Immunotherapy Advances SCLC Treatment Landscape

Partner | Cancer Centers | <b>Johns Hopkins Cancer Center</b>

The new standard of care for the frontline treatment of patients with extensive-stage small cell lung cancer should be atezolizumab and chemotherapy, based on results from the IMpower133 trial.

Christine Lee Hann, MD, PhD

The new standard of care for the frontline treatment of patients with extensive-stage small cell lung cancer (SCLC) should be atezolizumab (Tecentriq) and chemotherapy, based on results from the IMpower133 trial, said Christine Lee Hann, MD, PhD.

This global, randomized phase III trial demonstrated an improvement in survival with the addition of the PD-L1 inhibitor to standard carboplatin and etoposide in patients with extensive-stage SCLC versus the chemotherapy regimen alone.

After a median follow-up of 13.9 months, the median overall survival (OS) in the experimental arm was 12.3 months compared with 10.3 months with chemotherapy alone (HR, 0.70; 95% CI, 0.54-0.91; P = .0069). Median progression-free survival (PFS) was 5.2 months in the atezolizumab arm compared with 4.3 months in the placebo arm.

In the cohort of 403 treatment-naïve patients, all patients received four 21-day cycles of carboplatin AUC 5 mg/mL/min intravenously (IV) on day 1 and 100 mg/m2 etoposide IV on days 1 through 3. Patients were also randomized 1:1 to receive either concurrent atezolizumab at 1200 mg IV on day 1 (n = 201) or placebo (n = 202) during the induction phase. Treatment was followed by maintenance therapy with atezolizumab or placebo, according to the previous random assignment, every 3 weeks until progressive disease or loss of clinical benefit.

Moreover, single-agent nivolumab (Opdivo) was granted an accelerated FDA approval in August 2018 for the treatment of patients with SCLC with disease progression following platinum-based chemotherapy and 1 other line of therapy, marking the first drug approval in this disease in nearly 20 years.

However, other immunotherapy strategies have not shown the same activity. For example, in the phase III CheckMate-451 trial, the combination of nivolumab and ipilimumab (Yervoy) did not improve OS versus placebo as a maintenance therapy for patients with extensive-stage SCLC without disease progression following frontline platinum-based chemotherapy.

OncLive: What are the recent advances in SCLC therapy?

How do you see researchers compounding this data for future advancement?

In an interview during the 2018 OncLive® at the 2018 State of the Science Summit™ on Advanced Non—Small Cell Lung Cancer, Hann, an associate professor of Oncology at Johns Hopkins School of Medicine, discussed how recent data have shaped SCLC treatment.Hann: Some of the most exciting recent news emerged at the 19th World Conference on Lung Cancer. Stephen V. Liu, MD, presented results from the IMpower133 study which evaluated first-line chemotherapy in combination with the PD-L1 inhibitor atezolizumab. This was the first study in the frontline setting to show improved survival benefit; in fact, there was improvement in PFS and OS in patients who received the combination. We believe this can now be considered the new standard of care for frontline treatment of this patient population.There is a lot to look forward to. In the last couple of years, we have had a tremendous emergence of data both on the biological end and on the clinical side. We understand the disease better and we have discovered new agents, such as checkpoint inhibitors, that have efficacy in this space. The checkpoint inhibitors have been effective in the second-line setting and beyond.

What are some of these emerging molecular targets and targeted therapies?

In fact, nivolumab received FDA approval in August 2018 in the third-line setting of SCLC; this was the first drug approval we had in 2 decades and it was a major accomplishment in the field. We are now looking at combinations and new molecular targets in this space.There has been a renewed interest in studying SCLC. Consequentially, there has been increased funding from the National Cancer Institute to help us understand the disease better. [This renewed interest in SCLC] has emerged in parallel with technological advances that allow us to obtain a deep genomic understanding. We are now able to get epigenetic and proteomic profiles of the cancer. In the last 5 years, there has been increasing information on the proteins expressed in SCLC that may be targets.

What is a remaining unmet need in SCLC?

What is your take-home message to community oncologists?

It is going to take a long time to really tease through all these details, but we are moving in the right direction. SCLC is a cancer with a very high tumor mutation burden, so there is probably a role for combined targeted therapies.There have been very few studies looking at limited-stage SCLC. While there is curative potential with chemotherapy and radiation, the vast majority of patients recur locally and distantly. There are studies with immune-checkpoint inhibitors underway in this space, and those [data] will be very useful. With the encouraging data we saw with durvalumab (Imfinzi) in stage III non—small cell lung cancer, we believe there is great potential for earlier-line immunotherapy.We have a new standard of care for first-line treatment of SCLC. Multiple studies will also be read out in the next year or so that will expand our armamentarium even further. We will see data pertaining to the use of checkpoint inhibitors in the maintenance setting, whether [they are being used] in combination or as single agents. Long-term biomarker studies are also essential.

Liu S, Mansfield A, Szczesna S, et al. First-line atezolizumab plus chemotherapy in extensive-stage small-cell lung cancer [published online September 25, 2018]. N Eng J Med. doi: 10.1056/NEJMoa1809064.