1. Case Studies in Advanced/Metastatic NSCLC
Dr Tan Jiunn Liang
Clinical Specialist (Respiratory Medicine)
Department of Medicine
Universiti Malaya Medical Centre

2. Outline Case study – patient with driver mutation
Case study – patient without driver mutation
Discussion

3. Case 1 :
Patient with driver mutation

4. Mr S
51 years old
Ex-smoker (10 packed-years)

5. Timeline
2010
March

6. Timeline
2010
Private hospital
March

7. Timeline 2010 Private hospital 2.5cm left lower lobe T1bN0Mx
March
2.5cm left lower lobe
T1bN0Mx
SUV Max 3.5

8. Timeline 2010 Private hospital
March
SUV Max 3.5
No systemic intra-operative lymph node staging!
(as some of the lymph nodes were normal looking)
Pathological staging:
T1bN1M0
April

9. Timeline 2010 Private hospital
March
SUV Max 3.5
April
Moderately differentiated adenocarcinoma

10. Timeline 2010 Private hospital
March
SUV Max 3.5
April
Moderately differentiated adenocarcinoma
No mutation detected
(using Sanger sequencing)

11. Completed 4 cycle of adjuvant chemotherapy
Timeline
May 2010
2010
Private hospital
UMSC
March
SUV Max 3.5
Normal MRI brain
Completed 4 cycle of adjuvant chemotherapy
April

12. Timeline 2010 May 2010 2011 2013 Private hospital UMSC
March
SUV Max 3.5
Completed 4 cycle of adjuvant chemotherapy
6-monthly surveillance PET/CT scan
April

13. Timeline 2010 May 2010 2011 2013 Private hospital UMSC
Recurrence at spine
March
SUV Max 3.5
Completed 4 cycle of adjuvant chemotherapy
6-monthly surveillance PET/CT scan
April

14. Timeline 2010 May 2010 2011 2013 2014 Private hospital UMSC
March
SUV Max 3.5
Recurrence at spine
Surgery in Oct
Then followed by Radiotherapy to the spine
Also given monthly Zometa
Subsequently treated with chemotherapy
(Carbo/Pemetrexed x 6 then maintenance x 8)
Completed 4 cycle of adjuvant chemotherapy
6-monthly surveillance PET/CT scan
April

15. Timeline 2010 May 2010 2011 2013 2014 Private hospital UMSC
March
SUV Max 3.5
Recurrence at spine
Surgery + chemotherapy + radiotherapy + zometa
Completed 4 cycle of adjuvant chemotherapy
New Recurrence
at spine
6-monthly surveillance PET/CT scan
April

16. Timeline 2010 May 2010 2011 2013 2014 Private hospital UMSC
March
SUV Max 3.5
Recurrence at spine
Change to second line chemotherapy
Repeated another radiotherapy
Started on monthly denosumab
Surgery + chemotherapy + radiotherapy + zometa
Repeat the EGFR mutation testing
Completed 4 cycle of adjuvant chemotherapy
New Recurrence
at spine
6-monthly surveillance PET/CT scan
April

17. Timeline 2010 May 2010 2011 2013 2014 Private hospital UMSC
SUV Max 3.5
Recurrence at spine
March
Change to second line chemotherapy
Repeated another radiotherapy
Started on monthly denosumab
Surgery + chemotherapy + radiotherapy + zometa
Completed 4 cycle of adjuvant chemotherapy
New Recurrence
at spine
EGFR mutation detected at exon 21 (L858R)
6-monthly surveillance PET/CT scan
April

18. Selection for Molecular Testing in NSCLC
All pts with an adenocarcinoma component should be tested[1,2]
Pure SCC diagnosis is appropriate for EGFR mutation and ALK testing in some clinical settings[1]
Young, never, or light smoker
Small biopsy specimens
Pack-Yrs[2]
EGFR
Mutation, %
95% CI
Never 52
48-56
1-5 34
25-43
6-10
26-44
11-15 18
11-26
16-25 11
7-16
26-50 8
6-11
51-75 9
5-13
> 75 4
2-8
mut, mutation; NSCLC, non-small-cell lung cancer; SCC, squamous cell carcinoma.
1. Lindeman NI, et al. J Thorac Oncol. 2013;8:
2. D’Angelo SP, et al. J Clin Oncol. 2011;29:
3. NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v

19. Timeline
Oct
2014
UMSC
Started on Gefitinib
Stable disease

20. Meta-analysis of Randomized First-line EGFR TKI Studies: Improved PFS
mut, mutated; TKI, tyrosine kinase inhibitor.
Lee CK, et al. J Natl Cancer Inst. 2013;105:

21. First-line Treatment With EGFR TKIs vs Chemotherapy in EGFR-Mutated NSCLC
TKI, tyrosine kinase inhibitor.
1. Maemondo M, et al. N Engl J Med. 2010;362: Mitsudomi T, et al. Lancet Oncol. 2010;11: Mitsudomi T, et al. ASCO Abstract Zhou C, et al. Lancet Oncol. 2011;12: Zhou C, et al. Ann Oncol. 2015;26: Rosell R, et al. Lancet Oncol. 2012;13: Sequist LV, et al. J Clin Oncol. 2013;31: Yang JC, et al. Lancet Oncol. 2015;16: Wu YL, et al. Lancet Oncol. 2014;15: 24

22. LUX-Lung 3+6: OS by del(19) and L858R Mutation Status for Afatinib vs Chemo
Yang JC, et al. Lancet Oncol. 2015;16:

23. Patient was asymptomatic of progression
Timeline
Oct
2014
May 2015
UMSC
Started on Gefitinib
Another
New Recurrence
at spine
Patient was asymptomatic of progression
Stable disease

24. Timeline Oct 2014 May 2015 May 2016 UMSC Started on Gefitinib Another
New Recurrence
at spine
Patient was asymptomatic of progression
ALK & ROS1 mutation testing were sent
Stable disease
Changed to Afatinib as requested by the patient

25. LUX-Lung 7: PFS With First-line Afatinib vs Gefitinib in EGFR-Mutated NSCLC
PFS significantly longer with afatinib vs gefitinib
Afatinib benefit observed for most subgroups
NSCLC, non-small-cell lung cancer.
Park K, et al. Lancet Oncol. 2016;17:

26. Timeline Oct 2014 May 2015 May 2016 UMSC Started on Gefitinib Another
New Recurrence
at spine
Worsening bone
metastases
Patient was asymptomatic of progression
ALK & ROS1 mutation testing were negative
Stable disease
Changed to Afatinib as requested by the patient

27. Timeline Oct 2014 May 2015 May 2016 July 2016 UMSC
Started on Gefitinib
Another
New Recurrence
at spine
T790M detected from ct-DNA
Worsening bone
metastases
Patient was asymptomatic of progression
Started on Osimertinib
ALK & ROS1 mutation testing were negative
Stable disease
Changed to Afatinib as requested by the patient

28. Disease Progression on EGFR TKI in NSCLC With EGFR Sensitizing Mutations
PD: Clinical characteristics
Rapid global progression
Slow growth globally
Growth in several areas, but not all
PD: Molecular characteristics
Unknown (other pathways)
EGFR T790M (exon 20)
MET amplification
PIK3CA
AR, acquired resistance; NSCLC, non-small-cell lung cancer; PD, progressive disease; SCLC, small-cell lung cancer; TKI, tyrosine kinase inhibitor.
At the time of progression on an EGFR TKI (either erlotinib or afatinib or gefitinib), a patient should have a biopsy prior to switching therapy. Now, there are different types of progression that we see in patients. There are patients that may have progression in multiple sites—what is referred to here as rapid global progression—or patients who are slow growth globally. In these patients, if we are considering switching therapy, a biopsy is mandated in order to determine if we should treat them with the third-generation inhibitor that is approved in EGFR T790M-positive patients, osimertinib. Or should we treat them with chemotherapy if they are EGFR T790M negative?
For patients who have only growth in an isolated area or patients who have progression in the CNS, it may be reasonable to administer local therapy to patients at that time and continue them on their TKI, and only switch therapy if they have progression in more than 1 site.
When we look at the chart on the right, the most common mechanism of acquired resistance to EGFR TKIs is a presence of the EGFR T790M mutation. Multiple other mechanisms have been reported and, perhaps clinically, the other most important mechanism of resistance is transformations to small-cell lung cancer. And that’s one of the very reasons that we should be performing biopsies at the time of progression. For patients who have transformation to small-cell lung cancer, their treatment strategy changes from traditional non-small-cell lung cancer therapies to therapies that are associated with small-cell lung cancer. We know for these patients, their overall prognosis is also worse. Other important mechanisms of resistance include MET amplification, HER2 amplification, and BRAF mutations. There are multiple different strategies that are currently underway, trying to target patients with these mechanisms of resistance.
Camidge DR, et al. Nat Rev Clin Oncol. 2014;11:

