Lung Cancer (August 2017): Molecular Oncology Tumor Boards

ASCO University
Aug 09, 2017 6:56 AM

Participant 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. Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.

This Molecular Oncology Tumor Board is led by Drs. Christine Lovly, MD, PhD (Medical Oncologist, Vanderbilt-Ingram Cancer Center) and Laura Tafe, MD (Pathologist, Dartmouth-Hitchcock Medical Center).

Participants 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.

When posting, please abide by the terms and conditions of this website.

Comments

14881

ASCO University
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 09, 2017 6:57 AM

Patient Case

Age/Sex:  47-year-old female

Medical History: Mrs. H is a 47-year-old female light former smoker (5 pack year history, quit 7 years ago) with no significant past medical history. She presented with non-productive cough, which was unabated by two rounds of antibiotics for presumed community acquired pneumonia. She also has pleuritic left sided chest pain, 5/10.

CT scan of the chest and abdomen revealed a LLL lesion, pathologically enlarged lymphadenopathy (left mediastinal, left hilar, and right supraclavicular), and numerous liver lesions. Brain MRI did not reveal any intracranial disease.

Type of Tumor: CT guided biopsy of a  LLL lesion revealed NSCLC, "adenosquamous" histology.

Relevant Markers:  Immunostains were positive for CK7, TTF1, MOC-31, and cytokeratin 34betaE12

Prior Treatment History/Response:  None

Co-morbidities: None

Initial molecular studies: Sequencing of EGFR exons 18-21 did not reveal any EGFR mutations. ALK fluorescence in situ hybridization (FISH) was positive. 67% of 200 nuclei were positive for the ALK rearrangement.

14886

ASCO University
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 09, 2017 6:58 AM

Discussion Questions

1. What are acceptable approaches for ALK testing?
2. What systemic therapy would you offer?

Vinicius Lorandi, MD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 12, 2017 7:54 PM

I think nowadays FISH for ALK testing is becoming more and more questionable. There are several papers addressing this issue, especially considering we have had some papers showing better sensitivity and especificity with IHQ when compared to FISH. NGS may be an alternative to those cases when IHQ was used as a screening test.

I believe that TKIs should always be considered as first line choice of treatment and patients should always be encouraged to enroll in a clinical trial. It is still quite often that not all patients are actually tested for the most common driver mutations, especially in Southern American countries. Therefore, IHQ - being cheaper and faster - has gained more and more space as a strategy to overcome this issue.

14891

Nathan A. Pennell, MD, PhD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 09, 2017 9:45 AM

I believe that ALK immunohistochemistry is also an adequate test to detect ALK, with advantages of speed and cost over FISH (which is the FDA-approved test). I am not sure, however, if a positive IHC result needs to be verified by FISH or if treatment can proceed on IHC alone, I have heard different answers to this and am very interested in Dr. Tafe's input.

I have my opinion about first line treatment for ALK+ NSCLC but will keep the suspense up and see what others have to say first!

14896

Anis Toumeh, MD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 09, 2017 11:15 AM

I agree that IHC is a valid testing option for ALK. Some data showed that even in cases where IHC was positive and FISH was negative, NGS was positive for ALK (Pekar-Zlotin et al. The Oncologist doi: 10.1634/theoncologist.2014-0389) 

I am also interested in the faculty's thoughts on this matter. 

At this point, my choice will be between Crizotinib and Ceritinib as both are approved by FDA. I am, however, very impressed with the ALEX data and would probably choose Alectinib as a firstline treatment, when approved, given the tolerabiligy and the great CNS activity

 

 

 

14906

Laura Tafe
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 9:18 AM

Course Faculty Response

What are acceptable approaches for ALK testing?

Molecular testing guidelines put forth by CAP-IASLC-AMP for the selection of lung cancer patients for EGFR and ALK tyrosine kinase inhibitors were released in July 2013 (Lindeman, 2013). The CAP-IASLC-AMP Updated Molecular Testing Guideline for the Selection of Lung Cancer Patients for Treatment with Targeted Tyrosine Kinase Inhibitors has been released in Draft form and publication is expected later this year.  The updated guidelines reaffirm and update most of the 2013 guidelines and also incorporate some important new recommendations including testing for ROS1 gene rearrangement in all lung adenocarcinoma patients.

