“The importance of first-line and second-line targeted agents is obvious”

Nir Peled MD, PhD, FCCP, Head of the Thoracic Cancer Unit, Thoracic Cancer Service, Davidoff Cancer Center, Petah Tikva, Israel

Nir Peled MD, PhD, FCCP, Head of the Thoracic Cancer Unit, Thoracic Cancer Service, Davidoff Cancer Center, Petah Tikva, Israel

Which parameters should be taken into consideration regarding the choice of EGFR TKIs in a lung cancer patient with an activating EGFR mutation?
When EGFR mutations are diagnosed in the first-line setting, we have the luxury of having three options today. However, it is important to discriminate between the different types. EGFR mutations normally occur on exons 18 to 21. Most of the activating mutations will respond to all EGFR TKIs; however, the uncommon locations, for example exon 18, tend to respond more strongly to afatinib than to the other first-line TKIs, gefitinib and erlotinib. Aberrations on exon 20 are normally associated with a lack of response to the current drugs. Providing therapeutic options for patients with exon 20 mutations is a true unmet need, because they do not respond well to the new immunotherapies either, which means that they can only receive chemotherapy. These patients make up 4 % to 9 % of the EGFR-positive population, which accounts for approximately 17 % of lung cancer cases, thus constituting a considerable proportion of patients.

As the EGFR TKIs showed comparable PFS results in the big studies, toxicity is a selection criterion. Gefitinib, erlotinib and afatinib have similar toxicity profiles, but according to our daily experience, diarrhoea tends to occur more often with afatinib, as well as nail abnormalities, which can become a significant burden for many patients. We can control both diarrhoea and skin eruptions, but nail issues and paronychia are less well controlled; indeed, often they force us to decrease the afatinib doses. Patients can switch to another EGFR TKI if they are in need of increased tolerability. However, the LUX-Lung 7 trial, which was a direct comparison of afatinib and gefitinib, revealed a 27 % reduction in the risk of progression or death with afatinib over gefitinib [1]. Another aspect is that a combined study analysis showed that patients with exon 19 abnormalities derive an OS benefit from afatinib treatment over chemotherapy [2], whereas the trials conducted with the other EGFR TKIs were not able to show OS improvement compared to chemotherapy in the first-line setting. This might also be a consideration.

In our daily practice, we take into account the type of mutation and the physical appearance of the patient. If the patient is an old lady with a body weight of 50 kg, afatinib would not be my first choice, but a young or middle-aged person with exon 19 mutation or other mutations can benefit from this treatment. Some of our patients also have HER2 aberrations, such as amplifications or mutations, on top of EGFR-activating mutations. These patients might experience an advantage due to the dual HER2 and EGFR blockade conferred by afatinib. Also, afatinib covers uncommon mutations, especially those in exon 18. Another consideration are brain metastases. Afatinib shows a favourable response rate of approximately 30 % with regard to brain lesions. I would consider afatinib for patients with brain metastases, rather than other EGFR TKIs. The other TKIs elicit brain responses too, but not as well as afatinib.

What about the second-line setting?
The most common resistance mutation is the T790M mutation, which occurs in approximately 60 % to 66 % of EGFR-TKI-treated patients. To date, only osimertinib has been approved for this patient population. This drug is very well tolerated, with less adverse events in comparison to previous drugs. The response rate was 66 % in T790M-positive patients [3], and brain responses have also been reported in a small series [4]. The PFS is approximately 10 months, so the results of the first-line therapy are duplicated. Studies on other drugs are ongoing. Interestingly, I have observed that a few cycles of chemotherapy can sometimes restore the sensitivity of patients who have progressed on anti-EGFR therapy, towards their previous EGFR TKI treatment. Obviously, the resistant clones are eradicated by chemotherapy, and re-challenge is then rendered possible. This is not an approved approach, of course. Recommendations on the optimisation of the management of EGFR-mutation-positive NSCLC have recently been released by the International Association for the Study of Lung Cancer [5].

What are the current recommendations with respect to the management of brain metastasis?
Brain metastasis is a big issue. Many of our lung cancer patients develop brain lesions, especially the ones with EGFR and ALK abnormalities, and many of them die due to leptomeningeal spread and brain involvement. Currently we are trying to avoid whole-brain radiation because of the long-term adverse effects of this treatment. If up to 10 or 12 isolated lesions are present, we perform stereotactic radiosurgery. Until 2 years ago, the upper limit used to be only three lesions. If imaging reveals more lesions and if they are asymptomatic, we might start EGFR or ALK TKI therapy and monitor the patient. If the metastases are symptomatic, we perform radiation of the single lesion that causes the symptoms. Wholebrain radiation therapy is only considered if the patient does not respond to TKI therapy and progression occurs.

