Bordoni Compares Trials in Extensive-Stage Small Cell Lung Cancer

During a virtual Targeted Oncology Case-Based Roundtable event, Rodolfo Bordoni, MD, director of Clinical Research at Georgia Cancer Specialists, discussed the clinical trials in the extensive-stage small cell lung cancer space.

Targeted Oncology^TM: How would you approach treating this patient? What additional workup would you order to inform your treatment recommendation (eg, PD-L1 expression)?

BORDONI: I don’t [test] for PD-L1 expression. [Treatment guidelines have] some stratification for patients with SCLC now that anti–PD-1/PD-L1 agents [are available]. We don’t [use these agents] because the trials didn’t consider PD-L1 expression in the eligibility criteria. In terms of workup, we don’t do a bone marrow biopsy [unless] the patient has severe cytopenia or there is suspicion that the patient may have a hematological or another specific underlying condition.

Is PD-L1 expression low in patients with SCLC?

About 4 years ago, we [conducted] a clinical trial in SCLC and some of the patients that were heavy smokers had high PD-L1 expression. That’s common in patients with small cell cancer.

Is immunotherapy an option for second-line therapy in SCLC?

Immunotherapy [can be used] in the second line. Lurbinectedin [Zepzelca] is now approved for second-line therapy. It’s chemotherapy, and those patients have to be selected in most cases. You have to use a growth factor stimulant [during treatment] because neutropenia can be significant. I used it 3 times. I didn’t have to use growth factors for the first cycle. That would probably be the best treatment for patients [resistant to first-line immunotherapy]. I wouldn’t go on another same-family anti–PD-1/PD-L1.

Ipilimumab [Yervoy] plus nivolumab [Opdivo] [is another option]. We have a phase 1/2a clinical trial right now [with] nivolumab and a second-generation ipilimumab that is about 10 times more effective. [Such] patients may qualify. This is a cohort expansion, so you don’t have to wait.

What are the National Comprehensive Cancer Network (NCCN) recommendations for this setting?

[According to] the NCCN guidelines for adjuvant and systemic therapy in ES-SCLC, the preferred [combinations are] carboplatin plus etoposide plus atezolizumab [Tecentriq], followed by [atezolizumab] maintenance; carboplatin plus etoposide plus durvalumab [Imfinzi] followed by durvalumab maintenance; and cisplatin plus etoposide plus durvalumab followed by durvalumab maintenance.1 If a patient cannot receive immunotherapy, others options are carboplatin/etoposide or] cisplatin/etoposide, and in very limited situations, carboplatin or cisplatin [plus] irinotecan. On March 30, 2020, the FDA approved durvalumab plus the standard-of-care chemotherapy as first-line therapy for ES-SCLC.²

Can you describe the IMpower133 study (NCT02763579) and how this regimen impact survival?

IMpower133 was a phase 3, randomized clinical trial of carboplatin, etoposide, and atezolizumab, followed by atezolizumab [maintenance in] patients with measurable ES-SCLC by RECIST criteria, good performance status, and no prior systemic therapy.³ Patients were treated for symptomatic brain metastases and if [they] became stable and the disease was under control by clinical and radiological parameters, they were eligible for randomization. There was [patient] stratification [by presence or absence of] brain metastases. The randomization was 1:1. Induction therapy was 4 cycles, 21 days each of atezolizumab [flat dose of 1200 mg intravenously (IV) on day 1] plus carboplatin and etoposide. The control group received placebo plus carboplatin [area under the curve of 5 mg/mL/min IV on day 1] plus etoposide [100 mg/m² IV, days 1 to 3].

Atezolizumab was used in the maintenance phase, in [both] the experimental and placebo groups, at the same dose for a control. Treatment was given until [disease] progression or loss of clinical benefit, and prophylactic cranial irradiation was indicated per local standard of care. The coprimary end points [were overall] survival [OS] and progression-free survival [PFS], and some secondary end points [were objective] response rate, duration of response, and safety.

