Evaluating the IMpower133 Trial of Atezolizumab for Patients with ES-SCLC

Balazs Halmos, MD, MS

During a Targeted Oncology Case-Based Roundtable event, Balazs Halmos, MD, MS, discussed the case of a 73-year-old patient with early-stage small cell lung cancer (ES-SCLC).

Targeted Oncology^TM: What data support the use of this regimen for such a patient with ES-SCLC?

HALMOS: The IMpower133 study [NCT02763579] was the first dually pivotal study to show the benefit of immunotherapy in the frontline setting for [ES-SCLC].¹ It was a large study of over 400 patients with extensive-stage disease, good performance status, and no prior treatment. It did allow patients with treated asymptomatic brain metastases, but not untreated. The stratification factors included sex, performance status, and brain metastases.

The randomization was straightforward, [induction with] carboplatin [CP] plus etoposide [E] plus atezolizumab [Tecentriq] in 1 cohort [vs placebo plus CP plus E in the second cohort]. [Induction therapy was given in four 21-day cycles], not 6; that’s important to remember. [After that, the cohort receiving atezolizumab received maintenance therapy with atezolizumab; those who received placebo during induction received placebo during maintenance.] The coprimary end points were overall survival [OS] and PFS [progression-free survival].

Please discuss the efficacy of the IMpower133 trial. OS is our true benchmark for measuring benefit. There was a median OS benefit of 2 months, which usually is viewed as a significant benefit by patients and by regulatory agencies. This reached that benchmark; it is a positive study with a hazard ratio [HR] of 0.7 [85% CI, 0.54-0.91; P = .007].

Just as important, or more important, is [that there was] some durable benefit of the checkpoint inhibitor. The longer follow-up in the CASPIAN [NCT03043872] and the IMpower133 study shows maybe about 10% of patients can stay well without progression long-term, as opposed to 0% or so without immunotherapy.^2,3 There are a small fraction of patients who seem to do exceedingly well. We’re unable to figure out yet who those patients will be.

The breakdown of subsets that do or do not benefit show that most of the patients [seem to have an OS benefit from] the addition of atezolizumab, [even though there were small subsets where the benefit may not be obvious].² [For example, those with brain metastases did not appear to benefit as much as those without brain metastases. However, this was a small number;] only 35 of those patients had brain metastases.^2,4 But it’s maybe something to highlight [for future study]. [Additionally,] the blood-based TMB [tumor mutational burden] determination by ctDNA [circulating tumor DNA] [didn’t appear to be a useful predictive biomarker for successful treatment outcomes with atezolizumab plus CP and E].

For this trial, they used blood-based TMB. Do you think going forward they will use tissue-based TMB?

I think the big problem with SCLC is that most studies have a hard time collecting tissue. Because in clinical practice, we get tiny specimens. This is a challenging disease to get a consistent [tissue] specimen, and be able to use that for deep-field analysis such as tissue-based TMB. I definitely see the benefit of a blood-based assay for this particular disease and also, SCLC has a high yield when it comes to ctDNA positivity.

In a way, it could be a realistic biomarker as opposed to some other cancer types where you don’t detect it. Almost 100% have some ctDNA in SCLC. I’m intrigued by it and in reality, there are trends. However, there’s no group that doesn’t benefit. What did the biomarker help if it just showed the spectrum of benefit, but didn’t identify who or who should not receive the drug? It doesn’t seem to be forceful enough or strong enough at present. I think it needs to continue to be investigated in biomarkers.

The number of patients with brain metastases was small, but these patients had a median OS of 1 month less on atezolizumab (8.5 months vs 9.7 months; HR 0.96; CI 95%, 0.46-2.01).2,4 Would this prompt you to not use it in patients with brain metastases?

The HR overall doesn’t look at the median value.^2,4 It looks at the overall separation of the curves. It’s still below 1.00, but just a tiny bit. But it’s 35 patients. I wouldn’t put too much weight on it, but maybe it highlights a potential issue that future studies are going to need to look at. We look at this very specific question in the CASPIAN study.^3,5 Because there, the results look a little bit more favorable.

I think 1 thing that you see is patients with brain metastases do worse because the median survival here is 8 to 9 months versus the 12 months otherwise.^2,4 This is definitely a poor prognosis subset, and I wouldn’t be too surprised if they have lesser benefits long-term from checkpoint inhibition. But we still tend to recommend immunotherapy, and we look at the CASPIAN study for this very specific question.^3,5

The response rates [in IMpower133] are somewhat higher with the addition of atezolizumab, but not dramatically.^1,2 If you look at [objective confirmed] responses, it’s almost the same, [60% with atezolizumab] and 64% [with placebo], so really no significant difference. There was ongoing response at 2 years. It’s the durable benefit of 9% versus 2%.

Adverse events [AEs] are very important. Chemotherapy has substantial toxicity and immunotherapy adds to that for immune-related AEs. Typically, in this context, neither atezolizumab nor durvalumab [Imfinzi] adds a significant percentage of high-grade AEs.^1,6,7

Which trial looked at durvalumab in this setting? The CASPIAN study added durvalumab to an E plus platinum [P] regimen.⁵ It was the clinician’s choice; they could have decided to use carboplatin versus cisplatin. There was a third arm looking at tremelimumab, which is a CTLA-4 [immune checkpoint protein] that has failed to find much of a home in oncology. Unfortunately, there’s been a lot of failed studies with it. But this study was positive for the arms of durvalumab plus chemotherapy versus chemotherapy [alone].

