nsclc updated august 2017 by dr. kirstin...

NSCLCUpdated August 2017 by Dr. Kirstin Perdrizet, PGY-5 Resident, University of TorontoReviewed by Dr. Adrian Sacher (Staff Medical Oncologist, Princess Margaret Cancer Centre, University of Toronto)

A) PUBLIC HEALTH

EPIDEMIOLOGY

• Incidence: 69.9 per 100,0001. Among both sexes it is the cancer with the highest incidence in Canada (numbers include SCLC) (2017 Canadian Cancer Statistics)

• Mortality: Most common cause of cancer death in Canada (51.4 deaths per 100,000) (numbers include SCLC) (2017 Canadian Cancer Statistics)

RISK FACTORS

• Environmental/Chemical/Infections: smoking, radiation therapy, air pollution, radon, metals (arsenic, chromium and nickel), ionizing radiation, asbestos, polycyclic aromatic hydrocarbons, pulmonary fibrosis, HIV infection, COPD, pneumoconiosis, possibly diets deficient in vitamins A and C (although yet to be confirmed)

• Genetic: inherited susceptibility variants for lung cancer have been found on several chromosomal loci such as15q25 (nicotinic acetylcholine receptor subunit CHRNA5) and 6q23-25, p53 carrier status, germline EGFR T790M mutation, 1-2% RET mut, polymorphisms p450.

PREVENTION & SCREENING

• Prevention: Smoking cessation • Screening: Evidence from the National Lung Screening Trial (NLST) found that

screening high- risk patients (defined as >/= 30 pack year smoking history or quit smoking <15 years ago and aged between 55 and 74 years old) with an annual low dose CT scan reduced lung cancer mortality by 20% and all cause mortality by 6.7%. N=53,454 randomized to 3 annual low dose CT vs PA CXR 24% CT vs 7% XRay detection~ 95% screenings were false positives in both groups

• The Prostate, Lung, Colorectal, Ovarian (PLCO) trial found that Chest X-ray is not effective for lung cancer screening, when compared to no screening.Canadian Task Force 2016 guidelines recommend Low dose computed tomography (LDCT)

• For adults aged 55-74 years with at least a 30 pack-year* smoking history who currently smoke or quit less than 15 years ago, we recommend annual screening with LDCT up to three consecutive times. Screening should ONLY be carried out in health care settings with expertise in early diagnosis and treatment

of lung cancer.

CCO guidelines on lung cancer screening are still pending as of July 3 2018; pilot projects are ongoing at multiple sites across Ontario. B) PRESENTATION & DIAGNOSIS

SYMPTOMS & SIGNS

Common Symptoms:

• Symptoms from local tumour effect: cough, hemoptysis, dyspnea, chest pain, hoarseness

• Symptoms from extrathoracic metastases to supraclavicular lymph nodes, liver, adrenals, bone, brain

• Symptoms from paraneoplastic syndromes: hypercalcemia symptoms, hyponatremia symptoms, cushings syndrome symptoms, hypertrophic osteoarthropathy symptoms, dermatomyositis/polymyositis symptoms, neurologic symptoms, hypercoagulable disorders

Common Signs:

• Signs from local tumour effect: airway compromise, hoarseness, superior vena cava syndrome, pancoast syndrome

• Signs from extrathoracic metastases to supraclavicular lymph nodes, liver, adrenals, bone, brain

• Signs from paraneoplastic syndromes: hypercalcemia symptoms, hyponatremia symptoms, cushings syndrome symptoms, hypertrophic osteoarthropathy symptoms, dermatomyositis/polymyositis symptoms, neurologic symptoms, hypercoagulable disorders

Common Presentations:

non resolving pneumonia, cough, hemoptysis, superior vena cava syndrome, Pancoast syndrome (Henry Pancoast, US radiologist described syndrome in 1924), paraneoplastic syndrome, majority of patients have advanced disease at presentation

INVESTIGATIONS

Laboratory: anemia, leukocytosis, thrombocytosis, eosinophilia has been reported in patients with large cell carcinoma, features of microangiopathic hemolytic anemia can be seen (ex. DIC/TTP), electrolytes (can show features of SIADH/ectopic ACTH secretion in small cell lung cancer patients), calcium, albumin, LDH, LFTs, CEA if elevated can help with assessment of treatment in patients with difficult-to-evaluate index lesions (ex. Bone lesions)

Diagnostic Imaging: CT Chest Enhanced that encompasses the liver and adrenal glands, CT head if neuro symptoms, MR brain if persistent neuro symptoms despite normal CT head, Bone scan if bony symptoms. PET scan in all patients where disease is felt to be confined to the thorax on initial imaging.