ALK can undergo rearrangement with multiple different partner genes including EML4, KIF5B and TFG among others resulting in multiple different transcripts and fusion proteins. Reverse transcriptase (RT) PCR assays require knowledge of the transcript sequence(s) you are trying to detect in order to design the primers.  RT-PCR is not an ideal screening assay due to the large number of partner genes and possible rearrangements. Testing strategies for ALK rearrangement may include FISH, IHC, and even next generation sequencing (NGS).

The VYSIS ALK Break Apart FISH Probe Kit is FDA approved for detection of ALK rearrangements in lung cancer tissue.  Because of the FISH probe design, ALK break-apart FISH assay can detect a rearrangement in ALK without needing to know the partner gene.  A single FISH assay utilizes very little tissue and can be performed in most laboratories; however, it can be challenging to interpret and should be reviewed by experienced personnel. The ALK FISH break–apart assay is interpreted as positive if at least 15% of tumor cells show signals separated by at least 2 probe diameters or a single 3' (orange) signal (deleted 5').

(View FISH Images)
   
Immunohistochemistry (IHC) using specific ALK antibodies, is an equivalent alternative to FISH for ALK testing.  This recommendation is supported by at least 20 studies. Two commercially available clones, 5A4  (Novocastra, Leica Biosystems, Buffalo Grove, IL) and D5F3 (Ventana, Tuscon, AZ) based assays showed clinically acceptable sensitivities and specificities when compared to ALK FISH results and expression also correlates with response to crizotinib in some patients that are negative for ALK rearrangement by FISH (Marchetti, 2016). In the U.S., the D5F3 (Ventana, Tuscon, AZ)

(View IHC Images)

Many institutions routinely perform additional molecular testing beyond EGFR and ALK analysis and a multiplexed assay, such as a next-generation sequencing (NGS) panel, is a very efficient approach to testing for multiple targets simultaneously; all of these assays are Laboratory Developed Procedures and the performance characteristics are determined by the individual laboratories at the time of validation.  Just recently the FDA approved the Oncomine™ Dx Target Test (Life Technologies), the only FDA approved NGS based assay available for solid tumor testing.  This assay detects single nucleotide variants (SNVs) and deletions in 23 genes from DNA and fusions in ROS1 from RNA.  This assay does NOT detect ALK fusions.

14911

Christine Marie Lovly, MD, PhD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 9:24 AM

Course Faculty Response

What systemic therapy would you offer?

In 2007, chromosomal rearrangements involving the gene encoding the ALK tyrosine kinase were first detected in patients with lung cancer (Soda, 2007). ALK rearrangements are found in up to 7% of NSCLCs (Kris, 2014). The presence of an ALK rearrangement confers sensitivity to ALK inhibition (Kwak, 2010). Similar to EGFR, tumor genotyping for ALK is now standard clinical care, and crizotinib is FDA-approved for the treatment of ALK+ NSCLC.

The first generation ALK TKI, crizotinib, has demonstrated significant activity in patients with advanced ALK+ NSCLC with a RR of 74% and a PFS of 10.9 months (hazard ratio 0.45) as compared to platinum-based chemotherapy (Solomon and Mok, 2015).

The first-generation ALK tyrosine kinase inhibitor (TKI), Crizotinib, is an ALK/ROS1/MET inhibitor that was initially approved by the United States FDA in 2011 for the treatment of advanced, ALK+ NSCLC. In two randomized phase III trials (PROFILE 1014 and PROFILE 1007), crizotinib produced significant improvements in ORR, PFS and quality of life compared to first- and second-line cytotoxic chemotherapy, respectively (Shaw, 2013) (Solomon, 2014). Of particular relevance to this case, in the PROFILE 1014 trial of first line crizotinib, the RR was 74% and PFS was 10.9 months (hazard ratio 0.45) as compared to platinum-based chemotherapy (Solomon and Mok, 2015). Based upon these studies, crizotinib emerged as a standard first-line therapy for advanced, ALK-positive NSCLC.

