Lurbinectedin Demonstrates Efficacy in First- and Second-line Small Cell Lung Cancer

Kartik Konduri, MD

During a Targeted Oncology Case-Based Roundtable event, Kartik Konduri, MD, medical director, Chest Cancer Research and Treatment Center, Baylor Charles A. Sammons Cancer Center, Texas Oncology, discussed the case of a 58-year-old patients with small cell lung cancer.

Targeted Oncology^TM: Would you offer prophylactic cranial irradiation (PCI) for this patient? Why or why not?

KONDURI: [It is important to consider a patient’s] performance status and age. PCI in elderly patients [can be] problematic in this scenario. There’s also the question of whether there is a benefit from PCI in the [overall] setting. Discussion should [occur] with a radiation oncologist, especially if there is a straight off, very good response.

Based on the immunotherapy studies, why should treatment be stopped after 2 to 4 cycles if the patient is tolerating treatment well?

The response [often] comes in the first 2 cycles. The big drop in the volume of disease comes in the first 2 cycles. Then there is a little more [reduction over] the next few cycles. In the past, when there was no immunotherapy to talk about, this is how [we] used to approach patients; 4 cycles or 6 cycles was the consideration at that time. If the patient was having an ongoing significant response, I would take it up to 6 cycles. That’s what they allowed in the control arm of the CASPIAN study [NCT03043872].¹

The question is: “Why not do the same thing with immunotherapy?” No one knows [the correct answer]. There are not much data to tell us one way or the other, so after 4 cycles [of immunotherapy treatment], I generally stop. It’s a judgment call, I think, beyond 6 cycles. In most circumstances you’re now talking about adding toxicities and a lack of significant benefit.

How do you define platinum-sensitive versus platinum-resistant SCLC?

There’s [some] strange terminology in SCLC, and physicians play around with it based upon their ease of utilization. Refractory disease is a situation where the patient progresses while on treatment. These patients have a more difficult circumstance and more aggressive disease. Refractory disease [indicates] no response to treatment. There’s also relapsed [disease], and the cutoffs are 90 days [or less, and] more than 90 days, in general. Less than 90 days is considered a resistant relapse. Patients [with a resistant relapse] might not do as well as patients who [relapse after] 90 days, which are considered sensitive relapses. A late relapse occurs at [approximately] 6 months [180 days]. In circumstances like this, the [most common] cutoffs that we have been using in SCLC are [less than] 90 days and more than 90 days. If you look at the package insert [for topotecan (Hycamtin)], [it is] approved for [use in patients who have progression after] 60 days.² For a patient who progresses a couple of months [eg, 2 months] after completion of platinum-based chemotherapy, that’s considered a resistant relapse. A patient who progresses after 90 days, which is about 3 months, would be considered to have a sensitive relapse.

What are your thoughts on the treatment options and the results of the poll?

Before we had any other pieces of data, topotecan was our main go-to. People were translated even into the resistant relapses even in the less-than-90-day settings. The data from the older topotecan studies suggest that the benefit is less, about 10%, but the response rates are not necessarily the whole story. Does it control the disease and so on and so forth is the issue.

Lurbinectedin seems to have caught favor with most of you, at 42%. About 21% would platinum rechallenge the patient. Twenty percent talk about clinical trial, which is never the wrong thing, and then topotecan.

What are the National Comprehensive Cancer Network (NCCN) recommendations for subsequent systemic therapy in patients with SCLC who experience disease progression?

[Current] NCCN guidelines [for patients with SCLC undergoing subsequent systemic therapy are divided by those who experience a relapse after] less than 6 months and those who have a [relapse after] more than 6 months.³ The [guidelines] do not parse out the recommendations for between 60 days or 90 days, etc. Any [patient] having [a relapse after] 6 months is considered as having a late relapse; therefore, a rechallenge with the original regimen is considered.

