NSCLC: An Overview of the Current Treatment Landscape

Elizabeth Waxman

We’ve seen a lot of changes in the field of lung cancer treatment across the past several years, especially recently.

Whitney Lewis

Yes, definitely. I don't think there's a single subtype of lung cancer that we treat the same now that we did 5 years ago. It's really such an exciting time in this disease state.

Elizabeth Waxman

And it's a little hard to keep up because it seems like weekly or monthly, there's something new coming up in lung cancer treatment. One area that’s seen a significant change is staging. For years, we went by the 7th edition AJCC staging system, and now we're in the 8th edition, which includes subsets of metastatic disease—I and IA, B, C—and splits out multiple organs or multiple lesions in one specific site. But broadly, I don't feel it's changed the overall treatment of lung cancer by stage; it's made it a little bit more succinct. A person with stage IIIC lung cancer is still going to get concurrent treatment, versus the standard IIIB patient.

Whitney Lewis

I agree. Part of the drive for the AJCC 8th edition was to recategorize patients and give them a better idea of what their expected survival could be based on the stage, instead of having a heterogeneous population and different expected outcomes within one stage. The 8th edition revamped tumor size and which lymph nodes and what sort of organs may have been invaded by the tumor. And not a whole lot changed in terms of the treatment by stage. It was really just recategorization.

Elizabeth Waxman

And now in histology, specifically adenocarcinoma and squamous cell carcinoma, it's really important to have a specific diagnosis. To me, that is the key to the treatment, as well as staging.

Whitney Lewis

Yes, absolutely. Historically, we didn't really care about the histology, but a lot of these trials later came out and started looking at the histologic subtypes and found differences with different treatments in post hoc analyses. Adenocarcinoma is more common, with about 40% of patients with non–small cell lung cancer; squamous cell carcinoma is about 30%; and then there's maybe 10% large cell neuroendocrines, and a hodgepodge of everything else, which, if you don't know what type of lung cancer you're treating, you would, like you said, treat completely differently. For example, is a typical carcinoid going to get chemoradiation? I agree that it's really important up front to know exactly what beast you're dealing with.

Elizabeth Waxman

Patients with adenocarcinoma, up until recently, would get platinum pemetrexed, and patients with squamous cell carcinoma would receive another platinum doublet therapy. But now we’re using immunotherapy to treat both disease types.

Whitney Lewis

Yes, even those chemotherapy treatments moved their way from the metastatic setting to the locally advanced setting. Immunotherapy has not yet necessarily, although there are trials looking at adding immunotherapy to concurrent chemoradiation. But to your point, if patients are getting concurrent, they may get a different chemotherapy regimen depending on their histology. And now depending on a patient’s stage, and of course other factors, our whole approach to treatment can change since we have all of these choices for advanced or metastatic NSCLC: immunotherapy, chemotherapy, the combination, etc.

Elizabeth Waxman

And patients with stage III disease—except for stage IIIA, which is usually resectable—generally receive concurrent chemotherapy and radiation therapy, but now we have maintenance therapy following concurrent treatment, and that's a new twist on the treatment.

Whitney Lewis

I would say that's probably been the biggest change to lung cancer treatment in the last few years. It is nice to have some familiar things too. So a stage IA disease will be resected and not receive adjuvant treatment; IB and IIA disease, depending on high-risk features, may get adjuvant treatment after resection; IIB disease will receive resection and then adjuvant chemotherapy; IIIA and IIIB disease, depending on the nodal status, may get resection followed by radiation or chemotherapy, but the IIIBs that are N2 disease, or the IIICs like you said, absolutely, those aren’t resectable patients. So they're likely going to get the chemotherapy concurrent with the radiation, and then, a year of adjuvant immunotherapy, which was so groundbreaking when we started doing that based on the results from the PACIFIC trial.¹

Elizabeth Waxman

Yes, I agree. The PACIFIC trial enrolled patients with stage III non–small cell lung cancer. They were not candidates for curative surgery, so they received concurrent chemoradiation. About one in four patients had neoadjuvant therapy as well. But this trial was actually great because it was done primarily in the community, not just in big hospitals, cancer centers. So it really is reflective of the normal lung cancer patient—course, comorbidities, management, etc.

