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The IMPower133 trial brought good news to the small-cell lung cancer (SCLC) community: Phase III of the study, which ran from , established that addition of atezolizumab (Tecentriq) to chemotherapy in the first-line treatment of extensive-stage SCLC (ES-SCLC) led to significantly longer overall survival (OS) than chemotherapy alone.

In an , Stephen V. Liu, MD, of the Lombardi Comprehensive Cancer Center at Georgetown University in Washington, and IMPower 133 colleagues, reaffirmed that adding the PD-L1 inhibitor to carboplatin plus etoposide (CP/ET) demonstrated "improved OS and a tolerable safety profile ... confirming the regimen as a new standard of care."

Other highlights from the new study included the following:

• At the updated analysis, median OS follow-up was 22.9 months, and 302 deaths had occurred. The median OS was 12.3 months with atezolizumab plus CP/ET versus 10.3 months with placebo plus CP/ET (hazard ratio 0.76, 95% CI 0.60-0.95, descriptive P=0.0154)

• At 18 months, 34.0% of patients in the study-agent arm were alive vs 21.0% in the placebo arm

• Treatment-related adverse events of special interest included immune-mediated rash, immune-mediated hypothyroidism, and infusion-related reactions

• Patients derived benefit from the addition of atezolizumab, regardless of PD-L1 immunohistochemistry (IHC) or blood-based tumor mutational burden status

The latter result was from an exploratory biomarker analysis, and the authors explained that "as there are no PD-L1 IHC-validated cutoffs in SCLC, PD-L1 prevalence was evaluated in a stepwise fashion in line with non-SCLC (NSCLC) PD-L1 IHC cutoffs."

Median OS in patients with PD-L1 expression of at least 1% tumor cells or tumor-infiltrating immune cells was 9.7 months in the study-agent arms and 10.6 months in the placebo arm. Those with a PD-L1 expression of at least 5% tumor cells or immune cells had a median OS of 21.6 months vs 9.2 months, respectively.

Liu's group pointed out that "PD-L1 expression in SCLC is highly variable, and indicate that expression ranges from 2% to 83%, depending on the assay and scoring algorithm used." In addition, "a caveat with the exploratory biomarker PD-L1 IHC analysis was the limited size of the biomarker-evaluable population, with only 34% of the enrolled study population included in the PD-L1 analyses."

In the following interview, , of the at the University of Florida in Gainesville, discusses the merits and drawbacks of IMPower133, and the message that lung cancer specialists who treat SCLC should take from this trial.

What are the most impressive results from the trial? Are there any findings that are still concerning to you even in these updated results?

Shah: For me, the most impressive result was the survival benefit. While it was not a huge OS benefit, for these patients with ES-SCLC it was still meaningful. The treatment options for SCLC patients have not really advanced in the last few decades. So IMpower133 offers an option for ES-SCLC patients, who haven't had a lot of choices until now. And it's a good option in terms of survival benefits.

An issue that still needs to be looked at are the side effects. A third of these patients experienced treatment-related adverse events. But side effects are also an issue with other PD-L1 inhibitors, so we need to make sure that we continue to track these side effects and not do the patient more harm than good with this treatment.

In the trial, the researchers said that clinical benefit was seen in atezolizumab plus CP/ET-treated patients with ES-SCLC independent of biomarker -- blood-based tumor mutational burden or PD-L1 -- status. What lessons can be gleaned from this related to the immune biology of SCLC?

Shah: That's a really interesting question that we need a better answer to. We know that in terms of tumor biology, SCLC has a higher mutation rate, and that these tumors tends to be more immunogenic.

It's good news that patients in the trial still saw a survival benefit from atezolizumab whether they had high or low PD-L1 expression. But IMpower133 was limited in terms of PD-L1 IHC analysis. What we need are larger, well-designed trials so that we can more accurately determine which patients will benefit the most from this treatment.

IMpower133 had 186 patients ages 65 and over. What lessons can be learned in terms of treating older patients with ES-SCLC?

Shah: It was good to see that IMpower133 had some older patients, although they did not state what age they considered patients to be "older." I think these results give physicians some confidence that they can give this agent to their older patients and that it offers efficacy and a reasonable safety profile.

We need a well-designed trial specifically in older patients to confirm this. We know that, as a population, we are seeing a rise in physiologic age and a higher level of comorbidities. In ES-SCLC patients, we tend to see a lot of those comorbidities, as many of these patients are chronic smokers. So confirmation that this treatment is suitable for those patients will be important -- that it will be well tolerated by patients -- beyond a survival advantage.

That was one of the issues we looked out in ["Utilization of Antineoplastic Agents and Medicare Spending in Elderly Patients With Extensive-Stage Small-Cell Lung Cancer Between 2001 and 2013"]. We know that older patients often don't receive treatment with antineoplastics because of concerns about toxicity. The immune checkpoint inhibitors [ICIs] do seem to offer an alternative treatment for these patients, but we need more data on how this treatment will impact quality of life.

Again, given that older patients don't often undergo treatment besides supportive care, IMpower133 is good news because there are so few other options.

Looking at the results , should SCLC specialists view atezolizumab as the best option in patients with ES-SCLC? What about other contenders such as durvalumab (Imfinzi) or pembrolizumab (Keytruda)?

Shah: I think ICIs have really given us more options in ES-SCLC. We have results from a phase III trial [] of durvalumab in combination with etoposide and either carboplatin or cisplatin as first-line treatment that showed 2 to 3 months OS and a 30% reduction in the risk of progression. And it's approved by the FDA in the first-line setting.

We also have pembrolizumab, which was less successful in ES-SCLC [in the trial] in that it failed to improve OS. So it's [FDA]-approved in the second-line setting.

While it's good to have a new option in the first-line setting, a question that we still need to answer is, if a patient receives an ICI in the first-line setting and relapses, then what's the best option in the relapse setting?

The cost of prescription medications and treatment is a hot-button issue in U.S. medicine now. A out of China reported that atezolizumab combination therapy was not more cost effective than chemotherapy alone at a willingness-to-pay threshold of $25,929/quality-adjusted life year in China. Could the cost be a barrier to the use of this agent in ES-SCLC patients? Are there other barriers to care delivery that you think will need to be addressed with this agent?

Shah: I think [the China study] was really interesting. Cost is a very important issue right now, especially with so many new agents approved. The cost of ICIs is high, and that definitely puts a lot of stress on the healthcare system in the U.S.

So I think cost does have to be factored into the decision-making process to some extent: Does the OS of a few months justify the high cost and financial burden to the healthcare system? For me, the answer is yes, if we are seeing that patients have a decent response to the treatment and some long-term survival benefit.

Going forward, I think what we need to focus on is fine-tuning this treatment option: Are there patients with certain characteristics or variables who seem to derive more benefit? Or are there patients who derived less benefit? Then we can target the therapy better to the patients who are most likely to benefit based on those factors, and potentially reduce the costs associated with this treatment.

We need to find a way, on a clinical level, to be more selective in finding patients who will benefit the most, and then costs should come down.

In terms of other barriers, we still need better biomarkers to predict which patients will have a reasonable response to treatment.

Read the study here and expert commentary about the clinical implications here.