Osimertinib Combinations Challenge the Standard of Care in EGFR-Mutant Lung Cancer

Zofia Piotrowska, MD, MHS

Zofia Piotrowska, MD, MHS

First-generation EGFR tyrosine kinase inhibitors (TKIs), such as erlotinib (Tarceva) and gefitinib (Iressa) have become established treatments for patients withEGFR-mutant lung cancer, but based on data from the phase III FLAURA trial, third-generation EGFR TKI osimertinib (Tagrisso) has raised the bar in terms of improving both progression-free survival (PFS) and overall survival (OS).

According to Zofia Piotrowska, MD, MHS, osimertinib is now the standard of care in the front-line setting for patients with lung cancer harboring anEGFRmutation. However, new studies are underway to evaluate the potential for combination therapy in these patients.

Many patients do well with chemotherapy as treatment, but about 30% of patients will not make it to the second-line setting for further therapy. By combining both osimertinib and chemotherapy, Piotrowska says patients may experience more benefit and improvements in survival. In prior phase III studies, first-generation TKIs plus chemotherapy have led to promising results.

Another potential combination that is being evaluated is the combination of the EGFR inhibitor plus anti-VGEF therapy, such as bevacizumab (Avastin) or ramucirumab (Cyramza). The combination of EGFR and VGEF therapies have demonstrated promising results in previous studies, so now investigators are evaluating the potential combination with osimertinib.

In an interview withTargeted Oncology, Piotrowska, a medical oncologist at Massachusetts General Hospital and an instructor at Harvard Medical School, discussed the role of EGFR inhibition as frontline treatment of patients withEGFR-mutant lung cancers, as well as the combinations with osimertinib that are currently underway and appearing promising for this treatment landscape.

TARGETED ONCOLOGY: What is the role of EGFR TKIs that you discussed during your presentation?

Piotrowska:The question is how we can improve the standard of care for patients with newly diagnosedEGFR-mutant NSCLC. The current frontline standard of care is osimertinib, which was established by the FLAURA trial. This was a randomized trial that compared first-line osimertinib to first-generation EGFR inhibitors and showed improvement in both PFS and OS when osimertinib was given as first-line therapy. FLAURA has led to the widespread use of osimertinib as the standard of care, so the question was how can we improve upon osimertinib.

There are a few different potential treatment strategies that have shown promise when combined with older EGFR inhibitors. At the meeting, we talked about the study supporting the use of first-generation EGFR inhibitors together with VGEF targeted therapies, including bevacizumab and ramucirumab. We have seen 2 phase III studies in that space showing improvements in PFS, and there will be an upcoming study looking at osimertinib plus bevacizumab versus osimertinib alone for newly diagnosed patients. We also talked about the studies that showed the combinations of gefitinib given concurrently with chemotherapy improve OS and PFS for newly diagnosed patients when compared with to gefitinib. Those were 2 large phase III studies, 1 done in Japan and 1 done in India.

Those studies were very compelling. They both showed an improvement in OS with the combination of an EGFR TKI with chemotherapy, but it’s hard to know how to interpret that data in an era where we have osimertinib as our standard of care in the first-line since that was not the comparator arm in those studies.

Again, we will have a study looking at this question; the FLAURA-2 trial will combine osimertinib with chemotherapy for newly diagnosed patients. Again, this is a randomized phase III study looking at osimertinib plus chemotherapy versus osimertinib alone. That study has the potential to change practice.

Finally, we talked about some of the ongoing studies looking at combinations of first- and third-generation EGFR inhibitors as a strategy to prevent the development of resistance through theT790MandT79Sresistance mutations.

Lastly, it is important to think about the potential of adding local therapies, such as consolidative radiation therapy to patients who are responding as a way of improving outcomes. Finally, I touched on the fact that maybe these combination strategies will work but won’t be necessary for everyone. Ultimately, we will need better biomarkers to identify whom they do well on osimertinib alone and be able to receive osimertinib in monotherapy versus those patients who may not have as good of a response and may need these combinations to benefit.

TARGETED ONCOLOGY: Could you give us a wider overview of the FLAURA trial and how these data impacted the treatment landscape?

Piotrowska:The FLAURA trial was a large randomized phase III trial done in multiple countries, which looked at the question of which is the best EGFR inhibitor to use first-line. It was done in an era where first- and second-generation EGFR inhibitors, such as erlotinib, gefitinib, and afatinib were the standard of care, but we knew many patients who progressed on those drugs developedT790Mresistance mutations inEGFR. For those patients, osimertinib had shown to be an excellent second-line option. We also saw osimertinib had a great safety profile, low rates of diarrhea and rash, and had good CNS penetration, so the activity we saw in the second-line setting led many to wonder would osimertinib be a better first-line therapy. FLAURA aimed to answer that question.