Lurbinectedin [(Zepzelca) is an option] for patients who have relapsed [after] 180 days. For patients [who have relapsed after] less than 6 months, you can consider topotecan, lurbinectedin, or a clinical trial. There are other recommended regimens, but the top 2 standard-of-care treatments are topotecan and lurbinectedin. Topotecan has been [available] for a long time, for progression after more than 60 days after initiation of front-line therapy. Lurbinectedin [received] accelerated approval for [patients with metastatic SCLC with disease progression on or after platinum-based chemotherapy].

[It is important to consider] the patient’s tolerance, prior therapies, and the timing of the relapse. Patients who progress while on treatment fare the worst, and those who progress in a short period of time after treatment do not do well on a long-term basis.

Can you describe the basket trial of lurbinectedin in patients with SCLC who experienced progression after front-line platinum-containing chemotherapy? What were the key efficacy results?

There was a phase 1 trial [NCT01970540] that used lurbinectedin with doxorubicin.4 Essentially, the trial showed [that] there was activity, there was a different way of dosing the treatment, and [it was associated with] a significant benefit for patients who had combinations of treatment even in resistant relapses. That [trial focused on outcomes occurring in] less than 90 days.

The phase 2 basket trial looked at 9 tumor types, and there were 105 patients with SCLC [NCT02454972].^5,6 These patients’ disease had progressed on platinum-based therapy. The requirements for those entering the trial were [absence of] brain metastases, ECOG performance status score less than or equal to 2, and only 1 prior line of chemotherapy. Treatment was given as 3.2 mg/m² [intravenously] every 3 weeks. Primary prophylaxis with granulocyte-colony stimulating factor was not allowed and probably not needed. The primary outcome was overall response rate. Most patients had an ECOG performance status score of 1, and there was a small proportion of never smokers in the SCLC cohort. [A total of] 30% had limited-stage disease and relapsed quickly. [Excepting the lungs], as expected, the most common sites [of cancer] were the lymph nodes, liver, and adrenal gland. CNS [central nervous system] involvement was seen in 4% of patients, [although] the trial design did not allow for patients to have any baseline CNS metastases.

PCI was given to 58% of patients previously. [A total of] 93% had 1 line of therapy, and 7% had a second line. [Approximately] 67% and 76% of patients had good responses,[partial and complete, respectively] to platinum therapy in the past. [A total of] 43% of patients [had a relapse within] 90 days and 57% [had a relapse after] 90 days.

There was a decent response of 35.2% in the overall population. The median duration of response was 5.3 months. [Among] patients who were responding, 43% were responding at 6 months. There [were no] complete responses. Most [35%] had a partial response. One-third had stable disease.⁵

Median progression-free survival for the patients who had [a relapse in] less than 90 days was 2.6 months. [For those with a relapse after] 90 days it was 4.6 months. Overall survival [OS] was 5 months in patients who had a chemotherapy-free interval less than 90 days [ie, resistant relapse] and 11.9 months for those who had an interval greater than 90 days.

What do we know about lurbinectedin in the second line for patients with SCLC who are candidates for a platinum rechallenge?

Results from a [prespecified] analysis [of patients with SCLC from the basket trial] were presented at the 2020 North America Conference on Lung Cancer by Vivek Subbiah, MD, from The University of MD Anderson Cancer Center and [recently published] in Lung Cancer.7 [Subbiah et al] looked at a small proportion of patients [from the] study who had a chemotherapy-free interval of more than 90 days [n = 20]. [This] scenario is considered a late relapse. What was outstanding was the median OS: 16.2 months. The overall response rate, [as determined by an] independent review committee, was 60.9%. The median number of cycles was 6.

Please discuss the adverse event (AE) profile for second-line lurbinectedin in the basket trial?

In the phase 2 study of lurbinectedin, there were many AEs,⁵ [but] they were not significant in general. Abnormalities in creatinine occurred. Hepatotoxicity is a well-known AE [with lurbinectedin] and drops in blood counts. Febrile neutropenia [of] grades 3 and 4 was experienced by approximately 5% [of patients] combined. One [case of] skin ulceration with extravasation occurred. Fatigue, nausea, and diarrhea are known AEs, [as well as] hematological toxicity, particularly neutropenia.

