Lung (December 2015): Molecular Oncology Tumor Boards

ASCO University
Dec 02, 2015 10:12 AM

User Instructions: Welcome to the Molecular Oncology Tumor Board Series! This educational initiative is a collaboration between the American Society of Clinical Oncology (ASCO), College of American Pathologists (CAP), and Association for Molecular Pathology (AMP).

A new case will be presented each month with discussions led by an expert pathologist and medical oncologist. This month’s topic is led by Drs. Philip Cagle (Houston Methodist) and Nathan Pennell (Cleveland Clinic). 

Users are encouraged to leave comments and post questions about the case in order to generate a wide discussion among the cancer care community. You can also receive email notifications when new comments are posted by clicking the “Follow this Conversation” option located at the bottom of this page.

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Supplemental resources related to the case are attached for reference.

Comments

11791

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 02, 2015 10:16 AM

Patient Case (Initial Scenario)

Age/Sex: 60 year old man with a 20 pack year smoking history, quitting 15 years ago.

Medical History: The patient presents with a 2 month history of low back pain which does not resolve with conservative measures and a plain film is ordered by his family physician showing a lytic lesion in the third lumbar vertebral body. Further imaging shows a 3cm left upper lobe lung mass with associated left hilar and mediastinal adenopathy. He has a nonproductive cough without hemoptysis, is not short of breath, and has no other pain. His appetite is good and he has not lost any weight. He is quite active, playing golf several times per week. His back pain is managed well with ibuprofen.

Type of Tumor: A transthoracic needle biopsy of the lung mass shows an adenocarcinoma histologically compatible with a lung primary.  The primary site is confirmed by positive TTF-1 immunostain.  

Relevant Markers:  Per protocol, EGFR mutation testing was performed and an Exon 19 deletion detected.  

Prior Treatment History/Response: none

Co-morbidities:  Hypertension, hyperlipidemia, coronary artery disease status post-stent placement 5 years prior.

Images/Scans/Pathology: CT scan as above. PET/CT was done showing the lung mass and adenopathy, as well as bony lesions in L3, L5, and the pelvis. MRI of the brain is done which is normal.
 

11796

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 02, 2015 10:17 AM

Discussion Questions

1.    Who should get routine molecular testing at diagnosis for NSCLC and what tests should be performed? 
2.    Given this patient’s age and smoking history are you surprised at the finding of an EGFR mutation?
3.    What is the most appropriate initial treatment for this patient?

11801

Anis Toumeh, MD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 02, 2015 2:08 PM

1- I believe it is standard practice to test for EGFR sensitizing mutations (exon 19 and 21 ) as well as ALK rearrangment and ROS1 in this case. 

2- Although the incidence/prevalence of these mutations is higher in young-non smoker women (esp from east Asia), data does show that age, smoking history and ethnicity are not consistently predictive of the mutational status of these tumors. 

3- Standard first line therapy with an EGFR TKI will be most appropriate. One can choose between Erlotinib, Gefitinib and Afatinib. Although the joint analysis from LUX-Lung 3 and 6 did show survival advantage with Afatinib in those who harbor Del 19 mutation, the individual trials did not show the same. Moreover, there are no publiushed definitive comparative trials between the different TKIs as yet. Until further data are available and given the toxicity profile of Afatinib, I would go for Erlotinib or Gefitinib as first line.  

11806

Francisco Jorquera Orlandi, MD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 03, 2015 3:36 PM

1- For our population we test all adenocarcinoma  patients, regardless of ethnicity or smoking status and also NOS and squamous cell carcinomas with an ever smoking status.

2-As previous comment stated, nor ethnicity, neither smoking status or age can predict the EGFR mutation appearance. For us there is a 21% of positivity in a strongly smoking prone population.

3-Any of three available drugs may be chosen. Until now, we have no comparative trial to address this point. As a trend we still use Afatib in fit patients who can eventually better tolerate it to gain this slightly and unconfirmed OS gain showed in the pooled analysis from LL3 and LL6, and Gefitinib for the unfit ones, due to milder side  effects profile. 