Diagnostic Procedures:

• Tissue diagnosis with sputum cytology, bronchoscopy, percutaneous fine needle biopsy, excisional or needle biopsy as appropriate for the patient

• Bronchoscopy to biopsy lung lesion • mediastinoscopy to biopsy lymph nodes > 1.0cm short axis on CT scan3

Pretreatment Evaluation:

Pulmonary function testing if patient is potentially operable as well as PET to confirm extend of disease+/- mediastinoscopy/EBUS

PATHOLOGY & MOLECULAR BIOLOGY - Common Histology:

• Small cell lung cancer (SCLC): 13% • Non-small cell lung cancer (NSCLC):

o Adenocarcinoma: 38% o Squamous cell carcinoma: 20% o Large cell carcinoma: 5% o Other NSCLC’s (ex. Adenosquamous carcinoma, sarcomatoid carcinoma,

carcinoid tumours): 24%

Common Metastatic Sites: pleura, other lung, liver, adrenal, bone, brain

Relevant Molecular Biology (bolded are most relevant and are guidelines based recommended testing, the underlined ones are not yet standard of care):

Epidermal growth factor receptor (EGFR) gene: A mutation in the EGFR gene is present in 15 – 30% of non-Asian and 30 – 60% of Asian patients with adenocarcinoma. 90% of the mutations are either a deletion of exon 19 or a point mutation in exon 21 (L858R) on the EGFR gene. Exon 20 insertions are generally confer resistance to first line EGFR TKIs

Anaplastic lymphoma kinase (ALK) gene: A fusion gene with ALK (typically ELM4) is present in 2 – 7% of patients with NSCLC. Some clinical and pathologic features that increase the likelihood of finding an ALK oncogene include: younger age, light/never smoking status, adenocarcinoma histology.

c-ROS oncogene 1 (ROS1): About 1% of lung adenocarcinomas are driven by a ROS1 fusion. These patients respond to Crizotinib.

BRAF v600E and non-V600E mutations are present in lung adenocarcinomas (2-3%) and can be targeted with BRAF/MEK inhibitors.

K-ras (30% of adenocarcinomas) associated with resistance to erlotinib and gefitinib and poorer prognosis

Met exon 14 skipping mutation (can be associated with resistance to TKI post treatment), can be targeted by crizotinib

RET fusion can also be targeted by crizotinib

NTRK fusion present in 3% of lung adenocarcinomas; targetable by TRK protein inhibitor larotrectinib ERBB2 mutations (typically exon 20) can be treated with HER2 targeted therapies (some respond to Afatinib as well as TDM1- based on single arm phase 1+2 studies). PD-L1 testing:

Characteristic

Pembrolizumab Nivolumab Durvalumab Atezolizumab

IHC assay developer

Dako Dako Ventana Ventana

Antibody clone

22C3 mouse 28-8 rabbit SP 263 rabbit SP142

Expression location

TCs and stroma TCs TCs TICs and TCs

Cut-off

Melanoma, bladder, NSCLC >=1% TC

NSCLC: >=1% to 5% TCRenal: >=5% TC

NSCLC, SCCHN: >=25% TC

Bladder, NSCLC, breast: IHC2 >5% to <10% TC or TIC or IHC3 >=120% TC or TIC

STAGING-

1) NSCLC Staging

TNM: - please see AJCC 8th edition

5-year relative survival rates for patients with non-small cell lung cancer by stage:

• 58% with stage I disease • 35% with stage II disease • 10-20% with stage III disease • 2% with stage IV disease

Reference - Surveillance, Epidemiology, and End Results (SEER) Survival Monograph 2007 PDF.

C) TREATMENT

I) NSCLC:LOCALIZED / ADJUVANT

Bottom Line General Approach:

• Stage I: surgery with lobectomy or pneumonectomy. Adjuvant platinum-based doublet chemotherapy may be considered in select Stage IB patients with tumours ≥ 4cm in diameter*.

• Stage II: surgery with lobectomy or pneumonectomy followed by adjuvant platinum-based doublet chemotherapy*. Consideration of adjuvant radiation therapy should be undertaken only if resection margins are positive.

• Stage IIIA: select patients are resectable especially T3N0M0 disease. Surgery should be followed by adjuvant platinum-based doublet chemotherapy*. Consider adjuvant radiation therapy in all Stage III patients. Those most likely to benefit are those with positive margins, N2 disease or infiltration to the chest wall. For operable patients with N2 disease, preoperative chemoradiation is recommended (triple modality treatment). Surgery is not recommended if the patient requires a full pneumonectomy.

• Cisplatin-based chemotherapy (cisplatin/vinorelbine) is the preferred treatment. A carboplatin-based regimen, such as carboplatin-paclitaxel (used in the CALGB 9633 trial1), can be used if there is a contraindication to cisplatin.

Prognosis: 66mos with adjuvant chemo vs 44 mos with surgery alone.

Important Phase III Clinical Trials:

ANITA Trial: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-small-cell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): a randomised controlled trial.

Reference: Douillard JY et al. Lancet Oncol. 2006;7(9):719.