While crizotinib has transformed the management of ALK+ NSCLC, in 2017, there are additional options for first line ALK directed therapy.

Ceritinib is a second generation ALK TKI with increased on-target activity against ALK (Mehra, 2012). Ceritinib was initially FDA approved for patients that developed progressive disease after first line crizotinib, based on the ASCEND-1 study (Kim, 2016) (Shaw and Engelman, 2014). More recently, the results of the ASCEND-4 trial were reported (Soria, 2017). This study randomized 376 patients with advanced treatment naïve ALK+ lung cancer to either ceritinib (189 patients) or to platinum-pemetrexed doublet therapy (187 patients). The median PFS was 16.6 months with ceritinib compared with 8.1 months in the chemotherapy arm (HR 0.55, 95% CI, 0.42–0.73; P < .0001). The RR was 73% with ceritinib versus 27% with chemotherapy. The median response duration was 23.9 months with ceritinib and 11.1 months with chemotherapy. Of note, the intracranial response rate was 57% with ceritinib versus 22% with chemotherapy. The most common AEs for ceritinib were diarrhea, nausea, vomiting, fatigue, and abdominal pain.

In May 2017, the FDA expanded the approval for ceritinib to include an indication for first-line treatment in patients with metastatic ALK+ NSCLC.

Alectinib is another second generation ALK TKI with increased on-target activity against ALK (Sakamoto, 2011). Similar to ceritinib, alectinib was initially FDA approved for patients that developed progressive disease after first line crizotinib, based on two single-arm studies (NP28673 and NP28761) (Ou, 2016) (Shaw, 2016). This year, at the ASCO Annual Meeting, the results of the Global-ALEX study - which compared first line alectinib head-to-head with crizotinib - were presented. This study randomized 303 patients with advanced ALK+ NSCLC to receive alectinib or crizotinib. The median PFS was 25.7 months with alectinib and 10.4 months with crizotinib. At 12 months, the incidence of brain metastases was lower with alectinib (9%) compared to crizotinib (41%). The most common  AEs for alectinib were fatigue, constipation, muscle aches, and swelling.

14916

ASCO University
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 9:25 AM

Patient Case Update

Mrs. H is treated with crizotinib. Within 1 month, she has symptomatic improvement with decreased cough and significantly decreased pain. After 2 cycles of crizotinib, CT scan showed a decrease in size of the tumors in the chest and in the liver. The dominant left sided lesion decreased in size from 5.8 x 3.1 cm. to 4.6 x 1.7 cm.  

Mrs. H continues on crizotinib for 14 months, at which time, interval CT scans show progressive disease in the liver.

14921

ASCO University
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 9:25 AM

Discussion Questions

1. What are mechanisms of acquired resistance to crizotinib?
2. What treatment would you offer for second-line therapy after crizotinib?

14926

Shrinkhala Khanna, MD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 1:14 PM

Ceritinib and alectinib can both be used. My preferred drug would be alectinib. Beaded on the ALEX data- alectinib should now be first line; is that right?

14931

Christine Marie Lovly, MD, PhD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 2:05 PM

Course Faculty Response

Thank you for the question! The results from the Global ALEX study were recently published (Peters, 2017). At present, alectinib has FDA breakthrough designation for the treatment of patients with advanced ALK–positive NSCLC who have not received prior treatment with an ALK inhibitor.

14936

Anis Toumeh, MD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 14, 2017 2:25 PM

1- Mechanisms of acquired resistance to crizotinib typically involve changes in the ALK gene or activation of signaling pathways that bypass ALK

2- Alectinib, Ceritinib and Brigatinib are approved as secondline options. Alectinib and Brigatinib are probably more tolerable than Ceritnib. Side effects profile are probably going to be a key in choosing between these agents. Unless contraindicated, I would proabably go with Brigatinib at this point as I have been impressed with the efficacy data, and it seems to be well tolerated with 20% dose reductions due to AE and ~8% discontinuation rate due to same. It can also be taken with or without food which may be more convinient to some patients. 

 

14941

Laura Tafe
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 18, 2017 9:29 AM

Course Faculty Response

What are mechanisms of acquired resistance to crizotinib?