11811

Chandrashekhar Jagannath Tamane
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 04, 2015 2:18 AM

My Question to the forum is ..

1.If EGFR & ALK is awaited and the patient is symptomatic are we justified in prescribing systemic chemotherapy for the patient ? 

2. systemic chemo with either anti EGFR/ ALK ? - any study ?

Dr.Chandrashekhar Tamane,   

 

11816

Nathan A. Pennell, MD, PhD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 04, 2015 9:44 AM

Dr. Tamane, Thank you for your questions.  

1)    In any patient who is symptomatic and requires urgent initiation of systemic therapy, chemotherapy is a reasonable choice if the molecular testing is not readily available. This is true even when the clinical suspicion is high for a targetable mutation! This comes up fairly often when the biopsy tissue is not sufficient for testing or simply is unavailable for some time due to logistic reasons. If a new biopsy is needed or testing is going to take a long time for some reason, and you don’t feel it is safe to wait, always remember that chemotherapy works at least as well in genetically defined subgroups of NSCLC as in pan-wild type NSCLC. Most studies show no difference in overall survival if TKIs are given first line or second, as long as they eventually get them.

2)    There have been many studies looking at combining chemotherapy with TKIs in the EGFR space although most were in all comers (e.g. INTACT, TRIBUTE, TALENT, etc) and not EGFR mutants, not so much in the ALK space to my knowledge. None of them have shown significant improvements in survival, or really any meaningful endpoint, with combinations first-line, so I would recommend TKIs be used as monotherapy.

 

11821

Nicholas Dean Reese, MD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 04, 2015 5:44 PM

1.  Beyond assessing for EGFR mutational status and for ALK and ROS1 translocations - what should be the standard "genetic/molecular" tests for newly diagnosed metastatic lung cancer?  How practical is it to assess for Her2 mutation/RET, etc in a community setting?

 

2.  Has anyone adopted first-line erlotinib + bev for EGFR mutated patients given the striking PFS data from Seto and the JO25567 phase II study?  It is certainly compelling phase II data and bev is approved and active in adenocarcinoma.

Philip Cagle
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 07, 2015 3:52 PM

Dr. Reese,
Thank you for your questions.  I address EGFR and ALK testing in my most recent update and to further answer your questions, please consider:

ROS1, RET, HER2, BRAF and MET are being considered for the revised 2016 CAP/IASLC/AMP guidelines.  Currently, the data has been extracted from the literature and is being audited and reviewed for draft recommendations that will be posted for public comment in early 2016.  Therefore, we are awaiting final guidelines for these additional biomarkers.   Currently, we can note the following: ROS1 and RET are translocations that can be detected by FISH, CISH, RT-PCR, NGS, or the other methods discussed for ALK.   IHC can be employed for ROS1 screening using the D4D6 clone, but RET IHC is currently less reliable.  HER2 activation in lung cancer is associated with mutations, mostly insertions in exon 20, which are independent of HER2 gene amplification.  BRAF is also activated by mutation.  Both HER2 and BRAF mutations can be identified by the techniques mentioned for EGFR mutation analysis.  MET is more complex. MET exon 14 deletions can be detected by mutation analysis methods and MET copy number can be detected by FISH, CISH, NGS and array comparative genome hybridization.  Currently, for detection of these less frequent biomarkers, community laboratories should be able to identify reference laboratories that can perform these tests if they do not wish to set these tests up themselves.

 

11836

Philip Cagle
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 07, 2015 3:24 PM

Course Faculty Response
1.)Who should get routine molecular testing at diagnosis for NSCLC and what tests should be performed? 