Regimen • Four cycles of vinorelbine (30 mg/m2 on D1, 8, 15 and 22

repeated q4 weeks X 4 cycles) plus cisplatin (100 mg/m2 on D1 q4 weeks X 4 cycles) vs. observation

Mechanism of Action of Experimental Drug

• Cisplatin: inhibits DNA synthesis by the formation of DNA crosslinks

• Vinorelbine: vinca alkaloid that binds to tubulin and inhibits microtubule formation

Primary Endpoint • OS

Inclusion/Exclusion Criteria

• Stage IB, Stage II, or Stage IIIA NSCLC previously resected

• Included: 35% IB, 20% II, 40% IIIA.

Size (N) • 799 evaluable patients

Results

• Survival: 66 mos chemo group vs. 44 mos observation group.

• OS 5y improvement by stage

o IB o IIo IIIA

62à64% (ns)39à52% (ns) (CI crosses 1)

26à42% (s)• Overall 8.6% increase OS 5y [NNT 11]

Toxicity • Grade 3 or 4 neutropenia, febrile neutropenia, nausea and

vomiting, constipation and peripheral neuropathy

• Common toxicities include renal failure, ototoxicity

Conclusion • Adjuvant vinorelbine plus cisplatin extends survival in patients with completely resected NSCLC, especially in Stage II and III disease.

Other Comments

NCIC BR.10: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer Reference: Winton T, Livingston R, Johnson D, et al. N Engl J Med 352:2589-97, 2005; Update 2010 - J Clin Oncol 2010 Jan 1;28(1):29-34.

Regimen • cisplatin 50mg/m2 D1, D8 q4w x 4 cycles + vinorelbine 25mg/m2 weekly x 16w vs. observation





Inclusion/Exclusion Criteria • Stage IB or II completely resected NSCLC • ECOG0or1

Size (N) • 482 patients

Results

• Survival: 94 months in chemo group vs. 73 months in observation group. HR for death 0.69, P = .04

• DFS/PFS/TTP: not reached in chemo group vs. 46.7 months in observation group. HR for recurrence 0.60, P < 0.01

• UPDATE 2010

• No SV benefit for IB with mOS 9.8 vs 11 years in general but if T > 4cm OS 5y 59% to 79% (s) [ARR 20% NNT 5]

• • Stage II mOS 3.6 at 6.8 years

Toxicity

• Neutropenia, Febrile neutropenia, fatigue, nausea, anorexia, vomiting, neuropathy, constipation

• Grade 3 or 4 toxicities were uncommon (<10%)

Conclusion

• Adjuvant vinorelbine plus cisplatin has an acceptable level of toxicity and prolongs disease-free and overall survival among patients with completely resected early-stage non–small-cell lung cancer.

Other Comments

• (e.g. any criticisms about the study)

Other Important Published Data:

1. LACE meta-analysis: Pignon JP, Tribodet H, Scagliotti GV, Douillard JY,

Shepherd FA, Stephens RJ, Dunant A, Torri V, Rosell R, Seymour L, Spiro SG, Rolland E, Fossati R, Aubert D, Ding K, Waller D, Le Chevalier T; LACE Collaborative Group. Lung adjuvant cisplatin evaluation: a pooled analysis by the LACE Collaborative Group. J Clin Oncol. 2008 Jul 20;26(21):3552-9. 5 studiesà4584 pts5 years absolute benefit of 5.4% with chemoNo benefit for stage I (IA or IB), HR 0.83 for both stages II and III (s)Effect did not vary with the drug added to CDDP (vinorelbine, etoposide)Chemo was better in pts with better KPSNo interaction between chemo and: sex, age, histology, type of Sx, planned RT or planned total dose of CDDP

2. IALT: The International Adjuvant Lung Cancer Trial Collaborative Group: Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected Non-Small-Cell Lung Cancer. N Engl J Med 350:351-360, 2004 Phase III CDDP duplet 3-4 cycles (could choose the combination) vs observation Stage I (36%), II (24%) and III (39%).CDDP with etoposide (56%),

vinorelbine (26%), vinblastine (11%), or vindesine (6%) N=1867 OS 5y 40% observationà44.5 % [NNT 25]No interaction with drug selected, age, sex, stage, Sx type, histology, KPS. All ns. [Note: However in the HR plot it looks like stage II and III benefited but stage I no]

3. Adjuvant Carbo-Paclitaxel CALGB trial - Strauss GM, Herndon JE,2nd, Maddaus

MA, Johnstone DW, Johnson EA, Harpole DH, et al. Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 2008 Nov 1;26(31):5043-5051. Survival was not significantly different (hazard ratio [HR], 0.83; CI, 0.64 to 1.08; P = .12). However, exploratory analysis demonstrated a significant survival difference in favor of adjuvant chemotherapy for patients who had tumors > or = 4 cm in diameter

4. Trials of consolidative immunotherapy (NCT02273375) with Durvalumab post-surgical resection are ongoing

LOCALLY ADVANCED (STAGE III)


• Treatment of Stage III patients is not standardized. However, the following general approach can be taken.

• Surgery may be considered in patients with clinical N0 disease, non-bulky N2 disease that are surgical candidates. If the patient is a surgical candidate, it is reasonable to discuss preoperative chemotherapy and/or radiation therapy.

• Combined concurrent chemo-radiation is recommended for inoperable stage III patients with good performance status (ECOG 0-2), minimal weight loss (<5% in the preceding 3 months) and good pulmonary reserve.

• For patients with bulky N2 disease, chemotherapy plus concurrent radiation therapy is indicated.

• Cisplatin-based chemotherapy (with either etoposide or vinorelbine) and thoracic radiation of 55Gy in 25 fractions to 66Gy in 33 fractions is the recommended treatment option. Chemotherapy can be administered either in full systemic doses with radiation therapy, weekly radiosensitizing doses, or a combination of both. Consider concurrent or sequential chemoradiation in patients with borderline performance status or moderate weight loss. Consider palliative

chemotherapy/radiation therapy in patients with poor performance status and severe weight loss (see management of metastatic disease).

• PACIFIC trial published 12/2017 reveals that Durvalumab 10mg/m2 q2weekly x12months post combined chemo/rads significantly improved PFS. Consolidative durvalumab is now approved in Canada, however it is not yet funded by most provincial funding bodies (as of July 2018), however a compassionate program is currently open

Pancoast tumour:

In patients with a superior sulcus (pancoast) tumour, trimodality therapy is favoured.

The optimal regimen for trimodality therapy has not been established but a reasonable approach is:

1. Concurrent chemotherapy with cisplatin and etoposide and 45 Gy of radiation therapy administered over 5 weeks. 60 to 66 Gy of radiation therapy is also acceptable.

2. If there is no evidence of progressive disease, surgical resection can be considered 3 to 5 weeks after completion of chemoRT.

3. Two additional cycles of chemotherapy with a platinum-doublet after surgery.

Reference: SWOG Intergroup Trial 0160 JCO 2007;25:313-318. PMID: 17235046.

Prognosis: 17 months with treatment- this is without updated OS data from PACIFIC


RTOG 9410: Sequential vs. concurrent chemoradiation for stage III non-small cell lung cancer: randomized phase III trial RTOG 9410.Reference: Curran WJ et al. J Natl Cancer Inst. 2011;103(19):1452.

Regimen

• Arm 1: cisplatin at 100 mg/m2 on days 1 and 29 and vinblastine at 5 mg/m2 per week for 5 weeks with 63 Gy TRT delivered as once- daily fractions beginning on day 50 (sequential)

• Arm 2: same chemotherapy regimen as arm 1 with 63 Gy TRT delivered as once-daily fractions beginning on day 1

(concurrent daily RT)

• Arm 3: cisplatin at 50 mg/m2 on days 1, 8, 29, and 36 with oral etoposide at 50 mg twice daily for 10 weeks on days 1, 2, 5, and 6 with 69.6 Gy delivered as 1.2 Gy twice-daily fractions beginning on day 1 (concurrent hyperfractionated RT)


• Cisplatin: inhibits DNA synthesis by the formation of DNA

crosslinks



Inclusion/Exclusion Criteria • Stage III NSCLC


Results

• Survival: mOS Arm 1: 14.6 months, Arm 2: 17.0 months, Arm 3: 15.6 months

• 5-year OS: Arm 1: 10%, Arm 2: 16%, Arm 3: 13%

Toxicity

• Grade 3 or 4 neutropenia, febrile neutropenia, nausea and

vomiting, constipation and peripheral neuropathy

• Common toxicities include renal failure, ototoxicity, esophagitis

Conclusion • Concurrent delivery of cisplatin-based chemotherapy with TRT confers a long-term survival benefit compared with the sequential delivery of these therapies

• PACIFIC: Durvalumab after Chemoradiotherapy in Stage III Non–Small-

Cell Lung Cancer N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937

Regimen durvalumab (at a dose of 10 mg per kilogram of body weight intravenously) or placebo every 2 weeks for up to 12 months after two cycles of platinum based chemotherapy combined with XRT


• Durvalumab: Anti PDL1 antibody

Primary Endpoint • Coprimary endpoints of PFS and OS


•Included: Stage III NSCLC, unresectable; ECOG 0-1, receipt of 2 cycles of platinum based chemotherapy with 54-66Gy XRT; last radiation dose within 1 to 14 days before randomization (after a protocol amendment, this criterion was changed to 1 to 42 days before randomization)

Excluded: previous exposure to anti–PD-1 or PD-L1 antibodies; active or previous autoimmune disease (within the past 2 years)

Size (N)

• 713 patients who underwent randomization, 709 received consolidation therapy, 2:1 randomization between treatment and placebo arms (473 received durvalumab and 236 received placebo)

Results

PFS: median progression-free survival 16.8 months with durvalumab versus 5.6 months with placebo; the 12-month PFS rate was 55.9% versus 35.3%, and the 18-month PFS rate was 44.2% versus 27.0%. OS: not mature- recent press release May 25 2018 states OS

endpoint has been met, but numbers not published

Toxicity

Grade 3 or 4 adverse events occurred in 29.9% of the patients who received durvalumab and 26.1% of those who received placebo 15.4% of patients in the durvalumab group and 9.8% of those in the placebo group discontinued the study drug because of adverse events

Conclusion • Consolidation immunotherapy significantly prolongs PFS in patients with unresectable stage III NSCLC

Other Important Published Data:

1. Meta-analysis - strongest evidence for combined modality therapy: Anonymous: Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. Bmj. 311:899-909, 1995

2. Randomized trial studying the benefit of adjuvant chemotherapy in stage III patients: Dillman RO, Herndon J, Seagren SL, et al: Improved survival in stage III non-small-cell lung cancer: seven-year follow-up of cancer and leukemia group B (CALGB) 8433 trial. [see comment]. Journal of the National Cancer Institute. 88:1210-5, 1996.

3. Furuse K, Fukuoka M, Kawahara M, et al: Phase III study of concurrent versus sequential thoracic radiotherapy in combination with mitomycin, vindesine, and cisplatin in unresectable stage III non-small-cell lung cancer. Journal of Clinical Oncology. 17:2692- 9, 1999

4. Stage IIIA evidence for adding surgery to chemorads - Radiotherapy plus chemotherapy with or without surgical resection for stage III non-small-cell lung cancer: a phase III randomised controlled trial. Albain, Kathy S et al. The Lancet 2009, Volume 374, Issue 9687, 379 – 386.

• Randomized trial evaluating surgery in the trimodality approach for stage III patients: Albain KS, Swann RS, Rusch VR, et al: Phase III study of concurrent chemotherapy and radiotherapy (CT/RT) vs CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): Outcomes update of North American Intergroup 0139 (RTOG 9309). J Clin Oncol (Meeting Abstracts) 23:7014-, 2005. – Published: Lancet 2009.

• N=396 pts T1-3pN2Mo NSCLC 1:1 rand to CDDP-Etop + 45 Gy with or without Sx (if not PD) mOS (ns) ~ 23mOS5y (ns) ~ 20-27%SV increased PFS by 2 m

(10.5 mà12.8 m) • 5y PFS increased 11%à22% with Sx but Rx related death 2%à8% [so NNT is

10 and NNH 17!!]

5. Pancoast tumour – North American intergroup prospective trial: Rusch VW et al. Induction chemoradiation and surgical resection for non-small cell lung carcinomas of the superior sulcus: Initial results of Southwest Oncology Group Trial 9416 (Intergroup Trial 0160). J Thorac Cardiovasc Surg. 2001;121(3):472. Wanted to test feasibility, there is no randomization110 pts T3-4, N0-1, superior sulcus NSCLC2 cycles CDDP-Etop with concurrent RT (45Gy)àif stable or responding = Sx95% completed induction CHRT; 80% had thoracotomy; 1.8% died postop76% complete resection with 56% complete response or minimal residual diseaseOS 5y 44% for all patients and 54% after complete resection (no difference between T3 and T4) Most recurrences were distant.

METASTATIC NSCLC DRIVER MUTATION NEGATIVE


In young patients (age < 75):

First-line therapy:

• If patient has PD-L1 by IHC >=50% testing on 22C3 or similar assay – consider pembrolizumabimmunotherapy 200mg Q3w until toxicity or progression

• If patient has PD-L1 by IHC <50%, on 22C3 or similar assay – consider palliative platinum- doublet chemotherapy for 4 to 6 cycles.

Maintenance therapy: Consider maintenance therapy with pemetrexed in patients with nonsquamous histology. Maintenance docetaxel and gemcitabine are less well- supported by the literature.

In non-squamous NSCLC regardless of PDL1 Status by IHC on 22C3 assay combination chemotherapy with platinum/pemetrexed and pembrolizumab can be considered (KEYNOTE189)

In squamous NSCLC regardless of PDL1 status by ICH on 22C3 assay combination chemotherapy (carbo/taxol, carbo/abraxane) and pembrolizumab can be considered (KEYNOTE407) (As of July 2018 only published as an abstract)

Second-line therapy:

• If patient received immunotherapy in the first-line setting, platinum doublet chemotherapy is the choice of treatment if they are fit enough

• If patient received platinum based chemotherapy in the first-line setting, nivolumab single agent, pembrolizumab single agent (if PD-L1>=1%), or atezolizumab single agent are all reasonable recommended second-line immunotherapy.

Third-line therapy: Single agent docetaxel/pemetrexed or erlotinib are all reasonable options post platinum doublet and immunotherapy.

In elderly patients:

• Advanced age (age > 70) alone should not preclude appropriate treatment. However, chemotherapy may be considered in appropriate elderly patients with ECOG </= 2 with adequate organ function and bone marrow reserve. Patients should be aware of the increased risk of toxicities and the uncertainty of overall benefit in the elderly population.

• Chemotherapy options for elderly patients include: platinum-doublet or single-agent vinorelbine

Prognosis: median OS with treatment: 6-14 months


Pembrolizumab versus Chemotherapy for PD-L1–Positive Non–Small-Cell Lung Cancer3 Reck et al. N Engl J Med 2016; 375:1823-183.

