Kim Evaluates Atezolizumab and Durvalumab for ES-SCLC

Edward Kim, MD

Edward Kim, MD, chair, Department of Solid Tumor Oncology, Levine Cancer Institute in Charlotte, NC, discussed the use of atezolizumab (Tecentriq) and durvalumab (Imfinzi) as treatment of a 73-year-old female patient with extensive-stage small cell lung cancer (ES-SCLC) during a virtual Case Based Peer Perspective event.

Targeted Oncology™: What are the treatment choices for patients with ES-SCLC?

KIM: The current NCCN [National Comprehensive Cancer Network] guidelines for ES therapy [say] that the preferred regimens are combinations; so, a 2-drug combination with the addition of immunotherapy.¹ Atezolizumab and durvalumab have been added to the guidelines [as preferred regimens]. They are [administered] with either cisplatin or carboplatin. Then other regimens, if you can’t give that, are listed. There are at least options here with different immunotherapies.

How do the data in this setting support the patient’s treatment?

The phase 3 IMpower133 [NCT02763579] study, published in the New England Journal of Medicine by lead author Leora Horn, MD, investigated 4 cycles of the triplet versus the doublet [regimens] and placebo.² There was maintenance immunotherapy afterward, with the single agent or placebo. Overall survival [OS] and progression-free survival [PFS] were the primary end points. All these patients had PS [performance status] 0 or 1 with ES disease, and they could have treated asymptomatic brain metastases.

The median OS was 12.3 months with atezolizumab versus 10.3 months with placebo [HR, 0.70; 95% CI, 0.54-0.91; P = .007]. Then the PFS was 5.2 months versus 4.3 months, respectively [HR, 0.77; 95% CI, 0.62-0.96; P = .02].

For the 2-year OS follow-up, the Kaplan-Meier curves stay tight together for the first 8 to 10 months, then there’s some separation, so maybe there is an effect with the maintenance [therapy].³ The curves start [to approach] each other as the data get past the 18-month period.

The 2-year OS rates by subsets had some positive [benefit], but many of the intervals cross the 1.00 range. So, not too [many] subgroups were statistically significant, but there is a trend toward a benefit observed with the atezolizumab-treatment arm.

The response rate with atezolizumab versus placebo was not what we’ve seen as far as an overall increase. In fact, objectively, it was less with the objective confirmed response rates [60.2% with atezolizumab vs 64.4% with placebo]. Partial responses were less [57.7% vs 63.4%, respectively]. There was good disease control overall, and there were high response rates, but it was still odd to not see that enhanced response rate with the addition of the immunotherapy.

The grade 3/4 adverse events [AEs] on both sides did not have a ton of difference.2 So, whether you start the triplet or the doublet, you’re not imparting many more AEs on patients. That’s something to think about. You’re not adding too much more toxicity, if any, in many areas.

Have you used durvalumab with platinum chemotherapy and etoposide to treat your patients? What are the data with this agent in this setting?

It has only been approved for a short period of time, and [many physicians] have already incorporated it.4 If they were happy with the current triplet, I think you’d see slower adoption, but the fact that people are jumping onto it means that there’s something else [going on].

The phase 3 CASPIAN study [NCT03043872] that led to the approval of durvalumab was published in Lancet.5 This was a large study, with over 800 patients receiving the triplet with durvalumab followed by the every-4-weeks regimen at 1500 mg versus the doublet. There was also a third arm that was durvalumab and tremelimumab with chemotherapy, followed by durvalumab. But this analysis was of the first 2 [cohorts].

The median OS was 13.0 months in the durvalumab arm versus 10.3 months in the placebo arm [HR, 0.73; 95% CI, 0.59- 0.91; P = .0047]. The PFS, though, was odd; as you look at the overall Kaplan-Meier curves, you can see that there’s a benefit, but they were overlapping early on. So, that median [PFS; 5.1 months vs 5.4 months, respectively] was a little deceptive on how the curve was shaped.

For OS by subgroup, everything favored the durvalumab arm. There were some small subgroups that had wide ranges, but [they still] favored durvalumab in these subgroups. None of the medians fall above 1.00.

The unconfirmed objective response rate here was 79% with durvalumab versus 70% without. The confirmed was 68% versus 58%, respectively. IMpower133 was about 60% to 65%, so it was in the same ballpark but a different magnitude.3 [These responses] all fell within a similar range; not anything huge, like 20% [difference], but definitely something incremental as far as improvement.

The AEs that occurred [included] neutropenia and anemia.5 Chemotherapy alone had more of an impact on AEs versus durvalumab with chemotherapy, which we’re not necessarily used to seeing. I don’t think we should read anything into it, other than that it seems like this drug was well tolerated. It didn’t show a huge worsening of AE events, similar to what we see with atezolizumab. It didn’t add too much from an AE standpoint.

How did the IMpower133 and CASPIAN trials differ?

There were 4 cycles in the IMpower133 study; there were 6 cycles in the CASPIAN. The PFS in the control arm was much higher in the CASPIAN study, but the overall hazard ratio was similar in both [IMpower133 PFS HR was 0.76; CASPIAN, 0.78]. The immune-related AEs were lower with durvalumab. So, there are a couple of choices out there. [There’s been an] indication of a desire to switch [in this setting], as far as atezolizumab versus anything else, so I think that’s reflective of what the data are speaking to.

What do you think of the patient’s smoking status?

It’s never too late to talk about smoking cessation, but it wouldn’t necessarily be on the top 3 [things to talk about]. You never know; maybe the smoking is helping to get the immunotherapy jacked up more, so [she has] constant antigen load stimulation.

Is there a difference with atezolizumab or durvalumab in patients with brain metastasis?

It wasn’t reported [in the CASPIAN or IMpower133 trials]. I’m sure they probably have some data behind it, but I have not seen that same data that were shown in the PACIFIC study [NCT02125461], where they showed the sites of disease; they allowed asymptomatic brain metastasis, so it might be clouded from that regard.

_References:

1. _{NCCN. Clinical Practice Guidelines in Oncology. Small cell lung cancer, version 3.2020. Accessed June 30, 2020. https://www.nccn.org/professionals/physician_ gls/pdf/sclc.pdf}
2. _{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}
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. _{FDA approves durvalumab for extensive-stage small cell lung cancer. FDA. Updated March 30, 2020. Accessed June 30, 2020. https://www.fda.gov/drugs/ resources-information-approved-drugs/fda-approves-durvalumab-extensive-stage-small-cell-lung-cancer#:~:text=FDA%20approves%20durvalumab%20for%20 extensive%2Dstage%20small%20cell%20lung%20cancer,-Share&text=On%20 March%2027%2C%202020%2C%20the,cancer%20(ES%2DSCLC)}
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}