Newly diagnosed patients withEXON19orL858Rwere randomized to either the standard arm of erlotinib or gefitinib or the experimental arm of osimertinib. The primary end point of the study was PFS, and a couple of years ago now, we saw the study was positive for PFS with improvement from about 10 to 19 months when we are looking at first-generation TKIs versus osimertinib. This year, we also saw the OS analysis was positive. We saw an improvement from about 32 to 39 months with osimertinib as first-line therapy. Both the PFS and OS results were encouraging and have led many of us to use osimertinib as our preferred first-line agent forEGFR-mutant lung cancers.

TARGETED ONCOLOGY: How are you selecting which patients should receive osimertinib in the first-line setting?

Piotrowska:For patients with the standard sensitizing mutations, such asEXON19andL858R, the FLAURA trial has led me to use osimertinib as the first-line therapy for all of those patients. Initially, when the FLAURA trial came out, there was some discussion about whether we should be sequencing these agents and if there was any benefit to first giving them either erlotinib or gefitinib and then if patients then developedT790M, leaving osimertinib as an option for second-line therapy. The challenge with that paradigm is that only about 60% to 70% of patients will developT7090Mand will get to the second half of that sequence, whereas if we give osimertinib first-line, we know they will benefit for hopefully as long as 19 months or longer. To me, I’ve always been taught to give your best drug first, so osimertinib seems to be that approach based on the FLAURA data.

I do still consider second-generation EGFR inhibitors for patients with the uncommon but still sensitizingEGFRmutation. Afatinib is the only FDA-approved therapy for those mutations right now. These are things like theG719mutations,S768I,and others. However, we have started to see now emerging data with osimertinib for those mutations as well. Data look promising, and I anticipate that we may begin to use osimertinib for those patients as well.

TARGETED ONCOLOGY: What combinations with osimertinib appear promising now?

Piotrowska:There are a few different approaches under evaluation in terms of combinations. The one I am most excited about would be the combination of EGFR inhibitors plus chemotherapy. The reason I am excited about these is because, over the last few years, we have seen 2 independent large phase III studies, each over 300 patients, from 2 different parts of the world. Both studies show that when chemotherapy is combined with a first-generation EGFR inhibitor, which in these 2 trials it was gefitinib, the combination improves not just PFS but also OS compared with using gefitinib alone. The 2 trials were NEG009 in Japan and a second was done in India. They both had a very similar design with newly diagnosed patients withEGFR-mutant lung cancers were randomized to gefitinib together with pemetrexed chemotherapy followed for 4 to 6 cycles followed by pemetrexed maintenance. In both of these studies, we saw consistent results with consistent improvements in OS for the combination of TKI and chemotherapy. It begs the question of why that might be, but based on what we have been seeing, many of these patients do not make it to second-line therapy.

As much as we want to say all of our patients get many lines of therapy and do well for long periods of time, in the FLAURA study with a population that was fit enough to be enrolled in a clinical trial, 30% of those patients never made it to second-line therapy. I think that’s really sobering. We know chemotherapy works well for those patients, and it’s a big detriment if they can’t access that type of treatment. Using it upfront first, ensures that patients get access to both TKI and chemotherapy.

There is also the potential that adding chemotherapy can help irradiate clones that may be surviving TKIs early on and help delay the development of resistance. For that reason, I think TKIs and chemotherapy are going to be important. There is an ongoing study called FLAURA-2, which will look at the same question looking at osimertinib plus platinum pemetrexed chemotherapy. I’m very excited to see those results.

Another treatment approach that is being evaluated is the combination of EGFR inhibitors with anti-VGEF therapies, such as bevacizumab or ramucirumab. That is based on the idea that we have known for a long time that there is a positive interaction between EGFR and VGEF therapies. We know patients withEGFRmutations tend to benefit from drugs like bevacizumab, and we have had prior phase II and III studies showing a combination of a first-generation EGFR inhibitor plus bevacizumab or erlotinib with ramucirumab both improved PFS when compared to the EGFR inhibitor alone. Those studies indicate that bevacizumab does have a role here and may improve outcomes, something we need to evaluate in the era of osimertinib. There will be an upcoming study of osimertinib plus or minus bevacizumab for newly diagnosedEGFR-mutant patients.

TARGETED ONCOLOGY: What is the main take home message?

Piotrowska: