Late-Stage Therapeutic Options in Lung Cancer
During a live virtual event, Benjamin P. Levy, MD, discussed the results of the IMpower 133 and CASPIAN trials of immunotherapy for patients with extensive-stage small cell lung cancer.
Targeted OncologyTM: What data support the use of carboplatin/etoposide plus atezolizumab in extensive-stage small cell lung cancer (ES-SCLC)?
BENJAMIN P. LEVY, MD: This was [based on] the IMpower133 trial [NCT02763579]. This was published in the New England Journal of Medicine [in 2018].1 It had a very simple design: carboplatin/etoposide versus carboplatin/etoposide plus atezolizumab [Tecentriq] for treatment-naive ES-SCLC. Patients with treated asymptomatic brain metastases were eligible. Patients received 4 cycles of either carboplatin/etoposide/placebo or carboplatin/etoposide/atezolizumab, and then went onto atezolizumab maintenance versus placebo maintenance. The coprimary end points were overall survival [OS] and progression-free survival [PFS].
The PFS was [5.2 months versus 4.3 months with placebo].1 Certainly, it was a modest benefit between the 2. The tails on the Kaplan-Meier curve for PFS do continue to separate, so it was statistically significant. The hazard ratio was 0.77, and the P value was .02. So, there was a modest benefit in PFS.
What is probably the most important is that there was an OS advantage, 12.3 months in the atezolizumab arm versus 10.3 months in the placebo arm.2 Interestingly, the Kaplan-Meier curves are diverged, and landmark analysis at 18 months showed OS rates of 34% versus 21% for placebo; that’s not too shabby. A lot of these patients have not been followed up. We’ll see if these curves remain diverged. But, because of the survival advantage, we have seen an FDA approval with atezolizumab in combination with chemotherapy.3
If we look at the univariate analysis, which is just a way to look at clinically significant subset analyses, patients that had brain metastases didn’t seem to benefit, but it was a wide confidence interval. Patients with or without liver metastases seemed to benefit. Patients with a blood-based tumor mutational burden level over 16 in the blood did better than those with less than 16, but I think in the intent-to-treat analysis, all patients seem to derive a benefit, minus the 35 patients with brain metastases.
[Comparing] the objective response rates [ORR] between the 2 arms, there wasn’t a lot of difference—ORR in both arms was around 60%—because chemotherapy alone elicits such a response that it was hard to beat that.1 So, there wasn’t a lot of difference in terms of responses between the 2 arms.
We see the usual adverse events [AEs] that we see with immunotherapy. I would argue that immunotherapy in combination with chemotherapy does not give you a higher rate of immune-related AEs versus immunotherapy alone, via cross-trial comparison. The addition of chemotherapy doesn’t seem to exacerbate immune-related AEs. Overall, this is a pretty well-tolerated regimen, without additional toxicities.
What clinical trial data led to the approval of durvalumab (Imfinzi) for patients with ES-SCLC?
This was [based on] the CASPIAN study [NCT03043872]. It is a very similar study [to IMpower133]; this is a 3-arm study, but I would ignore the durvalumab/tremelimumab arm. I am looking at the addition of durvalumab to etoposide/platinum [etoposide plus cisplatin or carboplatin] versus etoposide/platinum alone. Patients who got etoposide/platinum alone did have the option to get prophylactic cranial radiation. Patients who got durvalumab plus etoposide/platinum went on to receive durvalumab maintenance. It had a very similar patient population to IMpower133: asymptomatic or treated and stable brain metastases were permitted, and patients must have measurable disease. There were 800 patients randomly assigned. The primary end point was OS.
The updated analysis from CASPIAN is pretty compelling. It may change my practice. The difference between the 2 arms is [11.8%]; [17.6%] of patients are alive at 3 years, which is pretty remarkable, versus only 5.8% in the platinum/etoposide arm.4 Median OS with durvalumab is [12.9] months versus 10.5 months with platinum/etoposide alone.
Interestingly, counter to the IMpower133 data, it seemed like patients with brain metastases still had a wide confidence interval [potentially favoring durvalumab]. They allowed patients with stage III disease, who also had a wide confidence interval.4 But, most subgroups seemed to benefit.
There weren’t a lot of differences in PFS between the 2 arms.5 I would say that landmark OS is a lot better than landmark PFS.
[In terms of] the ORR and duration of response, there was a little bit of difference. There was a little bit higher ORR with durvalumab/platinum/etoposide versus platinum/etoposide alone.6 We did see a difference here, where we didn’t necessarily see the difference in the IMpower133 study.
We didn’t see any new safety signals with immune-related AEs.6 Most of the AEs were grade 1 or grade 2, and it was a pretty well-tolerated regimen.
What did you think of the differences between the 2 trials?
You’re not supposed to do [direct] cross-trial comparisons, but we do [try to compare them]. The median OS is about the same in each of the experimental arms, 12.3 months in IMpower133 versus 12.9 months in CASPIAN.2,4 PFS is around the same, while response rates may be a little bit higher in CASPIAN, 67% for durvalumab versus 60% in the atezolizumab arm of IMpower133.1,6 Looking at the grade 3 AEs, they are pretty similar. Immune-related AEs are a little bit higher in IMpower133 than in CASPIAN–almost double, interestingly enough. It is interesting to see that difference, and I don’t have a biological explanation as to why.
1. Horn L, Mansfield AS, Szczęsna A, et al. 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
2. Liu SV, Reck M, Mansfield AS, et al. Updated overall survival and PD-L1 subgroup analysis of patients with extensive-stage small-cell lung cancer treated with atezolizumab, carboplatin, and etoposide (IMpower133). J Clin Oncol. 2021;39(6):619-630. doi:10.1200/JCO.20.01055
3. FDA approves atezolizumab for extensive-stage small cell lung cancer. FDA. March 19, 2019. Accessed July 28, 2022. https://bit.ly/2Jkowds
4. Paz-Ares LG, Chen Y, Reinmuth N, et al. Durvalumab, with or without tremelimumab, plus platinum-etoposide in first-line treatment of extensive-stage small-cell lung cancer: 3-year overall survival update from CASPIAN. ESMO Open. 2022;7(2):100408. doi:10.1016/j.esmoop.2022.100408
5. Goldman JW, Dvorkin M, Chen Y, et al. 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. 2021;22(1):51-65. doi:10.1016/S1470-2045(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(15_suppl):9002. doi:10.1200/JCO.2020.38.15_suppl.9002