[For the Kaplan-Meier estimates] of OS, there was no early separation of the curve, but then [the curves] separated with a nice area under the curve. Median OS was 12.3 months for atezolizumab and chemotherapy versus 10.3 months for chemotherapy. One-year survival was 52% for atezolizumab and 38% for chemotherapy alone, with an HR that was significant at 0.70 [P = .007]. PFS also favored atezolizumab [HR, 0.77; P = .02]. One-year PFS was 12.6% [with initial atezolizumab and chemotherapy] versus 5.4% with initial chemotherapy alone. Median OS in the intention-to-treat population [median follow-up, 23 months] was 12.3 months versus 10.3 months, with a P value of .01.

What results stood out from the subgroup analysis of 2-year OS from IMpower133?

In a subgroup analysis of 2-year OS, every patient benefited from the intervention of chemotherapy and immunotherapy.⁴ However, brain metastasis was a poor prognostic factor. [The question is:] Was it a poor prognostic factor with the addition of immunotherapy to chemotherapy, or was it a poor prognostic factor for survival of [those] patients because of the underlying disease in the brain? The response rate at 2-year followup was 9.1% versus 2.3% for the atezolizumab and control [groups, respectively].

How did the adverse event (AE) profiles compare between the atezolizumab and control groups in IMpower133?

There were no significant differences [in the AE profiles of the 2 regimens in IMpower133].³

What was the design of the CASPIAN (NCT03043872) trial, and what were the key efficacy takeaways?

The CASPIAN trial was a phase 3 [trial] of very similar design [to IMpower133]; however, randomization was a 1:1:1 because there was a third arm.5 Durvalumab [was given with or without tremelimumab] in addition to chemotherapy every 3 weeks for 4 cycles followed by durvalumab maintenance until [disease] progression. The control arm was the same chemotherapy every 3 weeks for a total of 6 cycles, and prophylactic cranial irradiation was optional in the maintenance setting, but there was no maintenance treatment as a standard of care. The primary end point was OS. The secondary end points were PFS, overall response rate, safety, and patient-reported outcomes. [Eligible] patients were treatment- naive, had a good performance status, had asymptomatic or treated and controlled brain metastases, and had measurable disease by RECIST criteria. [A total] of 805 patients were randomized; this was a [large] clinical trial of patients with ES-SCLC.

OS was very similar to [IMpower133], with a median OS of 12.9 months [for durvalumab and chemotherapy] versus 10.5 months for the control, with an HR of 0.75 [P = .0032].^6,7 At 2 years, OS was 22% versus 14% in favor of durvalumab. After separation [in the Kaplan-Meier curve] around 6 to 8 months, the area under the curve was [similar] to the tail of the curve.

In a subgroup analysis of OS, patients who had liver metastases did poorly. The addition of the immunotherapy [was favorable] for patients [without] liver metastases. [Perhaps] this [outcome in patients with liver metastases was] because of the poor prognosis given by disease in the liver, maybe the burden of disease.

In an updated [analysis with median follow-up of 25.1 months], PFS was 5.1 months and 5.4 months for the durvalumab plus chemotherapy [and] the chemotherapy alone [groups, respectively]. The HR was 0.80. Confirmed objective response rate was interesting, at 68% for patients given durvalumab and chemotherapy versus 58% [given chemotherapy alone]. [Although] this difference seems significant, it didn’t translate into an improvement in duration of response. The median duration of response was 5.1 months in each arm.

For [durvalumab/tremelimumab/chemotherapy vs chemotherapy alone], the addition of tremelimumab didn’t change OS. [It] may have been detrimental on the effect of durvalumab in this group of patients.

What were the AE profiles of the durvalumab regimens in the CASPIAN trial, and how do they compare with those from IMPower133 (ie, atezolizumab)?

There was nothing significant [for safety in the CASPIAN trial]: [for AEs], all grades; 98.1% and 97.0% [for the durvalumab and chemotherapy group vs chemotherapy alone group]; grades 3/4, 62.2% [vs] 62.8%; serious AEs, 32.1% versus 36.5%.6 [However,] immune-mediated AEs were 10 times higher [20.0% vs 2.6%] with durvalumab [and chemotherapy than] control.

