Ongoing Research Builds Upon Advances in Stage III NSCLC, ALK+ Disease

Ronan J. Kelly, MD, MBA, addresses the paradigm shift in stage III unresectable non–small cell lung cancer before delving into the complex field of ALK-rearranged disease.

Ronan J. Kelly, MD, MBA

Although the PACIFIC trial introduced a new standard of care in the treatment of patients with inoperable stage III non—small cell lung cancer (NSCLC) by administering durvalumab (Imfinzi) post chemoradiotherapy, investigators are now trying to determine whether the combination of durvalumab plus chemoradiotherapy concurrently is safe and effective, said Ronan J. Kelly, MD, MBA.

“We have to make sure that whatever we are doing with radiation is safe. That'll be the first thing,” said Kelly, chief of oncology for the ten Baylor Scott and White Health System’s North Texas Cancer Centers and director of oncology at the Baylor Charles A. Sammons Cancer Center at Baylor University Medical Center in Dallas. “Obviously, if we can prove safety, we then have to see if [the approach is efficacious]; the hope is that it will be.”

In February 2018, the FDA approved durvalumab for the treatment of patients with unresectable stage III NSCLC who have not progressed following chemoradiotherapy. The practice-changing approval was based on data from the phase III PACIFIC trial, which showed a tripling in progression-free survival (PFS) with immunotherapy following chemoradiation versus chemoradiation followed by placebo.

Headway has also been made in treatment of patients with ALK-positive disease, for which there is now an array of effective agents available. However, the current preferred option in the frontline setting is the second-generation TKI alectinib (Alecensa), said Kelly, based on data from the phase III ALEX trial. However, brigatinib (Alunbrig), and the recently approved third-generation ALK inhibitor lorlatinib (Lorbrena), have also emerged as potential frontline options, he added.

In an interview at the 2019 OncLive® State of the Science Summit™ on Non—Small Lung Cancer, Kelly addressed the paradigm shift in stage III unresectable NSCLC before delving into the complex field of ALK-rearranged disease.

OncLive: What data have we seen with immunotherapy in stage III NSCLC?

Kelly: The key trial that we've seen in the past 2 years is the PACIFIC trial. This was a trial that really changed the way we treat patients with inoperable stage III NSCLC. For many years, we just had combination chemoradiation as the standard-of-care approach and we hadn't been able to improve on that. Now, with this particular trial, we randomized patients after definitive chemoradiation to receive either the PD-L1 inhibitor durvalumab or placebo. The trial results were actually very exciting. We saw that there was a tripling in PFS. Recently, a few months ago, we saw an OS benefit emerging, which we anticipate will get larger and larger as these data become more and more mature. That trial was really a landmark trial. When it was announced, the discussants said it had a tsunami[-type impact] in stage III NSCLC.

However, it's not the only trial. PACIFIC was with durvalumab, but other companies are now using their particular [checkpoint] inhibitors. We have seen some small data with pembrolizumab (Keytruda), which looks effective. We have also seen data with nivolumab (Opdivo). Furthermore, we have a whole new host of other trials evaluating various combinations. Can you actually give a PD-1 inhibitor with chemoradiation upfront and then go on consolidation PD-1 inhibitors? We are waiting to see that data.

The data to date has been in the inoperable stage III setting, and now we are moving a lot of these PD-1 inhibitors into the neoadjuvant setting. We have started to see some trial results showing the impact of PD-1 inhibitors before surgery in the neoadjuvant setting, which look quite promising. We are also seeing a whole plethora of trials combining radiation with PD-1 inhibitors or various combinations in the neoadjuvant setting. We will see a lot of those data emerge in the next couple of years.

Which patients with stage III NSCLC benefit most from immunotherapy?