Regimen

• Patients (pts) were randomized to 35 cycles of pembro 200 mg Q3W or 4-6 cycles of investigator’s choice of carboplatin or cisplatin + pemetrexed, carboplatin or cisplatin + gemcitabine, or carboplatin + paclitaxel, with optional pemetrexed maintenance for nonsquamous NSCLC

Primary Endpoint

• PFS


• Patients with advanced NSCLC of PD-L1 TPS ≥50% without treatable EGFR mutations or ALK translocations. Pts in the chemo arm could crossover to pembro upon PD.

Size (N)

• N=305

Results

• With 189 events, pembro significantly prolonged PFS over chemo (HR 0.50, 95% CI 0.37-0.68, P < 0.001; median 10.3 mo vs 6.0 mo). With 108 deaths, pembro also significantly prolonged OS (HR 0.60, 95% CI 0.41-0.89, P = 0.005; 6-mo OS 80% vs 72%).

This OS benefit was maintained at 12 and 18 months.

Toxicity

• Pembro was also associated with higher ORR (45% vs 28%), longer response duration (median NR vs 6.3 mo), and lower incidence of any-grade (73% vs 90%) and grade 3-5 (27% vs 53%) treatment- related AEs.

Conclusion

Pembro demonstrated superior PFS and OS over platinum-based chemo in pts with advanced NSCLC of PD-L1 TPS ≥50%. Along with the lower rate of treatment-related AEs, these data suggest pembro may be the new standard of care for first-line therapy of PD-L1–expressing advanced NSCLC without treatable oncogenic aberrations.

Other Comments

• Females, never smokers, and ALK/EGFR + patients generally less responsive to immunotherapy

First-Line Nivolumab in Stage IV or Recurrent Non–Small-Cell Lung Cancer Carbone et al. N Engl J Med 2017; 376:2415-2426.

Regimen • Randomized 1:1 to receive nivolumab 3 mg/kg IV Q2W or IC PT-DC (histology-based) Q3W (up to 6 cycles) until disease progression or unacceptable toxicity

Primary

Endpoint • PFS


• Patients with histologically confirmed and previously untreated stage IV or recurrent NSCLC, ECOG PS 0−1, and >=5% PD-L1 expression (n = 423)

Size (N) • N=541

Results

• Among the 423 patients with a PD-L1 expression level of 5% or more, the median progression-free survival was 4.2 months with nivolumab versus 5.9 months with chemotherapy (hazard ratio for disease progression or death, 1.15; 95% confidence interval [CI], 0.91 to 1.45; P=0.25), and the median overall survival was 14.4 months versus 13.2 months (hazard ratio for death, 1.02; 95% CI, 0.80 to 1.30).

• A total of 128 of 212 patients (60%) in the chemotherapy group received nivolumab as subsequent therapy.

Toxicity

• Treatment-related adverse events of any grade occurred in 71% of the patients who received nivolumab and in 92% of those who received chemotherapy. Treatment-related adverse events of grade 3 or 4 occurred in 18% of the patients who received nivolumab and in 51% of those who received chemotherapy.

Conclusion

Nivolumab was not associated with significantly longer progression-free survival than chemotherapy among patients with previously untreated stage IV or recurrent NSCLC with a PD-L1 expression level of 5% or more. Overall survival was similar between groups. Nivolumab had a favorable safety profile, as compared with chemotherapy, with no new or unexpected safety signals

Other Comments

• When the data was analyzed for PD-L1 >=50% subset, the OS/PFS were still similar between the two groups.

• KEYNOTE 189: Pembrolizumab plus Chemotherapy in Metastatic Non–

Small-Cell Lung Cancer • N Engl J Med 2018; 378:2078-2092 DOI: 10.1056/NEJMoa1801005

Regimen Cis/Pem chemotherapy x4 cycles + Pembrolizumab (200mg) or Placebo Followed by Pem maintenance + Pembrolizumab (200mg) or Placebo for up to 35 cycles


• Pembrolizumab: Anti PDL1 antibody

Primary Endpoint

• Coprimary endpoints of OS and PFS


•Included: non squamous NSCLC regardless of PDL1; ECOG 0-1, no prior treatment for metastatic disease

Excluded: squamous cell cancer; active or previous autoimmune disease (within the past 2 years), EGFR or ALK mutations

Size (N) • 616 patients, 2:1 randomization

Results

Published at follow-up of 10.5 months Estimated OS at 12 months was 69.2% in the pembrolizumab-combination group versus 49.4% placebo-combination group Improvement in overall survival was seen across all PD-L1 categories that were evaluated.

Median PFS was 8.8 months in the pembrolizumab-combination group and 4.9 months in the placebo-combination group

Toxicity Grade 3 or 4 adverse events occurred in 67.2% of the patients in the pembrolizumab-combination group and in 65.8% of those in the placebo-combination group.

Conclusion • Chemo in combination with immunotherapy improves PFS

Other Comments

Crossover was allowed

Difficult to know what to do for PDL1>50% as single agent Pembro superior to chemo, and this was not a comparator arm.