In a comparison of data [from] IMpower133 [atezolizumab plus chemotherapy] and CASPIAN [durvalumab plus chemotherapy], grade 3 AEs were more or less identical.3-7 For the [length of] follow-up [23 and 25 months, respectively], the number of patients randomized, and the intensity of treatment, there was a bit of a difference, maybe [more] favorable in CASPIAN. OS was 12.3 months with atezolizumab [plus] chemotherapy, 12.9 months with durvalumab [plus chemotherapy], and [similar for the] control arm [10.3 and 10.5 months, respectively]. The HRs for both trials were [similar, 0.76 and 0.75, respectively]. PFS was a little [longer] in the chemotherapy alone arm [5.4 months] than durvalumab plus chemotherapy [5.1 months], but the durvalumab and atezolizumab groups were similar [5.2 and 5.1 months, respectively]. The HRs were similar [in the IMpower133 and CASPIAN trials, (0.77 and 0.80, respectively)]. The HR was higher in the CASPIAN trial, probably because patients in the control arm did better in this trial.

Grade 3 or higher [AEs occurred in] 67.7% of patients given atezolizumab and 62.3% given durvalumab.^4-6 Some [physicians] believe that the 4% or 5% [difference] may be significant and a reason to use one [immunotherapy] versus another immunotherapy. I believe it’s different ways to measure. [For example], immune-related AEs were reported in 41% of the atezolizumab group versus 20% of the durvalumab group.4-7 For the control arms [ie, chemotherapy only], immune-related AEs occurred in 24% of [patients from IMpower133] versus 2.6% for [CASPIAN]. It [relates to] a different way to analyze and report, as well as grade, the AEs. The differences in AEs are difficult to compare—different regimens, different trials.

What was your reaction to the updated CASPIAN data? Will it affect your practice?

We were using the atezolizumab. We were comfortable with it, and now we have another option, and probably there is a third option that is going to be available soon. Because the [AE profiles] are similar, the little differences become difficult to evaluate and compare. They are equivalent. I choose the regimen [with which I am most] comfortable.

How do you address these possible immune-related AEs? What supportive care do you routinely offer patients with ES-SCLC?

You need to know the baseline to grade these immune-related AEs. Three or 4 times a day could be between grades 1 and 2, and the strategy will be different.

I would try to rule out infectious disease. I would follow the patient every day to see the direction this goes. I would definitely hold the immunotherapy for 3 or 4 weeks. I’m not sure [if I would] intervene. If the patient is able to drink, eat, and take some diarrhea medicine and doesn’t have any definite evidence of dehydration, some [physicians won’t] intervene until it is grade 3—for instance, with pembrolizumab [Keytruda] in the advanced setting for lung cancer and other conditions. This is a difficult question. I would follow the patient, [provide] full supportive care, give no corticosteroids, and hold the immunotherapy.

For the management of the patients with grade 3/4 diarrhea, you [can] start with a corticosteroid, but you need to be very attentive, because some of these patients don’t respond well, even [at a dose of] 2 mg/kg per day, and those patients may need another immunosuppressant agent.

_References:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 2.2021. January 11, 2021. Accessed March 5, 2021. https://bit.ly/38QiEoc}

_{2. FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. March 30, 2020. Accessed March 17, 2021. https://bit.ly/3s1jjuE}

_{3. Horn L, Mansfield AS, Szczęsna A, et al; IMpower133 study group. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer. N Engl J Med. 2018;379(23):2220-2229. doi:10.1056/NEJMoa1809064}

_{4. Reck M, Liu SV, Mansfield AS, et al. 17360 - IMpower133: updated overall survival (OS) analysis of first-line (1L) atezolizumab (atezo) + carboplatin + etoposide in extensive-stage SCLC (ES-SCLC). Ann Oncol. 2019;30(suppl 5):v710-717. doi:10.1093/annonc/mdz264}

_{5. 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}

_{6. Paz-Ares L, Dvorkin M, Chen Y, et al. Durvalumab Å} tremelimumab + platinumetoposide in first-line extensive-stage SCLC (ES-SCLC): updated results from the phase III CASPIAN study. J Clin Oncol. 2020;38(suppl 15);9002. doi:10.1200/JCO.2020.38.15_suppl.9002}

_{7. Goldman JW, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab, with or without tremelimumab, plus platinum–etoposide versus platinum–etoposide alone in first-line treatment of extensive-stage small-cell lung cancer (CASPIAN): updated results from a randomised, controlled, open-label, phase 3 trial. Lancet Oncol. 2020;22(1):51-65. doi:10.1016/S1470-2045(20)30539-8}