Mechanisms of resistance to crizotinib therapy are similar to those to EGFR TKI therapies including kinase domain point mutations, gene amplification and bypass signaling pathway activation.  

Multiple secondary acquired ALK resistance mutations have been identified in about 20% of patients with resistance to crizotinib (e.g., L1196M (“gatekeeper mutation” analogous to EGFR T790M), L1152R, C1156Y, I1151Tins, F1174L, L1198P, D1203N, and G1269A) (Gainor, 2016) (Huang, 2013).

However, some patients that become refractory to crizotinib therapy show response to second or third generation ALK inhibitors without the presence of an ALK resistance mutation, suggesting that crizotinib refractoriness may in fact be due inadequate suppression of ALK in many patients. In current clinical practice, second or third generation inhibitors are administered without testing for secondary ALK mutations.   

Up to 50% of patients with resistance to second-generation ALK inhibitors have acquired ALK mutations (G1202R, G1202 del, V1180L, S1206Y, E1201K, and other) (Gainor, 2016).  Notably, the G1202R mutation appears to be the most recalcitrant.

Target-independent mechanisms of ALK TKI resistance include 1) IGF-1R signaling (Lovly, 2014), 2) EGFR signaling (Katayama, 2012), 3) SRC signaling (Crystal, 2014), 4) KIT amplification (Katayama, 2012); and 5) EMT (Gainor, 2016). However, the frequency of these events remains undefined.

Tumors may employ multiple mechanisms of resistance simultaneously or in a step-wise fashion. The challenge becomes how to overcome second and third line resistance.

14946

Christine Marie Lovly, MD, PhD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 18, 2017 9:32 AM

Course Faculty Response

What treatment would you offer for second-line therapy after crizotinib?

Multiple ‘second’ and even ‘third’ generation ALK inhibitors have been developed to attempt to overcome crizotinib resistance (Table 3). These ‘next generation’ ALK inhibitors have greater on-target selectivity and potency towards ALK and also have increased CNS penetration compared with crizotinib. This field has moved incredibly quickly, and there is a great deal of information on this topic. Below, I will focus on and summarize those agents which have already received regulatory approval.

Ceritinib is FDA-approved for the management of crizotinib-resistant or intolerant, ALK-positive NSCLC. The activity of ceritinib in patients with crizotinib-resistance has been evaluated in two studies.

ASCEND-1 is a single-arm phase I trial in which 163 ALK inhibitor-pretreated patients were treated with ceritinib (Kim, 2016). The ORR was 56% and median PFS of 6.9 months. The median duration of response (DOR) 8.3 months.  Intracranial disease control rate 65% amongst 75 ALK inhibitor-pretreated patients who had brain metastases. The most common grade 3–4 AEs were diarrhea (6%), nausea (6%), elevated ALT (30%), and elevated AST (30%).

ASCEND-2 is a phase II trial in which 140 ALK inhibitor-pretreated patients received 750 mg po qday of ceritinib (Crino, 2016). All patients had received previous crizotinib. The ORR was 38.6% and median PFS was 5.7 months. The median DOR was 9.7 months. Intracranial ORR was 45.0%. The most common AES were predominantly grades 1 and 2 and included: nausea (81.4%), diarrhea (80.0%), and vomiting (62.9%).
 
Alectinib is also FDA-approved for the management of crizotinib-resistant or intolerant, ALK-positive NSCLC. The activity of alectinib in patients with crizotinib-resistance has been evaluated in two single-arm phase 2 studies (NP28673 and NP28761).  

For the NP28761 study, 87 patients who had all received prior crizotinib received alectinib 600 mg bid. 60% of patients had baseline brain metastases. The ORR was 48% and PFS was 5.7 months (Shaw, 2016). The median DOR was 13.5 months. Intracranial ORR was 75% amongst 16 patients with measurable CNS disease at baseline. The median duration of CNS response was 11.1 months. The most common AEs (mostly grade 1 or 2) were constipation (36%), fatigue (33%), myalgia (24%), and peripheral edema (23%). The most common grade 3–4 AEs were elevated CPK (8%), elevated ALT (6%), and elevated AST (9%).

