Treating Locally Advanced NSCLC: Additional Concerns

Heather Wakelee, MD:As a standard, we’ve used the weekly carboplatin/paclitaxel with consolidation carboplatin/paclitaxel for 2 cycles. We’ve also used cisplatin/etoposide. There are a couple of different regimens—usually day 1 through 5 and then day 8. It’s a complex regimen. But 2 cycles of that full dose are given during the radiation and then without consolidation. There’s also a cisplatin. Or carboplatin and pemetrexed is often used. There are fewer data there. One large trial didn’t necessarily show equivalency but has often been interpreted that way. That had a lot of consolidation chemotherapy.

We’re left with more questions now that PACIFIC has come up. On PACIFIC, patients who had any of those chemotherapy backbones along with radiation were able to be enrolled. On PACIFIC, patients did not get additional chemotherapy after concurrent chemotherapy and radiation. For someone who was getting cisplatin/etoposide, we know that anything else has never been shown to be helpful. So, 2 cycles of cisplatin/etoposide (EP 50/50) with radiation, often on that EP 50/50 regimen, that’s great. And then we just add durvalumab. I think everyone is very comfortable that we’ve done a very full, complete regimen that way.

When we’re doing weekly carboplatin/paclitaxel, as was done in this case, there are still a lot of questions. What do we do about that extra carboplatin/paclitaxel that’s normally given at full doses as 2 cycles for consolidation? We’ve never had data telling us that we don’t have to do that when we give the weekly carboplatin/paclitaxel, so there’s a little bit of discomfort. On PACIFIC, the patients who were getting weekly carboplatin/paclitaxel did not get additional chemotherapy. They stopped and then went on and got durvalumab.

When one looks at the data from PACIFIC, overall, there have been questions raised. One of the biggest criticisms is the fact that the progression-free survival on the control arm, on the chemotherapy-alone arm, was not as good as we would have expected. It’s true that the point of progression-free survival is counted from the completion of the chemoradiation. Chemoradiation takes a couple of months. So, if we add on to that, it’s about 5.6 months. You add another couple of months on to that. You’re still not quite in the progression-free survival range that we’ve historically seen with concurrent chemoradiation alone. And so, there’s some question. By having so many patients getting weekly carboplatin/paclitaxel, not getting any additional chemotherapy, maybe they were a little bit undertreated? I think that’s one thing to bring up. We don’t have answers to it yet.

For a patient who is not able to get cisplatin/etoposide, who gets weekly carboplatin/paclitaxel—like this patient—and then is going to go on to get durvalumab, it is important to start early. This patient had healed up after getting his chemoradiation. He was doing OK. They tried to get in and start treatment. The goal was really to start the durvalumab as soon as possible. In PACIFIC, they actually were trying to get everybody started within a fairly short time period. I don’t remember the exact range, but I think it was 3 or 4 weeks. They realized that was pretty tough, logistically, so they expanded it out. But there are some subsets that demonstrate that those who start sooner seem to do a little bit better. And there’s this whole idea that if you’re getting the chemoradiation—that’s when there’s the most antigen release—theoretically, that’s going to be the best time for durvalumab to have its strongest impact.

So, you want to start soon. Whether or not to add in the chemotherapy and then delay that has been the question. It was not done in PACIFIC. The standard approach from PACIFIC is to give your chemoradiation, start durvalumab as soon as you can, and continue it for a year. That’s where the benefit was seen. If someone is on weekly carboplatin/paclitaxel, do we try to give 1 or 2 cycles of chemotherapy before we start the durvalumab or not? That’s still unaddressed.

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