Thoracic Oncologist Highlights EGFR TKI Advances in NSCLC

Missak Haigentz, MD

The identification of sensitizing mutations along with the development of EGFR tyrosine kinase inhibitors (TKI) has been crucial to selecting the right treatment for select patients with non—small cell lung cancer (NSCLC), said Missak Haigentz, MD.

In September 2018, the FDA approved dacomitinib (Vizimpro) for the frontline treatment of patients with EGFR-positive NSCLC who harbor exon 19 deletion or exon 21 L858R substitution mutations. The approval was based on data from the phase III ARCHER 1050 trial, in which the second-generation TKI dacomitinib reduced the risk of progression or death by more than 40% compared with gefitinib (Iressa).

Data presented at the 2018 ASCO Annual Meeting showed that the median overall survival (OS) was 34.1 months in patients randomized to dacomitinib versus 26.8 months in those randomized to gefitinib. Median progression-free survival (PFS) for patients on the dacomitinib arm was 14.7 months compared with 9.2 months for those who received gefitinib (HR, 0.59; 95% CI, 0.47-0.74; P <.0001). The median duration of response was 14.8 months with dacomitinib versus 8.3 months with gefitinib (HR, 0.40; 95% CI, 0.31-0.53; P <.0001).

This approval followed that of osimertinib (Tagrisso), a third-generation EGFR TKI that was approved as a frontline treatment for patients with EGFR-mutant NSCLC in April 2018.

Haigentz, chief of Hematology and Oncology at Morristown Medical Center and medical director of Atlantic Hematology and Oncology for Atlantic Medical Group at the Carol G. Simon Cancer Center, noted that the next step for thoracic oncologists is the research of sequencing strategies for this class of agents, which also includes afatinib (Gilotrif) and erlotinib (Tarceva). The treatment-related adverse events highlighted in ARCHER 1050 is also something to consider, he added.

OncLive: Please provide an overview of your presentation.

In an interview during the 2018 OncLive^® State of the Science Summit™ on Non—Small Cell Lung Cancer, Haigentz discussed the impact of EGFR TKIs on the treatment of patients with NSCLC.Haigentz: The way that we view lung cancer compared with how we have viewed lung cancer in the past has drastically changed. It has changed over the last 20 years since I have been a fellow. We viewed lung cancer as a single disease where we knew of histological entities. Now, we view it as a large number of molecularly defined cancer types and genotypes for which we now have targetable mutations that are actionable and making huge differences in patients' lives.

I spoke about the EGFR mutation and the subset of patients who have sensitizing EGFR mutations. In the United States, this accounts for about 15% to 20% of NSCLC cases. In other parts of the world, this can be around 40% to 50%. These mutations tend to happen in never-smokers but can happen anywhere. It's a testament to translational science and cancer genomics that we've been able to identify patients at the right time to get the right drug.

Over my career, the development of EGFR TKIs since 2003 has been exciting to see. It's hard to imagine it's been 15 years. They started initially for unselected patients, but now over the last 5 years, we have several drugs that are FDA approved for patients with EGFR-positive NSCLC. These drugs have been developed over 3 generations. The generations have been associated with incremental increases in PFS over chemotherapy to the point where we no longer use chemotherapy as the standard frontline treatment.

Has the September 2018 approval of dacomitinib had an immediate impact on your practice?

Even in the past year, we now have 2 FDA-approved agents added to the armamentarium. I spoke about these 2 agents, which are osimertinib and dacomitinib. These are third- and second-generation TKIs, respectively. With dacomitinib as a single agent, we've finally seen a change in OS, which has been elusive. The question is, "Where do these fit into the landscape?"It's going to be an interesting challenge as far as selecting these agents for frontline treatment. In the ARCHER 1050 study, which is what led to the FDA approval, we saw an improvement in OS. It was a secondary endpoint, but it was the first time we saw an improvement in this area in a head-to-head comparison of 2 EGFR inhibitors. Dacomitinib was compared with gefitinib.

What are some other frontline considerations?

What is the potential of erlotinib combined with bevacizumab (Avastin) in this space?

The challenge with dacomitinib is that there are potential tolerability concerns compared with the first-generation TKI. Dose reduction will probably be prevalent, as we saw in the clinical trial. You have to weigh tolerability and benefit. When you look at osimertinib, it was FDA approved on the basis of PFS, nearly doubling what we saw with first-generation TKI. It also appears to be a more tolerable agent, with the addition of central nervous system penetrance. What we really need to see are the OS data with osimertinib. This will help us. The next question is how we sequence these drugs. Certainly, the type of sensitizing mutation is a very important consideration. By and large, the mutations that are well defined as being sensitizing are exon 19 deletions and exon 21. These comprise about 90% of the mutations for EGFR-positive NSCLC. We know there's another 10% to consider. Afatinib (Gilotrif) is the agent we typically use for those more uncommon mutations. That's really one of the more impressive things I took home from the 2018 ASCO Annual Meeting. The potential for combination therapies to improve outcomes is very exciting. There were 2 studies that showed considerable improvements in OS for EGFR-mutated NSCLC. Both studies were phase III and came from Japan. Erlotinib and bevacizumab were compared with erlotinib alone. There was a clear PFS advantage.

Could checkpoint inhibitors have a role in EGFR-mutant disease?

What sequencing strategies would you like to highlight?

What has been the greatest success in EGFR-mutated disease and how can we compound this moving forward?

Is there anything else you would like to add?

It really gives us some great insight as far as combinations with VEGF pathway inhibition. I'm not sure where this plays a role in the United States, but certainly where access is a challenge to second- and third-generation TKIs, this could be a promising approach. IMpower150 compared 4 drugs to 3 drugs, essentially. It was bevacizumab, carboplatin, paclitaxel, and atezolizumab (Tecentriq) versus the same regimen without atezolizumab. In that study, patients were eligible regardless of their driver mutation or EGFR status. In a subgroup analysis, the patients who did have driver mutations benefitted, as well. It's certainly put a different perspective on immunotherapy; perhaps it opens the door to considering this type of regimen for patients who do progress on EGFR inhibitors. The intriguing question is whether a patient who is starting on a second-generation TKI and progresses is going to be salvaged by osimertinib or another third-generation inhibitor. This is really an ongoing question and is subject for research at this point. I would say the greatest success has been identifying the right patients. Otherwise, we would be stuck using these agents for unselected patients and, essentially, those who won't benefit. All of our considerations toward improving quality of life have made tremendous differences. We're seeing less toxicity and making great headway. This is an exciting time to be a medical oncologist and being able to offer life-saving therapies. I share with patients that [our current treatments] are miracles, but temporary miracles. The future is going to be discovering resistance mechanisms earlier and intervening earlier, so we can win the game. There was a great article in JAMA Oncology about applying the game theory to oncology. I thought it was fascinating that we're almost on the losing end in the sense that we're giving a drug until disease progression. We should be thinking ahead of the cancer because we’re smarter than the cancer.

Mok T, Cheng Y, Zhou X, et al. Dacomitinib versus gefitinib for the first-line treatment of advanced EGFR mutation positive non-small cell lung cancer (ARCHER 1050): a randomized, open-label phase 3 trial. J Clin Oncol. 2017;35(suppl; abstr LBA9007).