29. Response Rates of EGFR T790M–Positive Cohorts to Osimertinib
DCR (CR, PR, or SD): 90% (95% CI: 84-94); activity in LM
D, discontinued; DCR, disease control rate; LM, leptomeningeal metastases; RECIST, Response Evaluation Criteria In Solid Tumors; SD, stable disease.
Jänne PA, et al. New Engl J Med. 2015;372: Jänne PA, et al. ELCC 2015; Abstract LBA3.
Yang, J C-H, et al. ASCO Abstract 9002.

30. 3 Generations of EGFR TKIs
m, mutated; TKI, tyrosine kinase inhibitor; WT, wild type.
This slide shows us the relative efficacy of the different EGFR TKIs that are FDA approved with regards to sensitizing mutations compared to the EGFR T790M mutation and acquired resistance. As you can see, erlotinib, afatinib, and gefitinib are all effective in patients with EGFR-sensitizing mutations, but what you can see is that high concentrations of erlotinib and gefitinib, and relatively high concentrations of afatinib are required in order to target EGFR T790M, while osimertinib is very effective at very low concentrations.
Li D, et al. Oncogene. 2008;27: Ranson M, et al. WCLC Abstract MO Moyer JD, et al. Cancer Res. 1997;57: Kancha RK, et al. Clin Cancer Res. 2009;15: 33

31. Third-Generation EGFR TKIs
NR, not reported; TKI tyrosine kinase inhibitor.
1. Jänne PA, et al. N Engl J Med. 2015;372: Sequist LV, et al. N Engl J Med. 2015;372: Sequist LV, et al. N Engl J Med. 2016;374: Park K, et al. ASCO Abstract Tan DS, et al. ASCO Abstract Goto Y, et al. ASCO Abstract 8014.

32. Timeline Oct 2014 May 2015 May 2016 July 2016 Jan 2017 UMSC
Started on Gefitinib
Another
New Recurrence
at spine
T790M detected from ct-DNA
Worsening bone
metastases
PET/CT scan:
Partial Response
Patient was asymptomatic of progression
Started on Osimertinib
ALK & ROS1 mutation testing were negative
Stable disease
Changed to Afatinib as requested by the patient

33. AURA3: PFS by Investigator Assessment
Median PFS significantly improved in all evaluated subgroups (age, sex, sensitizing EGFR mutation, CNS disease, and smoking history)
CNS, central nervous system.
This study met its primary endpoint with a significant improvement in progression-free survival for patients treated with osimertinib compared to platinum-based pemetrexed therapy with a median progression-free survival of 10.1 months for patients on osimertinib compared to 4.4 months for patients treated with platinum-based chemotherapy. The survival benefit was regardless of patient’s age, gender, their type of original EGFR mutation, whether it was deletion 19 or L858R, whether or not patients had CNS disease, and whether or not patients had a history of smoking. Based on this data, osimertinib has been approved for the treatment of patients with the EGFR T790M mutation as a mechanism of acquired resistance on a first- or second-generation EGFR TKI.
Mok TS, et al. N Engl J Med. 2017;376:

