomatic. They certainly may have a lot of comorbidities that we are trying to optimize. In addition, after this initial induction of chemoimmunotherapy, patients tend to derive significant clinical benefit and overall improvement, regarding symptom control and disease burden related to their cancer.

One caution has been that in the development of therapies in the maintenance setting for patients with SCLC, there has not been significant gain, especially with immunotherapy. This is based on data from the CheckMate 451 trial [phase 3; NCT02538666] where nivolumab [Opdivo] did not lead to improved outcomes in the maintenance setting.¹⁸

As new agents with different mechanisms of action show significant improvement and meaningful end points, such as DOR and OS, I think the maintenance phase [will be] the time when combination therapies could lead to significant benefits for patients.

Please discuss the recent data on lurbinectedin.

The single-arm phase 2 basket trial [NCT02454972] evaluated lurbinectedin in advanced solid tumors, focusing on patients with ES-SCLC who had progression on or after prior platinum-based chemotherapy.¹⁹ The trial met its primary end point of overall response rate, which in all comers was 35%.

There is a differential benefit in patients [depending on] prior exposure or chemotherapy-free interval of greater than 90 days or less than 90 days. The patients with a chemotherapy-free interval of greater than 90 days had a greater magnitude of benefit in terms of response rate. Data showed that the response rate was 45%, the median DOR was 6.2 months, and the median OS was 11.2 months, which was higher than in the overall cohort, approximately 9 months. These data support the use of lurbinectedinnot only in patients with platinum-refractory disease defined as a chemotherapy-free interval of less than 90 days, but also in patients with platinum-sensitive disease with a chemotherapy-free interval of greater than 90 days.

What would be a clinically meaningful DOR and PFS in relapsed SCLC after platinum-based chemotherapy that would encourage clinicians to consider lurbinectedin as second-line therapy?

One important aspect to note in clinical practice is that we are trying to balance toxicities in patients who are quite ill from their disease with strategies to manage AEs and provide meaningful improvement in their outcomes.

The overall response rate [is] an important benchmark to initiate the development of certain therapies in SCLC, [but] I do think that we have to move on from response rate, DOR, and PFS. OS is the most clinically meaningful end point, in my opinion, and yet a median DOR of 6 months and a median OS of about 1 year are encouraging.

I also think we have to consider the logistics of these therapies, developing the structure to support patients through second-line [therapy] and beyond. Considering the proportion of patients who progress to second- or third-line therapy, we must use our best therapies up front or in the second line. This is because only a small number of patients progress to the third line. Lurbinectedin is logistically easy to employ and can be employed in the academic or community settings.

As we gain more experience with tarlatamab in the academic and community settings, the monitoring aspect is going to be key, as well as the cost of inpatient vs outpatient therapy.

I do think that using tarlatamab earlier is going to be important given the logistics component and tarlatamab’s AE profile. Although, overall, the rates of grade 3 or higher CRS are quite low in a 10-mg dose, and no severe [cases of] ICANS were seen in this dose as well.

We need to think about how this will roll out in the clinical setting as we treat patients who were not eligible for clinical trials and who have more comorbidities or a performance status that is 2. Social support and caregiver support are also going to be important as we roll out tarlatamab to the clinical setting. However, this is an opportunity to continue to improve outcomes for patients with SCLC and have partnerships between community and academic settings to drive survival benefit.

How do the objective clinical outcomes of emerging targeted therapies for ES-SCLC compare with second-line treatment options?

For tarlatamab specifically, or T-cell engagers more broadly, one aspect that is showing promise, which is quite encouraging, is this notion that platinum-sensitive or platinum-resistant disease does not seem to matter in terms of improving outcomes.

Of note, other T-cell engagers in development for SCLC are MK-6070, the trispecific T-cell engager, and BI 764532.

In the extended follow-up of the DeLLphi-301 study, patients with platinum-resistant or platinum-sensitive disease derived similar benefit in terms of outcomes from tarlatamab.⁹ Thus, for patients with platinum-resistant disease, this seems to be a very promising strategy to employ, given what we know in terms of poor prognosis and outcomes with the traditional chemotherapy strategies like topotecan and the CAV [cyclophosphamide, doxorubicin, and vincristine] regimen.

Considering ADCs in regard to lurbinectedin, overall, with lurbinectedin there is a greater magnitude of benefit in the platinum-sensitive group of patients. However, comparing it with historical controls of topotecan and CAV regimen, lurbinectedin compares favorably even in the platinum-resistant population.

As we continue to develop ADCs with different payloads, it is crucial to evaluate biomarker data for I-DXd, which targets B7-H3 using immunohistochemistry. However, this approach has not proven effective in identifying patients who will benefit. Perhaps this biomarker needs to be further developed to give us a differential benefit in terms of outcomes and whether platinum-sensitive or platinum-resistant disease is going to be an important issue.

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