Wozniak Discusses Benefits of New Treatments in Extensive-Stage SCLC

Antoinette Wozniak, MD

Hematology/Oncology

UPMC Hillman Cancer Center

Pittsburgh, PA

Targeted Oncology^TM: Can you discuss the National Comprehensive Cancer Network (NCCN) guidelines for extensive-stage small-cell lung cancer (ES-SCLC)?

WOZNIAK: The preferred treatment, [according to the NCCN guidelines], is carboplatin [Paraplatin]-etoposide [Etopophos]-atezolizumab [Tecentriq] or carboplatin-etoposide-durvalumab [Imfinzi].¹ You also get maintenance therapy, and you can use cisplatin, but I don’t feel that there’s any advantage to using cisplatin in extensive-stage disease. Of course, if you don’t feel you can use immunotherapy because of comorbidities or other issues with the patient, then it would be doublet chemotherapy alone.

In certain circumstances, and I can only think of one [time] when I did this, there is the option of using irinotecan [Camptosar]….Several years ago there was a study that came out of Japan, when irinotecan came out and we were looking for better treatments.²

It was cisplatin and irinotecan vs cisplatin and etoposide, and in the Japanese population, cisplatin and irinotecan turned out to be significantly better in terms of survival. Then 2 studies were done in the United States: one that mimicked the Japanese study and one that was a little different in terms of the schedule of the drug, but they were both negative and…both the same. The only time I’ve used it was several years ago; there was an etoposide shortage and I used it, but other than that I don’t know [whether] anybody else uses irinotecan and platinum.

Can you discuss the IMpower133 trial (NCT02763579)?

The IMpower133 trial data were presented at the IASLC [International Association for the Study of Lung Cancer] meeting in September 2018.³ Patients [in the trial] were randomized 1:1 to receive chemotherapy in the form of carboplatin and etoposide with or without atezolizumab. Patients got atezolizumab maintenance or placebo until progression, and researchers did gather some information on PD-L1 but they did not require it for the trial. The one thing they did do was, in an exploratory fashion, look at tumor mutational burden [TMB] and they did this through blood, not through tissue.

Progression-free survival [PFS] was reached after a follow-up of 13.9 months, and the PFS stands out after about 4 months, but early on you don’t see too much. In fact, the median is probably about the same at 5.2 vs 4.3 months. When you start to look at the PFS rate at 1 year, you see 12.6% vs 5.4% for chemotherapy alone [HR, 0.77; 95% CI, 0.62-0.96; P = .02].

The overall survival [OS] of chemotherapy alone was 10.3 months [HR, 0.76; 95% CI, 0.60-0.95; P = .0154] and the median OS when combining [chemotherapy and] atezolizumab was 12.3 months.⁴ The median of 10 months for chemotherapy alone is very typical, but as you go farther out, they start to pull away. At 18 months, the survival was 34% for immunotherapy and 21% for the chemotherapy. This is a bit better than I remember when we were using chemotherapy alone all the time.

Basically, all the subgroups benefitted, including patients who had brain metastases.⁴ About 10% of the patients had brain metastases in this trial, and [investigators] looked at [TMB with median OS higher in the atezolizumab arm]. They had a cutoff at 10 based on some prior studies, and then they went up a little higher at 16, but it didn’t make any difference whether you had a lower or a higher [TMB]. All the patients, with whatever they had, benefitted from the addition of the immunotherapy.

You can see that the response rate was similar.^3,5 In fact, [it was] a tad higher for the placebo group. The complete and partial responses were about the same. The big thing was that patients who had an ongoing response at a 2-year follow-up were 9.1% vs 2.3%. It is about the tail of the curves, and we do see they separate out, and you can see the benefit going out farther.

Looking at some of the adverse events [AEs] related to the treatment, the AEs weren’t more with the immunotherapy combination than they were for chemotherapy alone, including the hematologic toxicity, which was similar.³ Overall, related to the trial regimen, they were very similar, including the grade of the AEs in both study arms.

What has your experience been with this regimen?

MAHAJAN: I have used it and I think it’s…identical to atezolizumab….As general oncologists, we use this drug from head and neck to toe. The hazard ratios in both trials were essentially the same, and the OS in that margin is essentially the same. I think it just comes down to convenience.

