Expert Recaps Immunotherapy Milestones in NSCLC

Thomas Eldridge Stinchcombe, MD

Immunotherapy has demonstrated efficacy in the non—small cell lung cancer (NSCLC) treatment paradigm, both as a single agent and in combination with chemotherapy.

Single-agent durvalumab (Imfinzi) showed promise in patients with unresectable stage III NSCLC, according to phase III results from the PACIFIC trial.¹ In the trial of 709 patients, the median progression-free survival (PFS) was 16.8 months with durvalumab compared with 5.6 months for placebo (HR, 0.52; P <.001). Based on these data the FDA is currently reviewing an application for the use of durvalumab in this setting.

The KEYNOTE-189 study of pembrolizumab (Keytruda) or placebo plus pemetrexed (Alimta) and either cisplatin or carboplatin met its coprimary endpoints of improved overall survival (OS) and PFS. This study serves as a confirmatory trial for pembrolizumab and chemotherapy combination, which was granted an accelerated approval for use in combination with pemetrexed plus carboplatin as a frontline treatment for patients with metastatic or advanced nonsquamous NSCLC, regardless of PD-L1 expression, in May 2017.

Another promising combination with chemotherapy is atezolizumab (Tecentriq) plus bevacizumab (Avastin), carboplatin, and paclitaxel. The addition of atezolizumab delayed progression or death compared with bevacizumab and chemotherapy alone for patients with advanced nonsquamous NSCLC, according to topline findings from the phase III IMpower150 trial presented at the 2017 ESMO Immuno-Oncology Congress.²

The atezolizumab regimen demonstrated a median PFS of 8.3 months compared with 6.8 months with bevacizumab and chemotherapy alone (HR, 0.62; P <.0001). The 12-month PFS rate was 37% with the atezolizumab-containing regimen and 18% with the bevacizumab plus chemotherapy regimen.

OncLive: What are the significant data with frontline pembrolizumab and chemotherapy in the KEYNOTE-189 trial?

What are some other combination regimens that are showing promise?

Durvalumab is also garnering some interest in the field. Can you discuss the data from the PACIFIC trial?

In an interview with OncLive, Thomas Eldridge Stinchcombe, MD, a professor of medicine and member of Duke Cancer Institute, recapped some of these data with immunotherapy as a single agent and in combination in NSCLC and what challenges the field is facing in 2018.Stinchcombe: The KEYNOTE-189 trial builds upon [cohort G] of the KEYNOTE-21 trial, which was a phase II trial that randomized patients to carboplatin/pemetrexed alone or carboplatin/pemetrexed with pembrolizumab. The phase II trial showed a robust response rate, PFS, and a trend toward OS. What we know at this time is that the phase III trial met the statistically significant improvement in PFS and OS. This serves as a confirmatory [study] to the promising results observed in the phase II trial.As for other combinations being developed with immunotherapy, the one that is furthest in development is the trial of carboplatin, paclitaxel, and bevacizumab alone or with atezolizumab. We saw this comparison of this 3-arm trial show promising improvement in response and a statistically significant improvement in PFS. The OS data are immature at this time.The PACIFIC trial randomized patients with stage III NSCLC to either durvalumab for 1 year or placebo. This trial showed a statistically significant improvement in response rate, as well as improvement in PFS, which was statistically significant in a difference of about 11 months. These are very promising results, because the treatment for stage III disease has remained unchanged for 20 or 30 years before this trial.

Are there any predictive markers yet?

If a patient develops resistance to immunotherapy, what are the next steps?

The next steps are to build upon durvalumab or single-agent immunotherapy, try to identify which patients are most likely to benefit [from that], and further investigate and observe the OS benefit—which is still pending.That is kind of the debate in the field; do you give this to everyone? It’s 1 year of therapy. We would like to be able to see who will benefit, but right now we give it to everyone. With the success of immunotherapy in the first- and second-line settings, one of the challenges that we now face is what to do with those patients who have progressed on immunotherapy. Clinically, there are many different types of progression on immunotherapy, including the patients who never responded, to patients who maybe had stable disease for 6 or 9 months, and then progress. This is an area of active investigation looking at novel immunotherapy combinations.

Is there any promise with coupling immunotherapy with radiation therapy?

Moving forward, what challenges need to be addressed with immunotherapy in lung cancer?

On the scientific side, we are trying to identify the mechanisms of resistance to immunotherapy so that we can better target and develop drugs.There is the idea that radiation and immunotherapy could have synergistic effects. Particularly, the radiation may stimulate the expression of tumor antigens, which in turn would stimulate immunotherapy. The trials right now are still preliminary, but we will see a lot of trials looking at the combination of radiation with immunotherapy in early-stage disease, as well as stage IV disease.The main challenge with immunotherapy is identifying the patients most likely to benefit, as well as patients who are least likely to benefit. Then, there is also a significant patient population that does not respond to immunotherapy. What [do we] do with the post-immunotherapy population in terms of the next lines of therapy?

The immunotherapy combinations with chemotherapy are coming to the forefront, and the 2 combinations under investigation should read out soon.

References

1. Paz-Ares L, Villegas A, Daniel D, et al. PACIFIC: A double-blind, placebo-controlled phase III study of durvalumab after chemoradiation therapy (CRT) in patients with stage III, locally advanced, unresectable NSCLC. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA1_PR.
2. Reck M. Primary PFS and safety analyses of a randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without atezolizumab in 1L non-squamous metastatic NSCLC (IMpower150). Ann Oncol. 2017;28(11). doi: 10.1093/annonc/mdx760.002.