Adding Atezolizumab to Chemotherapy Shows Promise in NSCLC

Stephen Liu, MD

The anti—PD-L1 agent atezolizumab (MPDL3280A) was recently investigated for safety and efficacy in combination with platinum-based doublet chemotherapy in treatment-naïve patients with advanced non–small cell lung cancer (NSCLC). Results from the phase Ib study were presented at the 2015 ASCO Annual Meeting.

The multiple-arm study looked at MPDL3280A with a different chemotherapy backbone in each arm: carboplatin plus paclitaxel (Arm C; n = 8) carboplatin plus pemetrexed (Arm D; n = 14) or carboplatin plus nab-paclitaxel (Arm E; n = 15).

Across all arms, the overall response rate (ORR) was 67% (48%-82%), with 60% ORR (19%-92%) in Arm C (3 partial responses [PRs]), 75% (45%-93%) in Arm D (9 PRs), and 62% (33%-83%) in Arm E (6 PRs, 2 complete responses).

Regarding the safety profile, the researchers concluded that the combination regimens were well tolerated. The most frequent all-grade adverse events included those commonly associated with chemotherapy, such as nausea (Arms C and D, 50%; Arm E, 73%), fatigue (Arm C, 38%; Arm D, 36%; Arm E, 73%) and constipation (Arm C, 25%; Arm D, 71%; Arm E, 27%).

OncLive spoke with Stephen Liu, MD, lead author on the study and assistant professor, Division of Hematology and Oncology, Georgetown University, to better understand the results and purpose of the uniquely designed trial, and how oncologists may need to rethink trial design when investigating similar novel agents.

OncLive: What was the purpose of this study?

Dr Liu: There has been a lot of excitement about immunotherapy checkpoint inhibitors. They are currently being explored primarily in the relapsed/refractory setting. Typically, in NSCLC, you want to use your best drugs first. We have found that saving drugs for later lines means that most patients will not have a chance to be exposed to those medications.

This is a slightly different strategy. Patients receive 4 to 6 cycles of platinum-based chemotherapy with concurrent MPDL3280A [15 mg/kg IV every 3 weeks], followed by MPDL3280A maintenance therapy until loss of clinical benefit. Patients in the pemetrexed arm could continue receiving pemetrexed until progression.

What were the findings?

In terms of efficacy, it is difficult to draw too many conclusions since this was a non-comparative study looking at safety. There was a signal of efficacy and the response rates were fairly high—across all three arms they were about 67%.

What is most compelling is that there was several compete responses. Complete responses in NSCLC with platinum-based chemotherapy are really unheard of. There is clearly a signal of activity there, but it needs to be explored further. We need a comparative arm with chemotherapy alone to really understand what the contribution of MPDL3280A is to toxicity and to efficacy. The next steps are randomized trials; phase III trials are currently being launched. There is a lot more information we need to get, which we hopefully will have in the coming months, but this is clearly a promising start.

Were there any concerns with safety?

What we saw, in terms of safety, is that there were no alarming signals. We didn’t see an increased signal for unexpected toxicities. We did see nausea, fatigue, and myelosuppression, but we saw nothing out of the ordinary that you would not expect with platinum-based chemotherapy.

What are the biggest challenges concerning platinum-based chemotherapy in NSCLC?

The standard first-line treatment for metastatic or recurrent NSCLC remains platinum-based chemotherapy. While chemotherapy will be effective for some, long-term benefit is not expected and long-term survival is very unlikely. Strategies to not only increase the likelihood of response, but to also make that response more durable to prolong the period of benefit, are really what we need in that setting.

How do you see the treatment of NSCLC evolving in the next 5 years?

Most of the excitement has been focused on the quality of responses that we are seeing with some of these new strategies. In terms of survival curves, we are seeing tail ends where a durable, meaningful response is something that we can now measure. There are 1-, 2-, and 3-year survival rates. That is not something we have expected from prior therapies. The potential for these new lines of treatment is very encouraging. Now we need to work on finding a way to deliver that therapy to more patients. We need to figure out how to determine which patients will benefit the most from these therapies and how they can achieve the maximum benefit from those therapies.

What needs to be done to make that happen? Should there be changes made in how clinical trials are designed?

The current climate for clinical trials really does mandate a new way of looking at these studies. Response rate as an endpoint made sense when a direct reduction in tumor burden was correlated with survival. With these newer agents, the mechanism is a little different. Seeing a dramatic reduction in the size of a tumor is not always necessary to derive benefit. Survival may not directly correlate with response rate. Survival ultimately needs to be examined on its own and response may no longer be an adequate surrogate. Our criterion for assessing response needs to change as our drugs and these new strategies evolve.

It is not just the endpoints that need to be reconsidered; it is our whole way of studying these new drugs and new combinations. Many of the newer agents demand a reworking of not only how we measure response, but also how we structure our approach to designing safety studies.

In the past, there was a direct correlation between dose and toxicities. It was considered best practice to use the maximum possible dose, because that was the dose that was going to be the most effective. That is no longer the case. A lot of our studies still rely on older trial designs. Those designs don’t necessarily make sense with this newer class of drugs. The maximum-tolerated dose is not necessarily the best dose. Lower doses may introduce the same benefit, but with lower toxicity. That direct linear relationship between toxicities and response no longer exists. The game has changed. We need to rethink how we are exploring these studies, and that is starting now.

Liu SV, Powderly JD, Camidge DR, et al. Safety and efficacy of MPDL3280A (anti-PDL1) in combination with platinum-based doublet chemotherapy in patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2015;(suppl; abstr 8030).