In general, per the 2013 CAP/IASLC/AMP lung cancer predictive biomarker testing guidelines, EGFR mutation testing and ALK rearrangement testing is recommended for samples of advanced NSCLC in which a diagnosis of adenocarcinoma is confirmed or cannot be excluded.   This is based on FDA approval of EGFR and ALK tyrosine kinase inhibitors (TKIs) for advanced lung cancer and FDA approval of companion diagnostics for ALK TKIs.  These guidelines encourage molecular testing in earlier stage lung cancers but the benefits of targeted therapy in early stage lung cancer are still under clinical investigation for example in clinical trials such as the Adjuvant Lung Cancer Enrichment Marker Identification and Sequencing Trials (ALCHEMIST).  Results of these clinical trials will be available in the not too distant future and new recommendations are anticipated on the basis of the results.  

Molecular testing of NSCLC may be reflex (all NSCLC specimens meeting certain criteria are automatically tested) or require the order of the oncologist.  Per the 2013 CAP/IASLC/AMP guidelines, EGFR mutation analysis is recommended for EGFR testing and immunohistochemistry (IHC) and FISH are not recommended.  In particular, current EGFR antibodies will miss less frequent EGFR mutations. There are multiple methods for EGFR mutation testing including Sanger sequencing, RT-PCR and pyrosequencing. EGFR mutations may also be detected by Sequenom massARRAY which uses MALDI-TOF mass spectrometry or next generation sequencing (NGS) which allows for detection of multiple mutations in multiple genes in a single assay.  With NGS, EGFR mutations are typically part of a panel of genes assayed using instruments such as Ion Torrent (Life Technologies) or Illumina (Solexa).  The 2013 CAP/IASLC/AMP guidelines recommended FISH for ALK translocations because of the number of possible ALK fusion partners and variants. Reverse transcriptase PCR requires a separate probe for each variant and fusion partner being tested and ALK IHC did not work well in lung cancers at the time. In 2011, the FDA had approved a companion diagnostic, the Abbott Vysis ALK Break Apart FISH Probe Kit to identify patients for crizotinib therapy.   In 2015, the FDA approved the ALK (D5F3) CDx Assay as an IHC companion diagnostic for crizotinib therapy.  ALK IHC is being reviewed for the revised CAP/IASLC/AMP lung cancer predictive biomarker testing guidelines expected to be published in 2016.  Screening for ALK translocations can also be done using real time quantitative PCR, anchored multiplex PCR and Sequenom mass ARRAY.  In summary, there are a wide range of options for testing for EGFR and ALK and the choice of test depends in large part on availability.

The 2013 CAP/IASLC/AMP lung cancer predictive biomarker testing guidelines recommended an algorithm of testing EGFR as the most common actionable mutation first, followed by ALK.  Since the absence of KRAS does not determine that EGFR mutation is present in NSCLC, KRAS testing was not recommended to exclude EGFR therapy.  Several additional predictive biomarkers are being evaluated for the revised 2016 CAP/IASLC/AMP guideline.  

2.)Given this patient’s age and smoking history are you surprised at the finding of an EGFR mutation?

The clinical profile of this patient is not a surprise.  As explained in the 2013 CAP/IASLC/AMP lung cancer biomarker testing guidelines, although there is a characteristic clinical profile associated with patients whose tumors have actionable mutations, many patients who have differing clinical profiles may have lung cancers with actionable mutations. There are so many exceptions to the clinical profile that many patients potentially eligible for therapy would be excluded based on clinical profile.  

11841

Nathan A. Pennell, MD, PhD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 07, 2015 3:35 PM

Course Faculty Response

1.) Who should get routine molecular testing at diagnosis for NSCLC and what tests should be performed? 

The short answer is that everyone with non-squamous non-small cell lung cancer (NSCLC) should routinely be tested at the time of diagnosis for targetable molecular derangements. I would refer you to the excellent discussion on this topic from the ASCO University Molecular Tumor Board discussion on ROS1 rearranged NSCLC earlier in 2015, but this is sufficiently important that it bears repeating.

