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

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

Case 1 : Patient with driver mutation

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

Timeline 2010 March

Timeline 2010 Private hospital March

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

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

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

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

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

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

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

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

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

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

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

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;8:823-859. 2. D’Angelo SP, et al. J Clin Oncol. 2011;29:2066-2070. 3. NCCN. Clinical practice guidelines in oncology: non-small-cell lung cancer. v4.2016.

Timeline Oct 2014 UMSC Started on Gefitinib Stable disease

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;105:595-605.

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;362:2380-2388. 2. Mitsudomi T, et al. Lancet Oncol. 2010;11:121-128. 3. Mitsudomi T, et al. ASCO 2012. Abstract 7521. 4. Zhou C, et al. Lancet Oncol. 2011;12:735-742. 5. Zhou C, et al. Ann Oncol. 2015;26:1877-1883. 6. Rosell R, et al. Lancet Oncol. 2012;13:239-246. 7. Sequist LV, et al. J Clin Oncol. 2013;31:3327-3334. 8. Yang JC, et al. Lancet Oncol. 2015;16:141-151. 9. Wu YL, et al. Lancet Oncol. 2014;15:213-222. 24

LUX-Lung 3+6: OS by del(19) and L858R Mutation Status for Afatinib vs Chemo Yang JC, et al. Lancet Oncol. 2015;16:141-151.

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

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

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;17:577-589.

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

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

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;11:473-481.

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;372:1689-1699. Jänne PA, et al. ELCC 2015; Abstract LBA3. Yang, J C-H, et al. ASCO 2016. Abstract 9002.

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;27:4702-4711. Ranson M, et al. WCLC 2013. Abstract MO21.12. Moyer JD, et al. Cancer Res. 1997;57:4838-4848. Kancha RK, et al. Clin Cancer Res. 2009;15:460-467. 33

Third-Generation EGFR TKIs NR, not reported; TKI tyrosine kinase inhibitor. 1. Jänne PA, et al. N Engl J Med. 2015;372:1689-1699. 2. Sequist LV, et al. N Engl J Med. 2015;372:1700-1709. 3. Sequist LV, et al. N Engl J Med. 2016;374:2296-2297. 4. Park K, et al. ASCO 2015. Abstract 8084. 5. Tan DS, et al. ASCO 2015. Abstract 8013. 6. Goto Y, et al. ASCO 2015. Abstract 8014.

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

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;376:629-640.

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.

Case 2: Patient without driver mutation

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

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

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

After 3 cycle of Pembrolizumab Partial Response

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 2017. Abstract 9000. Reck M, et al. N Engl J Med. 2016;375:1823-1833.

KEYNOTE-024: Pt Disposition With Extended Follow-up Median follow-up: 19.1 mos (range: 14.3-27.6 mos) ITT, intent to treat; mos, months; N/A, not applicable. Brahmer JR, et al. ASCO 2017. Abstract 9000.

KEYNOTE-024: PFS2 NE, not estimable; NR, not reached; PFS2, PFS with ≥ 1 subsequent line following study treatment. Brahmer JR, et al. ASCO 2017. Abstract 9000. Reproduced with permission.

KEYNOTE-024: OS NE, not estimable; NR, not reached. Brahmer JR, et al. ASCO 2017. Abstract 9000. Reproduced with permission.

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 2017. Abstract 9000.

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

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

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

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

After 2 cycle of Carboplatin + Pemetrexed

After completed 6 cycle of Carboplatin + Pemetrexed

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

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.5.2015.

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.

Any data on elderly patients?

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;28:2191-2197.

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;378:1079-1088.

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 2017. Abstract 9059.

ABOUND.70+: Pt Characteristics ECOG, Eastern Cooperative Oncology Group; PS, performance status. Langer CJ, et al. ASCO 2017. Abstract 9059.

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: 0.84-1.21]; 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 2017. Abstract 9059.

ABOUND.70+: Efficacy *1 CR in each arm. NE, not estimable. Langer CJ, et al. ASCO 2017. Abstract 9059.

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 2017. Abstract 9058. 2. Langer CJ, et al. ASCO 2017. Abstract 9059.

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

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):392-394.

Thank you!