Now, atezolizumab is a unique choice, but previously, durvalumab, at least in the maintenance, is the one you could use every 4 weeks. That’s convenient for the patient, and…that trial included the patients with brain metastases and [those] with cisplatin and carboplatin. I don’t think that makes a difference. It’s just for convenience.

CHOWDHARY: It seems because atezolizumab and carboplatin-etoposide were initially inducted onto our care pathway guidelines, we’ve decided to stick with that and not include durvalumab as well, which I would have preferred. I did have a question on the long-term [data]. I know on IMpower133 the 2-year survival data look…similar to CASPIAN [NCT03043872].^5,6 At 2 years, it’s roughly about 22%. But on IMpower[133], do you have any 3-year data, as CASPIAN does?

WOZNIAK: No, they haven’t reported out 3-year data. On IMpower133, they haven’t reported that out yet. I can tell you, at our institution [UPMC Hillman Cancer Center], because of cost, durvalumab has been put up front as the one to use. But we can use both, and we have a clinical trial that uses atezolizumab. I try to use what is the most appropriate if I have somebody on a trial and the trial designates specific immunotherapy. I can use either.

Can you discuss the CASPIAN trial?

CASPIAN is…different as a 3-arm trial.⁶ It’s chemotherapy alone, and durvalumab and chemotherapy, and then another double immunotherapy with a CTLA-4 inhibitor: durvalumab, tremelimumab, and chemotherapy. Patients were randomized 1:1:1, and you could use platinum or carboplatin. There was another difference…when you gave chemotherapy alone, you could utilize up to 6 cycles.

The 3-year follow-up was presented last year, and the results are similar.⁷ The median OS was almost 13 months [HR, 0.71; 95% CI, 0.60-0.86; P = .0003] and it was 12.3 months for IMpower[133].⁴ The chemotherapy arms were also comparable.

This is nice because you do have a 3-year survival rate; it’s 5.8% vs 17.6%.⁷ In SCLC, I think this is an accomplishment. We were looking at less than 5% at 5 years and there are [patients] who do well for a long period.

In the subgroup analyses, the number of brain metastases was similar at about 10%, and there were some stage III patients but very few, so there weren’t a lot of patients to look at there.

[The overall response rate was similar between both arms] but a little higher for the immunotherapy arm [at 67.9% vs 58% (odds ratio, 1.53; 95% CI, 1.08-2.18)].⁸ The median duration of response was 5.1 months in both arms [95% CI, 4.9-5.3]. Again, the data indicate that the addition of the immunotherapy resulted in a much better duration of response—not at the median but out at 12 to 24 months.

The AE results with the triplet chemotherapy and with the 2 immunotherapy agents were no better than just the durvalumab and chemotherapy alone.⁸ That’s why it didn’t go anywhere, but it’s interesting to note that the AEs were a bit more with the triplet chemotherapy [Table⁸].

I did bring out some of the differences between the 2 trials already and there was a longer follow-up for CASPIAN.^3-9 There was a difference in the amount of chemotherapy in terms of cycles you could do in the chemotherapy-alone arm. The addition of cisplatin, which I don’t think makes a difference, and the overall responses you can see. They’re not too much different. I don’t think that’s as important as looking at the control of the disease and the survival.

_REFERENCES

_{1. NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 2.2022. Accessed March 1, 2022. https://bit.ly/3NEQONG}

_{2. Noda K, Nishiwaki Y, Kawahara M, et al; Japan Clinical Oncology Group. Irinotecan plus cisplatin compared with etoposide plus cisplatin for extensive small-cell lung cancer. N Engl J Med. 2002;346(2):85-91. doi:10.1056/NEJMoa003034}

_{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. 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}

_{5. Reck M, Liu SV, Mansfield AS. 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-v711. doi:10.1093/annonc/mdz264}

_{6. 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}

_{7. Paz-Ares L, Chen Y, Reinmuth N, et al. Durvalumab_tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): 3-year overall survival update from the phase 3 CASPIAN study. Presented at: 2021 ESMO Congress; September 16-21, 2021; virtual. Abstract LBA61. Accessed May 26, 2022. https://bit.ly/3z0QNj2}

_{8. 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):9002-9002. doi:10.1200/ JCO.2020.38.15_suppl.9002}

_{9. 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/S1470-2045(20)30539-8}