The CAP/IASLC/AMP Guidelines released in 2013 (J Thorac Oncol. 2013 Oct;8(10):1343.) and endorsed by ASCO in 2014 (J Clin Oncol. 2014 Nov 10;32(32):3673-9.) recommend routine testing for the presence of EGFR mutation and ALK gene rearrangement in all NSCLC cases with nonsquamous histology, adenosquamous histology, or small samples where adenocarcinoma cannot be completely excluded. Importantly, clinical characteristics such as age, race, and smoking history should not be used to positively or negatively select patients for testing.

As for other potential targetable genes, a strong argument can be made that more comprehensive testing could be considered and I would refer you to the NCCN Guidelines, version 1.2015 on NSCLC for a more detailed discussion on emerging targeted agents for patients with genetic alterations beyond EGFR and ALK. Whether to do broader testing is a complicated question that depends on tissue availability, local expertise and resources, and questions of cost and reimbursement for testing. In 2015 ROS1 likely has the best evidence supporting up front testing in patients with nonsquamous NSCLC, while EGFR and ALK testing represent the minimum requirement.

2.) Given this patient’s age and smoking history are you surprised at the finding of an EGFR mutation?

Although EGFR mutations can be detected at a higher frequency in nonsmokers, women, and in younger patients, the evidence is clear that many if not most of the patients with EGFR mutation+ NSCLC do not fit the stereotypical phenotype (J Clin Oncol. 2011 May; 29(15):2066-2077; J Thorac Oncol. 2013 Oct;8(10):1343.), simply because of the much larger number of smoking-associated lung cancer cases. This is the rationale for testing everyone with nonsquamous NSCLC and not selecting patients for testing based on clinical criteria.

3.) What is the most appropriate initial treatment for this patient?

There have now been multiple phase 3 randomized clinical trials comparing EGFR tyrosine kinase inhibitors (TKIs) to platinum-based chemotherapy in previously untreated EGFR mutation+ NSCLC, and every one of them showed significantly better objective response rates (ORR) and progression-free survival (PFS) with the EGFR TKI than with chemotherapy. This has held true for gefitinib (N Engl J Med. 2009 Sep 3;361(10):947-57.), erlotinib (Lancet Oncol. 2012 Mar;13(3):239-46.), and afatinib (J Clin Oncol. 2013 Sep 20;31(27):3327-34) and all three drugs are now FDA-approved for previously untreated EGFR mutation+ NSCLC. None of these trials, however, showed an improvement in overall survival (OS) compared to chemotherapy, likely due to widespread crossover of patients in the control arms to TKI treatment as these drugs were widely available at the time of the studies. Nonetheless, based on essentially a doubling of response rates and PFS and a more favorable toxicity profile compared to chemotherapy, TKIs are the recommended first line therapy for patients with confirmed EGFR mutations. 

So which TKI should you use, gefitinib, erlotinib, or afatinib? No head to head comparisons have yet been published, although there is an ongoing trial comparing afatinib and gefitinib in EGFR mutation+ patients which has completed accrual (LUX-Lung 7). Until that trial is presented though, we can consider some differences between the various drugs. For example, afatinib tends to have more rash, diarrhea, paronychia, and stomatitis than the first-generation TKIs gefitinib and erlotinib, which could be a consideration for some patients. 

On the other hand, a recently published subset analysis of the afatinib phase 3 trials (LUX-Lung 3 and 6; Lancet Oncol. 2015 Feb;16(2):141-51.) indicated that there was a significant OS improvement with afatinib compared to chemotherapy in patients with the most common EGFR mutation, exon 19 deletion mutations. The improvement in median OS with afatinib was more than one year in both trials in this group, and this is in contrast to the other common mutation (L858R) for which there was an ORR and PFS benefit but no OS benefit. This survival benefit in exon 19 del patients was seen despite high crossover to first-generation TKIs in the chemotherapy arms, suggesting that afatinib may be more effective treatment in exon 19 del patients first line. For this reason, it is very reasonable to consider afatinib as a first line option for exon 19 del+ patients. For L858R+ patients, any of the TKIs is appropriate.