34. Discussion (EGFR Mutation–Driven NSCLC)
EGFR sensitizing mutations predict higher response rate, PFS, and QoL if treated with EGFR TKI first line
Several approved EGFR TKIs
Specific EGFR mutation is important to know since some predict resistance to EGFR TKIs (eg. exon 20 insertions)
Choice of specific EGFR TKI dependent on physician and patient preferences
Upon progression, postprogression biopsy is important to establish the mechanism of resistance
Liquid biopsy is an option
Osimertinib approved for pts with EGFR T790M-positive disease (preferred treatment choice)
NSCLC, non-small-cell lung cancer; QoL, quality of life; TKI, tyrosine kinase inhibitor.
So currently, for patients with EGFR mutation–positive non-small-cell lung cancer, we know that these mutations are predictive of a higher response rate, progression-free survival, and quality of life, if treated with an EGFR TKI first line.
It is important to know the type of EGFR mutation that a patient has prior to prescribing an EGFR TKI. For example, a patient with an exon 20 insertion is unlikely to respond to currently approved EGFR TKI therapies, and those patients should be preferentially treated with chemotherapy. The specific EGFR TKI choice may depend both on the physician and patient preferences. Upon progression, a patient should have a biopsy in order to establish the mechanism of resistance and determine the next therapy. Performing a liquid biopsy is an option for patients, but if negative, should not be used in selecting therapy, and those patients should go on to have a tissue biopsy.
Osimertinib is currently approved for patients who are EGFR T790M mutation positive as a mechanism of acquired resistance, and is a first choice of second-line therapy for these patients.

35. Case 2:
Patient without driver mutation

36. AWS Demographic data Age: 50 years old Ethnic: Malay Gender: Male
Co-morbidity: Hypertension
Smoking status:
Chronic smoker (30 packed years) – stopped in Oct 2015
Family history: No
ECOG PS: 1
Occupation:
Lorry driver

37. AWS Presented with Examination findings:
Pleutitic chest pain since Sept 2015
a/w loss of appetite & loss of weight
Examination findings:
Overweight
Left pleural effusion

39. AWS Progress: Randomised into Immunotherapy arm – 1st line treatment
Enrolled into Clinical Trial
ALK translocation – negative
PDL-1 - positive
Randomised into Immunotherapy arm – 1st line treatment

40. After 3 cycle of Pembrolizumab
Partial Response

41. KEYNOTE-024: Study Design
Randomized, open-label phase III trial
BICR, blinded independent central review; carb, carboplatin; cis, cisplatin; CT, chemotherapy; DoR, duration of response; ECOG, Eastern Cooperative Oncology Group; f/u, follow-up; gem, gemcitabine; NSCLC, non-small-cell lung cancer; pac, paclitaxel; PD, progressive disease; pem, pemetrexed; PFS, progression-free survival; PFS2, PFS with ≥ 1 subsequent line following study treatment; PS, performance status; RECIST, Response Evaluation Criteria in Solid Tumor; TPS, tumor proportion score.
Brahmer JR, et al. ASCO Abstract Reck M, et al. N Engl J Med. 2016;375:

42. KEYNOTE-024: Pt Disposition With Extended Follow-up
Median follow-up: 19.1 mos (range: mos)
ITT, intent to treat; mos, months; N/A, not applicable.
Brahmer JR, et al. ASCO Abstract 9000.

43. KEYNOTE-024: PFS2
NE, not estimable; NR, not reached; PFS2, PFS with ≥ 1 subsequent line following study treatment.
Brahmer JR, et al. ASCO Abstract Reproduced with permission.

44. KEYNOTE-024: OS NE, not estimable; NR, not reached.
Brahmer JR, et al. ASCO Abstract Reproduced with permission.

45. KEYNOTE-024: Conclusions
With longer follow-up, first-line pembrolizumab demonstrated continued OS benefit vs platinum-based chemotherapy in pts with PD-L1–positive advanced NSCLC
Median OS: NR vs 14.5 mos (HR: 0.63; P = .003)
OS curves remained separated even with effective crossover rate of 60%
PFS2 significantly prolonged for pts allocated to first-line pembrolizumab vs chemotherapy
Median PFS2: 18.3 vs 8.4 mos (HR: 0.54; P < .001)
Investigators concluded that first-line pembrolizumab should be standard of care for NSCLC pts with tumors having PD-L1 TPS ≥ 50% due to prolonged survival and improved safety profile vs platinum-doublet chemotherapy
NR, not reached; NSCLC, non-small-cell lung cancer; PFS2, PFS with ≥ 1 subsequent line following study treatment; TPS, tumor proportion score.
Brahmer JR, et al. ASCO Abstract 9000.