For the NP28673 study, 138 patients who had received prior crizotinib received alectinib 600 mg bid. The ORR was 50% and median PFS was 8.9 months (Ou, 2016). The median DOR was 11.2 months. Intracranial ORR was 57% amongst 35 patients with measurable CNS disease at baseline. The median duration of CNS response was 10.3 months. The most common AEs (mostly grade 1 or 2) were constipation (33%), fatigue (26%), and peripheral edema (25%). The most common grade 3–4 AEs were dyspnea (3%), elevated ALT (2%), and elevated AST (%).  

Brigatinib is another second-generation ALK TKI which is the most recently FDA-approved agent in the crizotinib resistance setting. The approval was based on the phase 2 ALTA trial, which enrolled 222 patients (Kim, 2017). Patients were randomized to receive brigatinib 90 mg qday (n=112) or 180 mg qday following a 7-day lead-in at 90 mg qday (n=110). ORR was 48% in the 90 mg arm and 53% in the 180 mg arm. PFS was 9.2 months in the 90 mg arm and 12.9 months in the 180 mg arm. After a median duration of follow-up of 8 months, median duration of response (DOR) was 13.8 months in both arms. Intracranial ORR in patients with measurable brain metastases at baseline was 42% in the 90 mg arm and 67% in the 180 mg arm. The most common AEs were predominantly grades 1 and 2 and included: nausea (arm A/B, 33%/40%), diarrhea (arm A/B, 19%/38%), headache (arm A/B, 28%/27%), and cough (arm A/B, 18%/34%). Early onset (median: 2 days) pulmonary AEs with occurred in 14 patients (all grades, 6%; grade = 3, 3%); none occurred after escalation to 180 mg in arm B. Seven of these patients were successfully retreated with brigatinib.

14951

Laura Tafe
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 23, 2017 11:20 AM

Course Faculty Summary

1. Approaches to testing for ALK rearrangements include FDA approved IHC ALK antibody assay and break-apart FISH.
 
2. Next-generation sequencing (NGS) is rapidly becoming incorporated into routine laboratory testing.  Not all NGS assays are equivalent.  Depending on the technology and methodology there are differences with respect to number of genes tested (“hotspot” panels, exome panels, etc.) and the ability to detect various types of genetic variants (single nucleotide variants (SNVs) insertions and deletions, structural variants, and copy number variants (CNVs)).  Therefore, it is essential to know what your laboratory’s assay can and cannot detect.

3. Mechanisms of ALK TKI resistance are multiple including ALK kinase domain mutations, ALK amplification, EMT and SCLC transformation.    

4. Reimbursement for molecular diagnostic tests is highly variable and remains a challenge for laboratories.

14956

Christine Marie Lovly, MD, PhD
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 23, 2017 11:22 AM

Course Faculty Summary

Now just 10 years since the initial pre-clinical report documenting the presence of ALK rearrangements in patients with NSCLC (Soda, 2007), the field has grown rapidly and remarkably to the point in which we now have robust evidence that the prospective identification and therapeutic targeting of ALK should be the standard of care. Four distinct ALK TKIs have already been FDA approved for patients with ALK+ NSCLC, and patients are now being routinely treated with multiple lines of ALK TKI therapy. Additional ALK TKIs are also being developed. With all of these distinct inhibitors, there are good options for our patients. However, several questions remains, including:

1. What is the optimal sequence of these inhibitors?
2. Will ALK TKIs be beneficial in the adjuvant setting?
3. What are mechanisms of acquired resistance to ALK blockade that do not involve modification of the ALK fusion protein? How will this resistance be overcome?

These questions are all being addressed in on-going or planned studies. Stay tuned to future Molecular Tumor Boards on this topic to receive updates. Thank you very much for your interest and attention!

14961

ASCO University
Re: Lung Cancer (August 2017): Molecular Oncology Tumor Boards
Aug 23, 2017 11:24 AM

Thank you to Drs. Lovly and Tafe for 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 and participants can claim CME credit and 1 ABIM MOC point through ASCO University.

Please check back in mid-September for a new case in this series related to prostate cancer.    

Have an interesting case in mind? Submit your hypothetical patient cases for consideration in an upcoming Molecular Oncology Tumor Board discussion forum.