What about combination therapy with an EGFR TKI? There is one phase 2 trial combining erlotinib plus bevacizumab in EGFR mutation+ NSCLC (Lancet Oncol. 2014 Oct;15(11):1236-44), which showed a 6.3 month improvement in median PFS in the combination arm compared to erlotinib alone. However, this was a single phase 2 trial and no differences in OS were noted. While this regimen shows promise, a confirmatory phase 3 trial would be needed to prove that the enormous added burden in both toxicity and cost would be worth the benefit.

11846

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 07, 2015 3:42 PM

Patient Case Update (Resistance Scenario)

The patient has a favorable response to afatinib 40mg daily and resolution of his back pain, although he does require one dose reduction to 30mg due to side effects including diarrhea, oral mucositis, and paronychia. After approximately 18 months restaging studies reveal multiple new 1-2cm liver lesions and stable primary lung mass. The patient remains asymptomatic and with a performance status of 0.

How tissue was acquired/preserved: no biopsy yet 

Testing Platform/Molecular Profiling:  No biopsy yet

11851

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 07, 2015 3:43 PM

Discussion Questions
1.    What is the most reasonable next step? 
2.    If a biopsy is obtained, what site would you biopsy?
3.    Is there a role for serum testing rather than a tissue biopsy in this situation?

11866

Philip Cagle
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 10, 2015 12:54 PM

3.)Is there a role for serum testing rather than a tissue biopsy in this situation?

Although there is excitement about the possibility of biomarker testing using cell free DNA from a lung cancer patient’s plasma or serum, this approach is still investigational and a tissue biopsy is still needed.

11871

Nathan A. Pennell, MD, PhD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 10, 2015 12:59 PM

1) What is the most reasonable next step?

Although first and second generation EGFR TKIs can be quite effective in managing advanced EGFR mutation+ NSCLC, most patients who initially respond will eventually develop progressive disease which is known as developing acquired resistance (AR) to the therapy. In any patient with AR to EGFR TKIs a repeat biopsy is the recommended first step if the progressing lesions are amenable to being biopsied safely. Although the traditional management of progressive disease would be to empirically switch therapy to chemotherapy in this situation, there are 2 situations in which the biopsy results could change the treatment plan.

First, repeat biopsy studies in this clinical situation show that 8-14% of patients who develop AR to EGFR TKIs will have had a phenotypic transformation to small cell carcinoma (Sci Transl Med. 2011 Mar 23;3(75):75ra26.), which does not respond to EGFR TKIs and would require a different chemotherapy regimen than would be used for lung adenocarcinoma. In this situation, small cell-specific regimens such as cisplatin or carboplatin and etoposide would be most appropriate.

The second important result would be to check for a secondary mutation in the EGFR gene, most commonly the T790M mutation in exon 20, which is present in 50-60% of patients with acquired resistance to EGFR TKIs. There are other known but less common mechanisms of AR as well, such as amplification of the MET oncogene, which might influence eligibility for clinical trials but would not be actionable outside of a study.

2.) If a biopsy is obtained, what site would you biopsy?

It is very important to make sure to biopsy one of the progressing lesions when looking for a mechanism of acquired resistance to EGFR TKIs. Biopsy studies in this situation have clearly shown that metastases can be quite heterogeneous and that progressing lesions may have identifiable resistance mechanisms such as T790M, while other sites of disease which are not progressing may lack the secondary mutations, leading to a false negative result (Science. 2007 May 18;316(5827):1039-43.).

Biopsies of bone lesions should also be avoided if possible, since decalcification of the bone during pathologic processing often destroys the DNA and makes testing more difficult.

3.)Is there a role for serum testing rather than a tissue biopsy in this situation?

Although tissue biopsy remains the gold standard for investigating mechanisms of acquired resistance (AR) to EGFR TKIs, a “liquid biopsy” has many potential advantages. It is much less invasive and is possible in almost every patient, whereas tissue biopsies carry some risk and are not always possible depending on the location of the lesion and the patient’s comorbidities. Liquid biopsies also have the potential to be repeated multiple times over the course of treatment, which is rarely possible for tissue biopsy. This could allow for detection of AR earlier than by standard radiographic means, although the clinical significance of earlier detection is not yet clear. Liquid biopsy may also hypothetically reduce issues with heterogeneity of AR mechanisms, since DNA from all sites in the patient may be detectable in the blood.