After patients received radiation with the chemotherapy, within about 6 weeks, they started adjuvant immunotherapy, specifically with durvalumab, and received that for a full calendar year, as long as they were tolerating it. In the placebo group, their progression-free survival was about 5 to 6 months, and as we've come out with PACIFIC with more and more timepoints, that spread keeps getting wider and wider. The 4-year overall survival now with durvalumab is almost 48 months, compared to about 29 months with placebo, which is a huge spread. And we have the opportunity to cure most patients, whereas before, a IIIC only had about a 5% chance of long-term survival from this disease. So this is an exciting, brand new treatment.

Whitney Lewis

Were there any notable toxicities, such as pneumonitis, with the addition of durvalumab following concurrent treatment?

Elizabeth Waxman

That was one thing that everyone involved with the trial was worried about, because one of the side effects of immunotherapy is interstitial lung disease, or pneumonitis. Radiation can cause the same thing. However, radiation pneumonitis was really rare in this trial, with only about 1.3% in each group. And pneumonitis itself not related was about 4% to 5% versus 2% to 3% with placebo. So it did increase it a little bit, but not to the point where the toxicities were outweighing the clear benefits of treatment.

Speaking of side effects from immunotherapy, what about patients who may have another virus like HIV or hepatitis? Is there a known contraindication for patients with issues such as those?

Whitney Lewis

I know when immunotherapy was first being studied, those populations were excluded from all the clinical trials. But as immunotherapy has made its way into the treatment landscape for not just lung cancer but for a lot of other solid tumors as well, they've started to collect some of these cohorts, and it seems like there's really no contraindication for patients who have other viruses like HIV or hepatitis. You probably want to involve their infectious disease team, just for increased monitoring, especially with hepatitis, because the immunotherapy can cause some inflammation in the liver, and you might want to monitor them a little bit more quickly or with increased frequency. But there's really no contraindication from that perspective. So that's great for those populations too, which historically weren't great candidates for the newest and greatest therapies, just because it can be a confounding factor for clinical trial enrollment.

Elizabeth Waxman

At this point, especially for patients with adenocarcinoma, a patient with NSCLC and a mutation should get the appropriate targeted therapy up front because it offers the best outcome for treatment. But having a mutation does not necessarily exclude a patient from getting immunotherapy. Is that correct?

Whitney Lewis

Absolutely. What we see with patients who have targetable mutations is that they may not have quite the same robust, long duration of response to immunotherapy, but it's certainly not a contraindication by any means. To your point, if they have untreated, metastatic disease, immunotherapy is not going to be your first choice, but if you have one of these rare patients with IIIB or IIIC disease, and they go through concurrent treatment, you can absolutely give them adjuvant durvalumab. That was a subgroup that was included in the PACIFIC trial. So it's not a contraindication: What therapy you choose first just depends on where they are in their disease and its treatment.

Elizabeth Waxman

Durvalumab is also approved for the treatment of small cell lung cancer with chemotherapy, right?

Whitney Lewis

Yes. And the dosing is actually really unique, and it's an easy thing to get confused. But for small cell lung cancer, patients receive a flat dose of 1500 mg over 60 minutes. With chemotherapy, it's every 3 weeks, but when patients go onto maintenance therapy, it's every 4 weeks. For non–small cell lung cancer adjuvant therapy, it's still weight based at 10 mg/kg, still over 60 minutes, but every 2 weeks. So it's very different and easy to flip-flop those two. Right now, the FDA approval is still very separate: every 2 weeks weight-based, or every 3-4 weeks flat dose. So there's really no mixing and matching right now.