Checkmate 227: Nivolumab plus Ipilimumab in Lung Cancer with a High Tumor Mutational Burden Hellmann et al. N Engl J Med 2018; 378:2093-2104 DOI: 10.1056/NEJMoa1801946

Regimen

DESIGNED AS A 3 PART STUDY; ONLY PART 1 IS PUBLISHED AND THIS IS PRESENTED HERE Multi-armed study: PD-L1 expression of at least 1% were randomly assigned, in a 1:1:1 ratio, to receive

• nivolumab plus ipilimumab • nivolumab monotherapy • chemotherapy

PD-L1 expression level of less than 1% were randomly assigned, in a 1:1:1 ratio, to receive

• nivolumab plus ipilimumab, • nivolumab plus chemotherapy • chemotherapy.

Mechanism of Action of

Experimental Drug

• Nivolumab: Anti PDL1 antibody

• Ipilumumab: CTLA4 antibody

Primary Endpoint

• Part 1 of the CheckMate 227 trial had two coprimary end points.

• PFS with nivolumab plus ipilimumab versus chemotherapy in a patient population selected on the basis of tumor mutational burden (pre specified >10 mutations/megabase considered high TMB).

• OS with nivolumab plus ipilimumab versus chemotherapy in a patient population selected on the basis of the PD-L1 expression level.


•Included: NSCLC (squam and non squam) regardless of PDL1; ECOG 0-1, no prior treatment for metastatic disease

Excluded: active or previous autoimmune disease (within the past 2 years), EGFR or ALK mutations

Size (N) • 1739 patients randomized

Results

The 1-year progression-free survival rate was 42.6% with nivolumab plus ipilimumab versus 13.2% with chemotherapy, and the median progression-free survival was 7.2 months (95% confidence interval [CI], 5.5 to 13.2) versus 5.5 months (95% CI, 4.4 to 5.8) (hazard ratio for disease progression or death, 0.58; 97.5% CI, 0.41 to 0.81; P<0.001). SECOND CO-PRIMARY ENDPOINT NOT REPORTED YET

Toxicity The rate of grade 3 or 4 treatment-related adverse events was 31.2% with nivolumab plus ipilimumab and 36.1% with chemotherapy.

Conclusion Progression-free survival was significantly longer with first-line nivolumab plus ipilimumab than with chemotherapy among patients with NSCLC and a high tumor mutational burden, irrespective of PD-L1 expression level.

Other Comments

No crossover between groups allowed

Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. Schiller JH et al. N Engl J Med 2002 Jan 10;346(2):92-8.

Regimen

• Arm 1: cisplatin + paclitaxel (24hs infusion) q3w

• Arm 2: cisplatin (D1) + gemcitabine (D1, D8, D15) q4w

• Arm 3: cisplatin + docetaxel q3w

• Arm 4: carboplatin + paclitaxel (over 3 hs) q3w


• Cisplatin/carboplatin: inhibits DNA synthesis by the formation of DNA crosslinks

• Gemcitabine: A pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of DNA polymerase and ribonucleotide reductase, cell cycle-specific for the S-phase of the cycle (also blocks cellular progression at G1/S-phase)

• Docetaxel/paclitaxel: inhibits depolymerization of tubulin therefore inhibiting DNA, RNA and protein synthesis.

Primary Endpoint

• OS


• Advanced NSCLC (Stage IIIB, IV or recurrent disease)

• Patients had to be previously chemotherapy-naïve (for lung cancer)

Size (N) • 1207 patients (1155 eligible patients)

Results

• Survival:mOS:Arm1=7.8mos,Arm2=8.1,Arm3=7.4,Arm4= 8.1 [The interest is between arm 3 and 4]

• MedianTTP:Arm1=3.4,Arm2=4.2(p<0.001whenArm1was compared to Arm 2 but cis/gem was likely to cause more renal toxicity [9% cis/gem vs 3% cis/paclitaxel])

• Response Rate: no significant difference. All Arms had response rates of 17 – 22%.

Toxicity • Cytopenias, infection, nausea, vomiting, weakness, neuropathy

Conclusion None of four chemotherapy regimens offered a significant advantage over the others in the treatment of advanced non–small-cell lung cancer.

Other Comments

• (e.g. criticisms about the study)

Phase III Study Comparing Cisplatin plus Gemcitabine with Cisplatin plus Pemetrexed in Chemotherapy-Naïve Patients With Advanced Non-Small-Cell Lung Cancer. Scagliotti GV, Parikh P, von Pawel J, et al: J Clin Oncol 26: 3543-3551, 2008

Regimen

• Arm 1: cisplatin 75mg/m2 D1 + gemcitabine 1250mg/m2 D1, D8

• Arm 2: cisplatin 75mg/m2 D1 + pemetrexed 500mg/m2 D1

• Both arms q3w x 6 cycles

• Mechanism of Action of Experimental Drug


• Pemetrexed: Antifolate; disrupts folate-dependent metabolic

processes essential for cell replication. Inhibits thymidylate synthase (TS), dihydrofolate reductase (DHFR) and other enzymes involved in folate metabolism and DNA synthesis

Primary Endpoint

• Noninferiority study comparing OS


• Chemotherapy-naïve patients

• Stage IIIB to Stage IV NSCLC

• ECOG 0-1

Size (N)

• 1725 patients

Results

• Survival: OS was noninferior between arms: Arm 1 = 10.3 months, Arm 2 = 10.3 months

• OS1y~42%andOS2y~15%

• OS was statistically superior for cis/pemetrexed vs cis/gem in patients with adenocarcinoma and large-cell carcinoma histology: 12.6 v 10.9 months, respectively.