Liquid biopsies using either circulating tumor cells (CTCs) or circulating free DNA (cfDNA; PLoS ONE 10(10): e0140712.; Clin Cancer Res. 2015 Oct 7. pii: clincanres.1031.2015. [Epub ahead of print] ) have been shown to be highly specific and reliable for detection of known EGFR mutations including T790M in matched tissue and blood studies. However, these technologies suffer from a relative lack of sensitivity in detecting mutations, and so false negative results may be an issue. Until blood testing had been rigorously validated, tissue biopsy remains the recommended test of choice, although in situations where biopsy fails or is not possible a liquid biopsy could be considered.

11876

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 10, 2015 1:03 PM

Patient Case Update (Part II)

A liver biopsy is obtained which shows the original exon 19 deletion EGFR mutation as well as a new mutation in exon 20 (T790M).

How tissue was acquired/preserved:  Fine needle aspirate biopsy was performed by radiology and a histologic diagnosis of metastatic adenocarcinoma.  A metastasis from the lung was confirmation by positive TTF-1 immunostain.

Testing Platform/Molecular Profiling: EGFR mutation testing disclosed a T790M mutation.

11881

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 10, 2015 1:05 PM

Discussion Questions
1. Given the presence of the T790M mutation, what would be the most appropriate treatment?
2. What other treatment options are available aside from the third-generation EGFR TKIs?
 

11891

Philip Cagle
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 14, 2015 11:16 AM

Course Faculty Response

Dr. Pennell will highlight some treatment options. 

11896

Nathan A. Pennell, MD, PhD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 14, 2015 11:29 AM

Course Faculty Response

1.)Given the presence of the T790M mutation, what would be the most appropriate treatment?

None of the currently approved EGFR tyrosine kinase inhibitors (gefitinib, erlotinib, or afatinib) have significant clinical activity in patients with T790M+ acquired resistance (AR). There are multiple EGFR mutation-specific inhibitors under development for T790M+ AR, including one that was recently approved by the FDA for this indication.

The 2 drugs furthest in development are rociletinib (CO-1686) and osimertinib (AZD 9291), both of which inhibit mutant EGFR at much higher affinity than wild-type EGFR and thus both have much less of the typical cutaneous and GI toxicity associated with the first generation TKIs. Both drugs have completed clinical trials in T790M+ patients and have demonstrated significant efficacy in this population.

Rociletinib has been tested primarily in T790M+ NSCLC patients, and has been shown to have a response rate of approximately 60% with a progression-free survival of about 7 months (N Engl J Med. 2015 Apr 30;372(18):1700-9; updated at ASCO 2015 J Clin Oncol 33, 2015 (suppl; abstr 8001). Patients on rociletinib have almost no rash, but have some unique side effects including hyperglycemia which occurs in about 35% of patients at the recommended starting dose.

Osimertinib also has been tested in both T790M+ and T790M-negative AR to first generation TKIs, and in T790M+ patients had a response rate of 61% and PFS of 9.6 months (N Engl J Med. 2015 Apr 30;372(18):1689-99). Very little rash or diarrhea was seen and mostly grade 1 or 2. Based on this trial, on November 13, 2015 the FDA approved osimertinib in NSCLC patients with confirmed T790M mutations as assayed by a companion diagnostic test.

Now that one of these drugs is approved in this setting, the recommendation in T790M+ patients would be to either use osimertinib or to enroll  patients on a clinical trial or expanded access program for one of these or the multiple other third-generation EGFR inhibitors in development.

2.)What other treatment options are aside from the third-generation EGFR TKIs?

