Updates Continue in Oncogene-Driven Lung Cancer

Jose M. Pacheco, MD, discusses the preferred therapeutic strategies for treating patients with NSCLC whose tumors harbor genetic alterations in EGFR, ALK, and ROS1.

Targeted therapies ensure more durable responses, better overall responses, and lower toxicity than historical therapy for patients whose tumors harbor oncogenic drivers, such as EGFR, ALK, ROS1, and BRAF, though questions remain on their placement beyond progression.

From a population-based standpoint, Jose M. Pacheco, MD, argued that osimertinib (Tagrisso) should be the preferred frontline EGFR inhibitor for patients with EGFR mutations. Following the results of the phase III FLAURA trial, the FDA approved the agent as a first-line treatment for patients with non—small cell lung cancer (NSCLC) whose tumors contain exon 19 deletions or exon 21 L858R substitution mutations within EGFR.

Patients randomized to osimertinib had a 54% reduction in the risk of progression or death compared with the first-generation tyrosine kinase inhibitors (TKIs) erlotinib (Tarceva) or gefitinib (Iressa). The median progression-free survival (PFS) with osimertinib and standard TKI therapy was 18.9 months (95% CI, 15.2-21.4) and 10.2 months (95% CI, 9.6-11.1), respectively (HR, 0.46; 95% CI, 0.37-0.57; P <.0001).1

For patients with ALK rearrangements, the phase III ALEX trial and subsequent FDA approval positioned alectinib (Alecensa) as the preferred frontline therapy for patients with ALK-positive metastatic NSCLC. The trial reported a 47% improvement in PFS with alectinib compared with crizotinib (Xalkori), a first-generation ALK inhibitor (HR, 0.53; 95% CI, 0.38-0.73; P <.0001).2

Pacheco noted that though second- and third-generation ALK inhibitors, such as brigatinib (Alunbrig) and lorlatinib, have yet to receive FDA approval in the frontline, they are likely to be adopted following progression on alectinib either on trial or off trial.

OncLive: What are some of the updates with oncogene-driven NSCLC that you shared?

In an interview during the 2018 OncLive® State of the Science SummitTM on Advanced Non—Small Cell Lung Cancer, Pacheco, an assistant professor of Medicine/Medical Oncology at the Colorado University School of Medicine, discussed the preferred therapeutic strategies for treating patients with NSCLC whose tumors harbor genetic alterations in EGFR, ALK, and ROS1, and stressed the significance of molecular testing.Pacheco: For my presentation, I spoke about the established genetic alterations for which we have approved targeted therapies. Those include EGFR activating mutations, ALK fusions, ROS1 fusions, and BRAF V600E mutations. We saw data from the FLAURA study presented within the past year suggesting that first-line osimertinib provides a PFS benefit for patients with traditional EGFR activating mutations; those include exon 19 deletions and L858R point mutations in exon 21. The PFS benefit for osimertinib compared with gefitinib or erlotinib was [nearly] 19 months versus 10 months.

From a population-based standpoint, it makes sense to give osimertinib first as opposed to [a later setting] for a few reasons. If you think about treating 100 patients with osimertinib, the median PFS could be 19 months if you go by the trial data. If you treat 100 patients with gefitinib or erlotinib, you would expect a median PFS around 10 months, but only 50% to 60% of those patients will be eligible for sequencing with osimertinib. Depending on the clinical trial you look at, 10% to 40% may not even get second-line therapy. From a population-based standpoint, using first-line osimertinib is the preferred thing to do as opposed to sequencing EGFR inhibitors.

I also spoke about ALK fusions. Within the past year, we saw the results of the ALEX trial looking at first-line alectinib versus crizotinib. There is a clear PFS benefit of 35 months versus 11 months for alectinib versus crizotinib; that is the preferred ALK inhibitor to use initially. While we don't have first-line overall survival (OS) data yet from that particular trial, we have single-arm survival data from a few different alectinib studies where the OS was 70% to 78% in the first-line setting at 3 years.