The immunotherapy plus chemotherapy cohorts received up to 4 cycles of EP plus durvalumab with or without tremelimumab. Not everybody in the chemotherapy-only cohort got [6 cycles], but I think about 60% of the patients [did]. This was a fairly heavily treated patient population in the control arm.

The OS was almost a copy of the IMpower133 data. [At 2 years, the OS in the CASPIAN study for those who received durvalumab plus EP was 12.9 months, compared with 10.5 months in those who received EP (HR, 0.75; 95% CI, 0.06-0.95; P = .0154)].^2,8 Adding tremelimumab provided no benefit in terms of the OS.8 The median OS was 10.4 versus 10.5 months, respectively, and the HR was 0.82 [95% CI, 0.68-1.00; P = .451]. It’s not significant. Now, of course, you would hope for this to be better than the other experimental arm, not just the chemotherapy arm. Tremelimumab didn’t add anything. In fact, if anything, it made the results a little bit less impressive. There’s no place for it.

Despite the fact that the control arm got 2 more cycles of chemotherapy on average, there was no early benefit for the control arm for the added chemotherapy. PFS at 6 months was 45.4% [95% CI, 39.3-51.3%] with durvalumab plus EP, and 45.8% [95% CI, 39.5-51.9%] with EP.8 At 24 months it was 11% [95% CI, 7.5-15.2%] with durvalumab plus EP, and 2.9% [95% CI, 1.2-5.8%] with EP—almost an identical experience as with the IMpower133 study]. One thing that I’ve definitely taken away from this study is not to use any more than 4 cycles of chemotherapy for patients with ES-SCLC.

The subset analysis [for the CASPIAN study showed that those] younger than 65 years old benefited more [HR, 0.76; 95% CI, 0.59-0.97] than those 65 and older [HR, 0.92; 95% CI, 0.69-1.22].⁸ Now, what I failed to mention, [is patients who had brain metastases that were] asymptomatic or [treated and stable off steroids and anticonvulsants] were allowed [in the study].5 There were no real differences in terms of the HR in those who had brain metastases.⁸

The objective response rates were about 10% higher with the addition of durvalumab to EP, at 67.9% [odds ratio, 1.53; 95% CI, 1.08-2.18], [compared with 58% with EP treatment]. Certainly, it’s much more impressive for immunotherapy patients than patients who have received only chemotherapy. The median duration of response was 5.1 months for both durvalumab plus EP and the control group.

The safety summary showed that grade 3 to 4 AEs are frequent, as expected with a platinum-based regimen, 70% in the durvalumab plus EP plus tremelimumab cohort, 62.3% with durvalumab plus EP, and 62.8% with EP.³ The experimental and control arm percentages are nearly identical. Immune-mediated AEs are much more frequent as expected in the immunotherapy arm, at 20% with durvalumab plus EP versus 3% with EP.

How do CASPIAN and IMpower133 compare? Is there anything that could determine how you pick between 1 drug versus the other?

They’re not supposed to do cross-trial comparisons, but these 2 studies, in my mind, are total copycats of each other. It’s unbelievable how well they match each other when you look at PFS [approximately 5 months for both studies’ treatment arms] or OS [approximately 12 months for both studies’ treatment arms].^1-3,5,8 The HR is 0.76 [in IMpower133] versus 0.75 [in CASPIAN] and even the AEs seem to be matching. In a way, it’s nice to see that the clinical trial can be replicated.

Let’s consider some practical issues you need to think about in your practice. Atezolizumab is approved only with carboplatin plus E; durvalumab is approved with E and either carboplatin or cisplatin.^6,7 Each drug is given every 3 weeks with chemotherapy. Afterward, durvalumab traditionally has been given every 4 weeks. Atezolizumab, in IMpower133, was given every 3 weeks but can be given [every 2 weeks or even every 4 weeks]—not a lot of differences. If your institution buys them at a different rate, that could make the difference.

Is there a difference in cost?

We bring it up each and every time and it seems like the most logical thing to do for companies to go down on the price a little bit. I don’t think either company has done that. I think they’re priced just around the same. But definitely, there’s some movement in that direction in the future— the generic immunotherapies that are being started and the subcutaneous versions. There are going to be developments, but for the coming years, I think you have 2 truly equal choices. Both are really a major breakthrough in a way for SCLC. I think both are totally appropriate to use. We just need to come up with your own decision tree.

_REFERENCES:

_{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):22202229. doi:10.1056/NEJMoa1809064}

_{2. 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). Abstract presented at: The 44th European Society for Medical Oncology Conference September 27, 2019-October 1, 2019. Ann Oncol. 2019;30(suppl 5):v710-717. doi:10.1093/annonc/mdz264}

_{3. Paz-Ares L, Dvorkin M, Chen Y, et al. 9002 - 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. Accessed June 2, 2021. Abstract presented at: The 2020 Annual Meeting of the American Society of Clinical Oncology. Accessed June 2, 2021. doi:10.1200/ JCO.2020.38.15_suppl.9002}

_{4. 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):619630. doi:10.1200/JCO.20.01055}

_{5. Paz-Ares L, Dvorkin M, Chen Y, et al. 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. Tecentriq. Prescribing information. Genentech, Inc; 2021. Accessed May 29, 2021. https://bit.ly/3x7cSJ1}

_{7. Imfinzi. Prescribing information. AstraZeneca Pharmaceuticals LP; 2021. Accessed May 29, 2021. https://bit.ly/34WOzky}

_{8. 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/S0140-2045(20)30539-8}