For patients who are chemotherapy naïve, stopping the first generation TKI and switching to platinum doublet chemotherapy can be effective. Although there was until recently controversy about continuing versus stopping the EGFR TKI during chemotherapy, the phase 3 IMPRESS trial settled that question by showing no improvement in survival with the continuation of the TKI when switching to chemotherapy (Lancet Oncol. 2015 Aug;16(8):990-8) . I would however recommend continuing the TKI until the patient is ready to start chemotherapy to prevent the rapid “flare” of disease which occurs in a subset of patients when they discontinue the TKI.

In addition, non-EGFR-directed clinical trials are always a possibility.

11901

Philip Cagle
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 16, 2015 3:17 PM

The Take-Home messages can be summarized as follows:

1. Per the 2013 CAP/IASLC/AMP lung cancer predictive biomarker testing guidelines, EGFR mutation testing and ALK rearrangement testing are recommended for samples of advanced NSCLC in which a diagnosis of adenocarcinoma is confirmed or cannot be excluded. Clinical trials are underway to determine if testing and treatment in earlier stage NSCLC are beneficial.

2. EGFR mutation analysis is recommended for EGFR testing and immunohistochemistry (IHC) and FISH are not recommended. There are many possible individual assays for EGFR mutation but techniques such as NGS are becoming more common. All of these tests should provide information about activating mutations as well as resistance mutations such as T790M.

3. There are two FDA approved companion diagnostics for ALk rearrangements in NSCLC, the Abbott Vysis ALK Break Apart FISH Probe Kit and the ALK (D5F3) CDx Assay. Other techniques may be used to screen for ALK rearrangements or identify specific translocations.

4.Several additional predictive biomarkers are being evaluated for the revised 2016 CAP/IASLC/AMP guideline.

11906

Nathan A. Pennell, MD, PhD
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 16, 2015 3:31 PM

Thanks to all for a great discussion. Based on the case and the topical direction of the question and comments, below are my individual case summary points of interest:

1) EGFR mutations are common (10-15% of NSCLC cases) and actionable but you won’t find them if you don’t look for them. Every patient with advanced nonsquamous NSCLC, regardless of clinical characteristics (e.g. smoking history, age) should have routine molecular testing for EGFR and ALK. While ordering this case by case may be OK for some oncologists, institutions should consider ways to make this happen automatically so that results can be available in a clinically meaningful timeframe (less than 10 working days is recommended; J Thorac Oncol. 2013 Oct;8(10):1343.) and to ensure no patients slip through the cracks.

2) EGFR tyrosine kinase inhibitors (erlotinib, gefitinib, and afatinib) are appropriate first-line options for all patients with activating EGFR mutations, with the choice of agent made primarily on side effect profile. One exception would be the possible advantage of afatinib in patients with exon 19 deletion mutations based on a large survival benefit compared to chemotherapy, although afatinib’s side effect profile may not be appropriate for every patient. The question of whether one TKI is better than another may be answered soon by the LUX-Lung 7 trial comparing gefitinib to afatinib in this population.

3)EGFR TKI monotherapy should be the standard of care outside a clinical trial. There is no convincing data that combining drugs with TKIs is more effective at prolonging survival than TKI monotherapy, but combinations clearly have increased toxicity and add significant expense.

4) Always consider a tissue biopsy in patients with EGFR mutation+ NSCLC at the time of progression on a first-generation TKI. This can be used both to eliminate the possibility of small cell transformation and to guide patients to a third-generation TKI in the event of a proven T790M mutation.

5) Don’t forget that traditional platinum doublet chemotherapy is as effective or even potentially more effective in EGFR mutation+ NSCLC patients than in wild-type patients, and can be a very good option when mutation status is not known or in the event of acquired resistance to TKIs.

11911

ASCO University
Re: Lung (December 2015): Molecular Oncology Tumor Boards
Dec 16, 2015 3:35 PM

Thank you to Drs. Cagle and Pennell leading the discussion of this case and also to all of those who contributed to the conversation! The forum is now closed to further comments but users have the opportunity to claim CME credit on ASCO University by clicking here.

Please check back in mid-January for a new case in this series.


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