Mooradian Compares IMpower133 and CASPIAN Trials in ES-SCLC

During a Targeted Oncology™) Cased-Based Roundtable event, Meghan Mooradian, MD, a clinical oncologist inMedical Oncology at Massachusetts General Hospital and instructor of Medicine Harvard Medical School in Boston, Massachusetts, discussed the case of a 73-year-old patient with extensive stage-small cell lung cancer (ES-SCLC).

Targeted Oncology^TM: What treatment regimen wouldyou recommend for this patient?

MOORADIAN: The current National Comprehensive Cancer Network ES-SCLC guidelines, which were updated in [August], look at the preferred regimens based on both the IMpower133 trial [NCT02763579], which is carboplatin/etoposide/atezolizumab [Tecentriq], as well as the CASPIAN trial [NCT03043872], which is cisplatin or carboplatin plus etoposide/durvalumab [Imfinzi]. Both regimens recommend immune checkpoint inhibitors [ICIs] maintenance therapy. For patients who are not immunotherapy candidates or for whom immunotherapy is not an option for whatever reason, chemotherapy alone is an option with category 2 evidence.¹

What data support the addition of the ICI atezolizumab to platinum-plus-etoposide chemotherapy?

The patients enrolled in the IMpower133 [trial] were treatment-naive patients with newly diagnosed ES-SCLC. Patients with treated asymptomatic brain metastases were eligible for enrollment. They were randomized 1:1 to either the triplet therapy of carboplatin/etoposide/atezolizumab followed by atezolizumab maintenance or [to] carboplatin/etoposide/placebo [followed by placebo maintenance]. The coprimary end points were overall survival [OS] and progression-free survival [PFS]. Key secondary end points included objective response rate [ORR], duration of response [DOR], and safety.²

The initial data, which showed median follow-up at about 14 months, demonstrated a 2-month OS benefit for the triplet arm. At 1 year, 52% of patients were alive in the triplet arm vs 38% in the chemotherapy-alone arm. Like other immunotherapy trials, there wasn’t a stark difference in the median PFS, but the PFS at 1 year had a benefit for the immunotherapy group, with 12.6% of patients alive at 1 year vs 5.4% in the chemotherapy-alone arm.²

At 2 years, the median OS was 12.3 months for the immunotherapy arm vs 10.3 months for the chemotherapy-alone arm [HR, 0.76; 95% CI, 0.60-0.95; P = .0154].²

Many of the subgroups showed a benefit for the immunotherapy arm, though there was no stark effect on those with brain metastases [HR, 0.96; 95% CI, 0.46-2.01]. Time will tell what can be done in this population that has an unmet need. Importantly, both PD-L1 and tumor mutation burden [TMB] were not incredibly prognostic. Whether someone had high or low TMB, the outcomes favored the immunotherapy arm. There was a stark difference in hazard ratio between those with higher TMB [HR, 0.58; 95% CI, 0.34-0.99] vs lower TMB [HR, 0.73; 95% CI, 0.49-1.08].³

The ORR of chemotherapy alone is often quite good in SCLC, with historic data ranging anywhere from 60% to 80% response rate. There was no stark improvement in response rates with the addition of immunotherapy. In some trials, patients have durable responses with the addition of immunotherapy, but the ORR is similar between groups. Most of these patients had partial responses, but in terms of an ongoing response at 2 years, the immunotherapy cohort showed a benefit of 10% vs 2% for those on chemotherapy-alone arm.^2,3

Safety was reasonable for the immunotherapy arm. There wasn’t a substantial increase in grade 3 or 4 adverse events [AEs] for the atezolizumab group compared with the placebo group. General toxicities primarily related to chemotherapy were similar in both groups.2

What data support the addition of the ICI durvalumab to platinum-plus-etoposide chemotherapy?

The patients enrolled in the CASPIAN trial were treatment-naive patients with extensive-stage disease and a good World Health Organization performance status. Patients with asymptomatic or treated and stable brain metastases were eligible. They had measurable disease by RECIST, and the 805 patients were randomized 1:1:1 to durvalumab plus tremelimumab, which is a novel CTLA-4 antagonist, plus chemotherapy; durvalumab/ etoposide plus carboplatin or cisplatin; or etoposide plus carboplatin or cisplatin [EP] alone, which was the standard-of-care arm.

