Treating Unresectable Locally Advanced NSCLC

Heather Wakelee, MD:The treatment of stage III non—small cell lung cancer has been controversial for a number of years. We really haven’t moved the field forward for a long time. There were questions on the total radiation dosing that were looked at through a recent study. That did not change practice at all. There have been a lot of questions around the best chemotherapy regimens. Until recently, we have just continued debating many issues. Do we do radiation? At what dose? How much surgery do we do? Or, no surgery? Which chemotherapy? Do we do consolidation or not? We kept asking the same questions. We just went in circles.

The first time we had a real significant improvement in the past couple of decades was with the PACIFIC trial, where the addition of consolidation durvalumab after completing chemoradiation significantly improved progression-free survival. It nearly tripled it—from around 6 months to 17 or 18 months.

We don’t yet have survival. The overall survival data are going to be important. It would be shocking if they’re not positive, given that really striking progression-free survival benefit and the fact that if we are able to get these immune drugs in at the right time, it could theoretically change cure, as opposed to some of our other treatments such as the TKIs, where we really don’t expect them to be a curative approach. Rather, we expect more of a continued suppressive approach. There’s real hope that with PACIFIC, with using the PD-L1 inhibitor durvalumab, we’re actually changing and shifting to more cure.

If a patient with stage 3 lung cancer recurs, sometimes they’ll recur locally. In this case, we can think about doing additional radiation or surgery, and maybe they’ll have a chance at cure. But most patients are going to recur in a more systemic way, and we only have systemic treatments for them. It depends on timing. If it’s been more than 6 months, we’ll often think about treating them as if they were newly diagnosed. The new standard of care for our patient with adenocarcinoma without any contraindications is going to be to combine chemotherapy and pembrolizumab. This is based on the KEYNOTE-189 data that came out in April of 2018. So, we would treat with that. There’s some chance of response. For someone who’s already had durvalumab, we don’t really know how that impacts responses to the combined chemotherapy and checkpoint inhibitor later on, but that would still be considered the standard approach.

If a patient then progresses at that point, and they’ve already had another round of chemotherapy and a checkpoint inhibitor, we don’t really know. There are very few data. There are a lot of ongoing trials looking at other checkpoint inhibitors. The standard would be to give something like docetaxel and ramucirumab or just other chemotherapy as a single agent. But those response rates are all going to be relatively low.

Transcript edited for clarity.

• A 64-year-old man presented with shortness of breath and persistent cough of 18 months’ duration; recently, he has experienced chest pain, fatigue, and blood in his sputum. After consulting with his primary care physician, he was referred for oncology evaluation
• Patient history includes
  • Current smoker (1/2 pack day)
  • Hypertension
  • Acute MI at age 60
• Evaluation and follow up testing reveal
  • Non-small cell lung cancer in left lung and 2 lymph nodes (Stage IIIa)
  • WHO performance status: 1
  • Histology: adenocarcinoma
  • EFGR, BRAF,andALK/ROS1mutation status: wild-type
  • PD-L1 status: ≥25%
• He underwent multidisciplinary evaluation and was not a candidate for surgery; he was treated with chemoradiotherapy:
  • Concurrent carboplatin-paclitaxel doublet chemotherapy and radiotherapy (60 Gy)
  • Achieved partial response
• He had no disease progression 20 days after his last radiotherapy treatment, and began treatment with durvalumab