In the phase III trial with crizotinib, patients were randomized to crizotinib versus chemotherapy. The 3-year OS was only 70%, so it was a little less. We're seeing a clear PFS benefit of 35 months versus 11 months, so alectinib has now moved into the first-line setting as the preferred ALK inhibitor. One of the challenges is we don't know what the best ALK inhibitor to use after alectinib is. There are lots of trials trying to answer that question. Though alectinib is now a preferred first-line ALK inhibitor, that may not hold up after we see the results of the trials with brigatinib versus crizotinib in the first-line setting or lorlatinib versus crizotinib.

Following alectinib for ALK-positive NSCLC, what is your approach?

For ROS1 fusion—positive lung cancer, the current FDA-approved therapy is crizotinib. The median PFS in 2 different studies ranged from 16 to 19 months. We've seen first-line data from entrectinib, which is a new ROS1 inhibitor. It hasn’t been approved yet. The first-line data from nearly 30 patients that was presented at the 2017 World Conference on Lung Cancer suggested a 30-month PFS. In the near future, that will become the preferred ROS1 inhibitor; it will likely end up being approved. Right now, I've been trying to enroll patients on a clinical trial looking at brigatinib in the second-line setting post-progression on a second-generation ALK inhibitor. I've been enrolling my patients who were previously treated with alectinib on a trial of brigatinib. These patients will first get a biopsy to determine what molecular markers we can find to help predict benefit from brigatinib following alectinib or another second-generation ALK inhibitor.

Now, we are beginning to learn more about mechanisms of resistance to ALK. We know that, following a first-generation ALK inhibitor such as crizotinib, roughly 20% to 25% of patients may develop ALK mutations in the ALK protein itself. Following ceritinib (Zykadia), alectinib, or brigatinib, roughly 50% of patients will develop a mutation in the ALK protein that leads to resistance.

Preclinically, it looks like lorlatinib may work better for a particular ALK mutation, G1202R. There was a patient in the phase II study of brigatinib who had a G1202R mutation who responded to brigatinib. There have also been patients with G1202R mutations who have not responded to brigatinib. We have limited data from lorlatinib in patients with that particular ALK mutation, but it does appear that patients with that particular ALK mutation may do better with lorlatinib than other ALK inhibitors.

What is the biggest challenge in treating patients with driver mutations?

What do you hope community oncologists apply to their practices?

If I knew that a patient had a G1202R mutation and lorlatinib was approved, I would prescribe them that. If I had a way to get them in an expanded access program with lorlatinib, I would get them that. Otherwise, following alectinib, if I didn't know they had that mutation or I couldn't identify a particular mutation, I would give them brigatinib either on or off trial. It’s very important that when we have clinical trials, we try to get biopsies when people develop worsening disease. That is how we were able to come up with the drug osimertinib. We found a T790M mutation and a pretty sizable percentage of patients who progressed on erlotinib or gefitinib were able to benefit.For most patients, from a population-based standpoint, using osimertinib as an initial EGFR inhibitor will benefit more patients than trying to [administer it later] because you will lose patients going from one line of therapy to the other. Sequencing will only benefit those patients who are going to develop the T790M resistance mechanism.

Waiting for the results of molecular testing is very important, so that you can give your patient the right treatment. I once saw a patient who was going to get immunotherapy and his PD-L1 expression was 60%. He had his molecular testing on bone; the way a bone biopsy is processed caused false negative results. When we did a rebiopsy, we found an ALK rearrangement. He would have received a completely wrong therapy that he probably would not have responded to. If someone is “crashing and burning,” you can give them chemotherapy with or without an immune checkpoint inhibitor if they can't wait 1 or 2 weeks.


  1. Ramalingam S, Reungwetwattana T, Chewaskulyong B, et al. Osimertinib vs standard of care (SoC) EGFR-TKI as first-line therapy in patients (pts) with EGFRm advanced NSCLC: FLAURA. In: Proceedings from the 2017 ESMO Congress; September 9-12, 2017; Madrid, Spain. Abstract LBA2_PR.
  2. FDA Approves Genentech’s Alecensa (Alectinib) as First-Line Treatment for People with Specific Type of Lung Cancer. Genentech. Available at: http://bit.ly/2zmLda7. Published November 6, 2017. Accessed August 7, 2018.