The difference in this trial was that carboplatin or cisplatin could be used and patients had the ability to be treated for up to 6 cycles in the control arm, in contrast with the IMpower133 study in which only carboplatin was used and patients were treated for 4 cycles. [The arms containing durvalumab continued with it as maintenance until progression of disease, and patients in the standard-of-care arm] were eligible for optional PCI [prophylactic cranial irradiation] if indicated. Primary end point was OS, and secondary end points [were PFS, ORR, safety and tolerability, and patient-reported outcomes].⁴

Like the IMpower133 study, this study met its primary end point with an improvement in OS in the durvalumab-plus-chemotherapy arm with a margin of 2 months and a near identical hazard ratio of 0.75, which is very similar to the IMpower133 study. At 2 years, 22% of patients were alive in the immunotherapy arm vs 14% in the chemotherapy-alone arm.⁵

In the subgroups, there was improvement across the board in the immunotherapy arm, although several areas crossed the confidence interval of 1. Patients with central nervous system or brain metastases had a slightly better hazard ratio of 0.79 compared with 0.96 for the IMpower133 study, but both crossed the confidence interval—so again highlighting a somewhat unmet need in this population. Generally, there was an improvement when immunotherapy was added for most patients with newly diagnosed ES-SCLC.5

The median PFS [was not impressive for the immunotherapy vs chemotherapy-alone arm], but there could be a benefit in DOR.5

There was a statistically significant benefit in ORR when durvalumab was added to EP. It was 68% in the immunotherapy arm vs 58% in the chemotherapy-alone arm. The median DOR, though similar at the landmark of 12 months, favored the addition of immunotherapy at 24 months. Hopefully, this benefit will plateau and persist beyond 2 years of therapy.⁶

The [durvalumab-tremelimumab-chemotherapy] arm did not meet the prespecified end point. [The median OS was 10.4 months vs chemotherapy alone, which was 10.5 months (HR, 0.82; 95% CI, 0.68-1.00; P = .0451)]. It was not statistically significant in terms of improvement in OS, so this was a negative arm in the study. Although we saw durvalumab plus chemotherapy improve OS, adding tremelimumab did not show that improvement and only added toxicities.⁵

All AEs were seen across the spectrum, but grade 3 or 4 toxicities were highest in the dual-ICI-plus-chemotherapy arm. The immune-related adverse events [irAEs] were 36% in the dual-ICI-plus-chemotherapy arm, 20% in the durvalumab-plus-chemotherapy arm, and 2.6% in the chemotherapy-alone arm. AEs leading to death [grade 5] were very similar between the durvalumab-plus-chemotherapy arm [and the] chemotherapy-alone [arm].6

How do the data from the IMpower133 and CASPIAN trials compare?

The IMpower133 and CASPIAN trials had very similar median follow-ups, OS data, and hazard ratios, which were 0.76 and 0.75, respectively. The ORR seemed to favor the CASPIAN study at 68% vs 60%. The control arms were different with the IMpower133 arm receiving 4 cycles or less of carboplatin, whereas the control arm of CASPIAN received up to 6 cycles of either carboplatin or cisplatin and optional PCI if indicated.^2-4,6

The occurrence of irAEs in the immunotherapy arm was 41% in IMpower133, which is higher than historical data, and 20% in the CASPIAN trial. A reason for this difference could be the trial design of IMpower133, which was a double-blind study, and CASPIAN was an open-label study. This could have allowed the investigators to better attribute toxicity when it occurred.^2,6

Atezolizumab with chemotherapy is usually administered [every 3 weeks before chemotherapy, and] then after 4 cycles of chemotherapy, [it can be given every 2, 3, or 4 weeks, depending on dosage].⁷ Durvalumab is typically given every 3 weeks in combination with chemotherapy and then every 4 weeks as a single agent in the maintenance phase.⁸ The warnings and precautions are very similar for both immunotherapy agents, with irAEs being predominant.

_REFERENCES:

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small Cell Lung Cancer, version 2.2021. Accessed August 22, 2021. https://bit.ly/3yb9pc8}

_{2. 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}

_{3. Reck M, Liu SV, Mansfield AS, et al. 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-v717. doi:10.1093/annonc/mdz264}

_{4. Paz-Ares L, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab plus platinum-etoposide vs 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}

_{5. Goldman JW, Dvorkin M, Chen Y, et al; CASPIAN Investigators. Durvalumab, with or without tremelimumab, plus platinum-etoposide vs 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. 2021;22(1):51-65. doi:10.1016/ S0140-2045(20)30539-8}

_{6. Paz-Ares LG, Dvorkin M, Chen Y, et al. Durvalumab ± tremelimumab + platinum-etoposide 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. Tecentriq. Prescribing information. Genentech Inc; 2021. Accessed August 22, 2021. https://bit.ly/2XMjHmBc}

_{8. Imfinzi. Prescribing information. AstraZeneca; 2021. Accessed August 22, 2021. https://bit.ly/3D9wgZe}