How do patients do on topotecan as a second-line therapy for SCLC?

Von Pawel et al [conducted a] study in 211 patients.8 [All patients] were considered sensitive to frontline therapy [but had] disease progression more than 60 days after its completion. 2 The trial compared topotecan and CAV [cyclophosphamide, doxorubicin, and vincristine].8 CAV was the standard of care. There were no differences in response rate, duration of response, time to progression, or OS.

OS was about 5.8 months [with topotecan] versus 5.7 months [with CAV] for patients with platinum-sensitive disease. Oral topotecan was found to be equal to IV [intravenous] topotecan.

US Oncology also participated in this network study. There was no significant difference in outcomes for patients based on oral versus IV. [Both] oral and IV [formulations] are approved for use.² There are other trials and other studies; these are the seminal kind of data that resulted in the approval [of topotecan].

What warnings and precautions are listed in the prescribing information for topotecan and lurbinectedin?

Interstitial lung disease and extravasation and tissue injury are the major issues with topotecan.2 There is an extravasation issue with lurbinectedin, but [it is listed as a warning] for topotecan. Myelosuppression, hepatotoxicity, and embryofetal toxicity are known problems with lurbinectedin.⁹ [The topotecan prescribing information also includes] the requirement that absolute neutrophil count is at least 1500 cells/ mm3 and platelet count [is at least] 100,000/mm³ [when] starting treatment. Reducing the dose or withholding the dose should be considered.

How do you modify dosing for lurbinectedin?

Practical considerations for lurbinectedin [include infusion] over 60 minutes at 3.2 mg/m² and dose reductions as [needed to] 2.6 mg/m² and 2 mg/m² for the first and second dose reductions, [respectively]. If a patient experiences grade 4 neutropenia, the drug [should be withheld] until neutropenia comes down to grade 1 [or less], then [resumed at a] reduced dose. If a patient has thrombocytopenia of grade 3 [or greater], withhold and then reduce the dose. If a patient has grade 2 hepatotoxicity, withhold until grade 1, but lurbinectedin can be resumed at the same dose. If a patient has\ grade 3 [hepatoxicity, withhold until grade 1 or less], and the dose should [be] reduced. These [AEs and necessary dose reductions] are not surprising.

What would you do if this patient had brain metastases?

[The basket] trial did not allow patients with CNS metastases [at baseline].5,6 But, there were up to 25% to 30% response rates with topotecan for patients with brain [metastases]. [In the trial, there was] a proportion of patients who did have brain metastases [at baseline], but they were treated and cleared of brain metastases. They were not active brain metastases. Patients might have had PCI. They might have had a few brain metastases that were treated.⁸

There is a concern [about overusing lurbinectedin in patients with brain metastases]. I find it very hard to believe that [patients with refractory/relapsed SCLC] will have a significant benefit with second-line [topotecan]. In resistant relapsed SCLC, the data are about 10% to 12%. It becomes an issue of benefit with the approximately 22% response rate.

The basket trial [with lurbinectedin] was a small, single-arm study with 105 patients, and not randomized. [In patients who] are free of brain metastases, I will recommend lurbinectedin over topotecan. If the patient is not doing well and their performance status is around 2, I favor lurbinectedin. [With topotecan,] I use the 5-day regimen, which is standard. That regimen has shown benefit. In the 3-day regimen or the weekly regimen, there are less efficacy data and they show less beneficial outcomes even in other disease states. The problem is that the 5-day regimen is not easy to do, it causes cytopenias, and you need to have primary prophylaxis. If the patient has asymptomatic brain metastases, I generally recommend topotecan with the hope that it will cross the blood-brain barrier and have an impact. [With] extremely short relapses, I don’t know if there’s any particularly great drug.