If we observe responses of the extracranial lesions, and at the same time, cerebral progression, this means that the drug does not penetrate the blood-brain barrier well enough. In this situation, the administration of bevacizumab is an option, as well as radiation of the brain. An interesting phase II study yielded a median PFS of 16 months with first-line bevacizumab plus erlotinib in patients with advanced EGFR-mutation-positive NSCLC [6]. Another phase II first-line trial showed a median PFS of 14.4 months with the combination of bevacizumab and gefitinib [7]. These results exceed those obtained with any of the EGFR TKIs as a single agent. For the time being, this approach is based on phase II data only, but I hope it is going to be approved by the FDA soon. It is a very interesting option for many patients.

How is the role of re-biopsy currently defined?
Re-biopsy is a relevant topic, because the patients dislike being punctured; the procedure is painful and invasive. Many times, disease progresses in a heterogeneous way, which is why singlesite biopsies do not reflect progression well enough. Liquid biopsy, on the other hand, offers advantages in the detection of resistant mutations. The sensitivity of the technology is not 100 % yet, but we are improving on it every day. If no tissue is available, liquid biopsy is a very good choice, also in the up-front setting, especially in the case of positive EGFR mutation testing. Liquid biopsy works well for the main mutations; it is less accurate for amplification and translocation. Personally, I have had very good experience with liquid biopsy. At our clinic in Israel, we use it as a routine assessment for patients who have progressed after first-line EGFR TKI therapy. I would even say that it should not be restricted to the second line, but that it can also be used in the first line. Normally, we only do re-biopsy if two negative liquid biopsy results have been obtained. Biopsy would be performed according to the PET scan results, to isolate the most resistant site.

What notable advances have recently been made in the field of molecular diagnostics?
It is the lung cancer patients who benefit most from the considerable advances in the field of molecular profiling. Due to increased sensitivity and knowledge accumulated over the years, TKIs can nowadays be offered to almost 30 % of these patients. Next-generation sequencing increases the number of patients who are diagnosed with EGFR-positive mutations. Polymerase chain reaction misses many of the positive cases. In addition to abnormalities of EGFR, ALK and ROS-1, cMET amplifications and mutations (as exon 14 skipping) can be diagnosed, which are as common as ALK rearrangement, at approximately 4 % to 5 % of the adenocarcinoma population. It is possible to detect RET translocation and HER2-positivity. BRAF mutation is common not only in melanoma, but also in lung cancer. For ALK testing, we used to perform a FISH-based analysis, but now we are shifting towards immunostaining, which is much more sensitive, for many reasons. Next-generation sequencing allows us to diagnose more patients with a target-to-treat approach, and therefore we can serve the community in a better way. The importance of treatment with first-line and second-line targeted agents is obvious, as it has already been shown in many studies that not only quality of life is improved, but also response rates and overall survival. We do our best to profile the tumour properly before deciding upon chemotherapy.

A technology I expect to be implemented in many countries in the next 1 or 2 years is droplet digital PCR. This works via automated systems, requires a much smaller amount of tissue than the other methods, and is highly sensitive, highly specific, and has low cost. For the time being, liquid biopsy is only used at the time of progression. In the future, we might perform repeated liquid biopsies during monitoring and change therapy as soon as different clones occur, but this approach is still subject to research.


  1. Park K et al., Afatinib versus gefitinib as first-line treatment of patients with EGFR mutationpositive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial : Lancet Volume 17, No. 5, p577–589, May 2016
  2. Yang JC et al., Afatinib versus cisplatin-based chemotherapy for EGFR-mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol 2015; 16: 141-151
  3. Yang J et al., Osimertinib (AZD9291) in pretreated pts with T790M-positive advanced NSCLC: updated phase 1 (P1) and pooled phase 2 (P2) results. J Thorac Oncol 2016; 11(4 Suppl): S152-3
  4. Ricciuti B et al., Osimertinib (AZD9291) and CNS response in two radiotherapy-naïve patients with EGFR-mutant and T790M-positive advanced non-small cell lung cancer. Clin Drug Investig 2016 May 13 [Epub ahead of print]
  5. Tan DS et al., The International Association for the Study of Lung Cancer consensus statement on optimizing management of EGFR mutation positive non-small cell lung cancer: status in 2016. J Thorac Oncol 2016; 11(7): 946-963
  6. Seto T et al., Erlotinib alone or with bevacizumab as first-line therapy in patients with advanced non-squamous non-small-cell lung cancer harboring EGFR mutations (JO25567): an open-label, randomized, multicenter, phase II study. Lancet Oncol 2014; 15(11): 1236-1244
  7. Ichihara E et al., Phase II trial of gefitinib in combination with bevacizumab as first-line therapy for advanced non-small cell lung cancer with activating EGFR gene mutations: the Okayama Lung Cancer Study Group Trial 1001. J Thorac Oncol 2015; 10(3): 486-491