46. After 9 cycle of Pembrolizumab
Smaller primary….. But new ribs erosion..

47. Palliative Radiotherapy to left chest wall lesion 20Gy /5#

48. AWS Continue another cycle of Pembrolizumab after Radiotherapy
Repeat CT scan:

49. AWS Subsequently We withdraw the patient from the clinical trial
We started him on Chemotherapy
Carboplatin + Permetrexed

50. After 2 cycle of Carboplatin + Pemetrexed

51. After completed 6 cycle of Carboplatin + Pemetrexed

52. Currently On maintenance Gemcitabine (on-going)
Unable to afford Pemetrexed anymore

53. Maintenance Therapy for Pts With Nonprogressive Disease*
Bev, bevacizumab; CT, chemotherapy; Pem, pemetrexed; PS, performance status; SD, stable disease.
NCCN. Clinical Practice Guidelines in Oncology: non-small-cell lung cancer. v

54. NSCLC Maintenance Therapy: Advantages and Disadvantages
Maintains disease control
Improves PFS
Improves OS
Maintains quality of life
Opportunity to treat more pts
Pts support maintenance therapy
Cumulative toxicity with Grade 3/4 AEs in 30% to 40% of pts
Cost
Lack of reliable predictive biomarkers
AE, adverse event; NSCLC, non-small-cell lung cancer; OS, overall survival.

55. Any data on elderly patients?

56. Treatment and Outcomes of Adv NSCLC in the Elderly: SEER/Medicare Database
NSCLC, non-small cell lung cancer
Davidoff AJ, et al. J Clin Oncol. 2010;28:

57. IFCT-0501: Doublet vs Single-Agent Chemotherapy in Elderly Adv NSCLC
Doublet chemotherapy (Carboplatin/Paclitaxel) superior to single- agent (Gem or VNR) chemotherapy in elderly patients with advanced NSCLC
CI, confidence interval; HR, hazard ratio; NSCLC, non-small cell lung cancer; OS, overall survival
Quoix E, et al. Lancet. 2011;378:

58. ABOUND.70+: Study Design
AUC, area under the concentration curve; NSCLC, non-small-cell lung cancer; PD, progressive disease.
Primary endpoint: incidence of grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression (assessed at baseline; Days 1, 8, 15 of each cycle; end of treatment; 28 days after last dose)
Secondary endpoints: PFS, OS, ORR, safety
Langer CJ, et al. ASCO Abstract 9059.

59. ABOUND.70+: Pt Characteristics
ECOG, Eastern Cooperative Oncology Group; PS, performance status.
Langer CJ, et al. ASCO Abstract 9059.

60. ABOUND.70+: Safety and Tolerance
Higher median cumulative nab-paclitaxel dose, longer treatment duration in treatment arm with 1-wk break
No significant difference in incidence of grade ≥ 2 peripheral neuropathy or grade ≥ 3 myelosuppression (RR: 1.01 [95% CI: ]; P = .9258)
Grade ≥ 2 peripheral neuropathy: 37% vs 36% for Q3W and Q3W with 1-wk break
Grade ≥ 3 myelosuppression: 71% vs 64% for Q3W and Q3W with 1-wk break
RR, relative risk.
Langer CJ, et al. ASCO Abstract 9059.

61. ABOUND.70+: Efficacy *1 CR in each arm. NE, not estimable.
Langer CJ, et al. ASCO Abstract 9059.

62. nab-Paclitaxel in NSCLC: Conclusions
nab-paclitaxel + carboplatin is active and well tolerated in higher-risk pt populations with advanced NSCLC
In elderly pts, incidence of peripheral neuropathy and myelosuppression similar with or without 1-wk break after each 3-wk treatment cycle[2]
Higher treatment exposure in noncontinuous arm may improve outcomes
Investigators support use of this regimen in these poorer-prognosis pts
ECOG, Eastern Cooperative Oncology Group; NSCLC, non-small-cell lung cancer; PS, performance status.
1. Gajra A, et al. ASCO Abstract Langer CJ, et al. ASCO Abstract 9059.

63. Take Home
Advances in management of advanced NSCLC had shown to be able to prolong PFS and OS
Age is not part of the consideration for option of treatment

64. Updated Treatment Algorithm for Advanced-Stage NSCLC (2016)
NSCLC, non-small-cell lung cancer; PS, performance status.
Updated from Gandara DR, et al. Clin Lung Cancer. 2009;10(6):

65. Thank you!