All of the patients who can receive definitive chemoradiation are potentially eligible for this approach if they don't have exclusion criteria for a PD-1 inhibitor. The interesting caveat from [the PACIFIC] trial was that in those patients who had PD-L1 expression less than 1% (PD-L1 negative) on their tumor cells, it didn't look like there was an OS benefit. We are trying to understand why that was the case. There is a lot of speculation at the moment, but we are going to see more data emerging over the next couple of years. We are looking at various subgroups [of PACIFIC] because there was a slight imbalance in the arms. [For example], in 1 arm, there were more females [and] more patients with adenocarcinoma; there was also an abnormal placebo performance; the investigators are looking at the data to understand it a little bit more. Certainly, in those patients who had PD-L1 expression greater 1%, there was a significant PFS and OS benefit.

What are researchers hoping to accomplish with the ongoing studies you mentioned?

We need to see if a combination approach with a PD-1 inhibitor and chemoradiation will be safe. We were concerned in the PACIFIC trial that adjuvant PD-1/PD-L1 inhibition was going to cause more pneumonitis, but we didn't see that. We know that radiation can change the immune microenvironment, and we know that chemotherapy can [as well]. Can we bring more cytotoxic immune cells into and near the tumor and get rid of some of the negative immune modulators, like regulatory T cells and myeloid-derived suppressor cells . We just have to wait and see, but, let's first prove that what we're doing with these earlier trials is safe. Then, we [can] see [if there is] an efficacy signal.

The million-dollar question with immunotherapy is what to do after PD-1 inhibitors. If we give everyone with stage III disease chemoradiation or chemoradiation plus a PD-1 inhibitor, what do we do later on in that patient's journey with cancer if they progress? That's going to be a challenge. Can we give another PD-1 inhibitor or a different chemotherapy backbone? Can we identify a new IO-IO combination that will help us overcome immune resistance? That's going to be a big problem in the next couple of years, but there are many studies ongoing at the moment. Hopefully we will see some breakthroughs.

Moving into ALK-positive NSCLC, what is your optimal frontline agent and beyond?

This is a moving target because we now have FDA-approved ALK inhibitors. Crizotinib (Xalkori) was really the single agent that we had, but that's what we call a first-generation ALK inhibitor. We now have several second-generation ALK inhibitors, such as alectinib, brigatinib, and ceritinib (Zykadia). We also have a third-generation inhibitor that has been approved by the FDA: lorlatinib. There are also many ALK inhibitors emerging, like ensartinib and repotrectinib (TPX-0005), so we need to see how this all plays out.

In the frontline setting, in 2019, alectinib is probably the go-to drug, although brigatinib is now beginning to enter that space. Then the question becomes, “What do we give after that?” It certainly looks like if a patient has an ALK mutation as part of their resistance, then lorlatinib can be effective. If there are other oncogenic driver pathways, we have to try to overcome that. Crizotinib may still have a role in a small percentage of patients.

Really, the take-home message in the ALK story is that we need to do next-generation sequencing in patients and they need to have repeat biopsies. Doing this allows us to decide which ALK inhibitor we should prescribe according to what the resistance pathway is.

How would you describe the future outlook for these patients?

We are certainly seeing patients live a long time. Are we curing patients with ALK-targeted agents? I don't think that's the case yet. We are definitely developing exciting and more effective ALK inhibitors. We are able to induce quite significant effects in patients who have brain metastases with drugs that are really able to penetrate the brain very well. That's exciting for patients because that used to be a sanctuary site. Crizotinib didn't really pass into the blood-brain barrier.

Patients are living for years, but the question is what to do after we run out of ALK inhibitors. Also, what do we do if a patient develops another oncogenic resistance pathway? There are ongoing studies looking at if we can give a combination of another targeted agent with an ALK inhibitor. We'll have to see, because there may be increased toxicity [with that approach].


  1. Antonia SJ, Villegas A, Daniel D, et al; PACIFIC Investigators. Overall survival with durvalumab after chemoradiotherapy in stage III NSCLC. N Engl J Med. 2018;379(24):2342-2350. doi: 10.1056/ NEJMoa1809697.
  2. Peters S, Camidge DR, Shaw AT, et al. Alectinib versus crizotinib in untreated ALK-positive non—small cell lung cancer. N Engl J Med. 2017;377(9):829-838. doi: 10.1056/NEJMoa1704795.