Are there any emerging data in this setting?

The phase 3 ATLANTIS trial [(NCT02566993) assessed] lurbinectedin plus doxorubicin versus [physician’s choice of] topotecan or CAV.¹⁰ Lurbinectedin 2 mg/m² [was given] with a flat dose of doxorubicin 45 mg/m² for 10 cycles, followed by lurbinectedin maintenance versus CAV or topotecan. [This design] was based upon a phase 1 study where they looked at the combination in this situation. In the past, they [observed] that when they combined a slightly different dosing, there was a response rate of 92% in 27 patients with a chemotherapy-free interval of greater than 90 days and a 5.8-month progression-free survival. For those with [an interval] less than 90 days, a response rate of 33% [was observed] with a progression-free survival of 3.5 months. [However, ATLANTIS was] a negative trial [according to a recent] press release.¹¹ The primary end point of OS was not met. The secondary end points favored the [lurbinectedin combination]. [The ATLANTIS trial did not use the] 3.2 mg/m² [dose of lurbinectedin], which is the standard accelerated approval FDA regimen. If [the secondary results] mirror that of the basket study, [this combination may be beneficial].

_References:

_{1. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN investigators. Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised, controlled, open-label, phase 3 trial. Lancet. 2019;394(10212):1929-1939. doi:10.1016/S0140-6736(19)32222-6}

_{2. Hycamtin (topotecan) for injection. Prescribing information. Novartis; 2018. Accessed March 10, 2021. https://bit.ly/3rAGX0F}

_{3. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 2.2021. Accessed March 1, 2021. https://bit.ly/3t1ffdU}

_{4. Calvo E, Moreno V, Flynn M, et al. Antitumor activity of lurbinectedin (PM01183) and doxorubicin in relapsed small-cell lung cancer: results from a phase I study. Ann Oncol. 2017;28(10):2559-2566. doi:10.1093/annonc/mdx357}

_{5. Trigo J, Subbiah V, Besse B, et al. Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial. Lancet Oncol. 2020;21(5):645-654. doi:10.1016/S1470-2045(20)30068-1}

_{6. Perez JMT, Leary A, Besse B, et al. Efficacy and safety of lurbinectedin (PM1183) in small cell lung cancer (SCLC): results from a phase 2 study. J Clin Oncol. 2018;36(suppl 15):8570. doi:10.1200/JCO.2018.36.15_suppl.8570}

_{7. Subbiah V, Paz-Ares L, Besse B, et al. Antitumor activity of lurbinectedin in second-line small cell lung cancer patients who are candidates for re-challenge with the first-line treatment. Lung Cancer. 2020;150:90-96. doi:10.1016/j.lungcan.2020.10.003}

_{8. von Pawel J, Schiller JH, Shepherd FA, et al. Topotecan versus cyclophosphamide, doxorubicin, and vincristine for the treatment of recurrent small-cell lung cancer. J Clin Oncol. 1999;17(2):658-667. doi:10.1200/JCO.1999.17.2.658}

_{9. Zepzelca (lurbinectedin). Prescribing information. Jazz Pharmaceuticals; 2020. Accessed March 10, 2021. https://bit.ly/3rDgQq1}

_{10. Farago AF, Drapkin BJ, Lopez-Vilarino de Ramos JA, et al. ATLANTIS: a phase III study of lurbinectedin/doxorubicin versus topotecan or cyclophosphamide/doxorubicin/ vincristine in patients with small-cell lung cancer who have failed one prior platinumcontaining line. Future Oncol. 2019 Jan;15(3):231-239. doi:10.2217/fon-2018-0597}

_{11. Jazz Pharmaceuticals and PharmaMar announce results of ATLANTIS phase 3 study evaluating Zepzelca in combination with doxorubicin for patients with small cell lung cancer following one prior platinum-containing line. News release. Jazz Pharmaceuticals. December 3, 2020. Accessed March 1, 2021. https://bit.ly/3v7Qhvo}