• OS was statistically superior for cis/gem vs cis/pemetrexed in patients with squamous cell histology: 10.8 v 9.4 months, respectively.

• Quality of Life: Less grade 3 and 4 side effects with cis/pem v cis/gem

Toxicity

• Anemia, neutropenia, thrombocytopenia

• Febrile neutropenia

• Alopecia

• Nausea

• Peripheral neuropathy

Conclusion

• In advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

Other Comments • (e.g. criticisms about the study)

Paclitaxel–Carboplatin Alone or with Bevacizumab for Non–Small-Cell Lung Cancer Alan Sandler, M.D., Robert Gray, Ph.D., Michael C. Perry, M.D., Julie Brahmer, M.D., Joan H. Schiller, M.D., Afshin Dowlati, M.D., Rogerio Lilenbaum, M.D., and David H. Johnson, M.D. N Engl J Med 2006; 355:2542-2550

Regimen

• Arm 1: paclitaxel 200 mg/m2 + carboplatin AUC 6 q3w for 6 cycles

• Arm 2: paclitaxel + carboplatin + bevacizumab 15mg/kg q3 weeks. Chemotherapy was given for 6 cycles. Bevacizumab was given until disease progression.


• Carboplatin: inhibits DNA synthesis by the formation of DNA

crosslinks

• Paclitaxel: inhibits depolymerization of tubulin therefore inhibiting DNA, RNA and protein synthesis.

Primary Endpoint

• OS


• Stage IIIB or stage IV non-squamous NSCLC

• No prior chemotherapy

• ECOG0or1

• No prior hemoptysis 1⁄2 teaspoon or more

• No bleeding diathesis or coagulopathy

• No therapeutic anticoagulation

• No regular use of aspirin > 325mg/day, NSAIDs or other inhibitors of platelet function

• No radiation therapy within 21 days prior to enrollment

• No surgery within 28 days prior to enrollment

• No CNS metastasis


Results

• Survival: mOS Arm 1: 10.3months, Arm 2: 12.3months (s)

• OS 1y 44% arm 1 51% arm 2[NNT 17]

• OS 2y 15 arm 1 23% arm 2 [NNT 12]

• PFS: Arm 1: 4.5months, Arm 2: 6.2months

• Quality of Life: not reported.

Toxicity

• Common grade 3 or higher side effects: neutropenia, hypertension, proteinuria, bleeding events

• Rates of clinically significant bleeding were significantly higher in the bevacizumab group (4.4% vs 0.7%). [NNH 27]

• Treatment-related deaths were higher in the bevacizumab group, including 5 deaths from pulmonary hemorrhage.

Conclusion

• Bevacizumab added to carboplatin and paclitaxel resulted in improved overall survival in advanced NSCLC patients with an increased risk of treatment-related death.

Other Comments

Prospective randomized trial of docetaxel versus best supportive care in patients with non-small- cell lung cancer previously treated with platinum-based chemotherapy.Shepherd FA et al. J Clin Oncol. 2000 May;18(10):2095-103.

Regimen

• Arm 1: docetaxel 100mg/m2 + best supportive care (BSC)

• Arm 2: docetaxel 75mg/m2 in 1 hr q3w + BSC

• Arm 3: BSC alone


• Docetaxel: inhibits depolymerization of tubulin therefore inhibiting DNA, RNA and protein synthesis.

Primary Endpoint

• OS


• Unresectable locally advanced or metastatic NSCLC

• ECOG </= 2

• Must have received prior therapy with a platinum-containing chemotherapy regimen

• No brain mets

• No peripheral neuropathy greater than grade 2


Results

• Survival:

• Arm 1: docetaxel 100mg/m2 – mOS 5.9 months (ns)

• Arm 2: docetaxel 75mg/m2 – 7.5 months (s) Arm 3: BSC – 4.6 months OS 1y 11% BSCà37% Docet (75 mg/m2) [NNT 6]

• TTP: TTP was longer for docetaxel patients (10.6 weeks) compared to BSC (6.7 weeks).

• RR: ORR for docetaxel patients was 5.8%. Partial response rate was 7.1% for docetaxel.

• Quality of Life: Improved QOL was seen for docetaxel patients in comparison to BSC patients

Toxicity • Febrile neutropenia, cytopenias

• Asthenia, diarrhea, cardiac side effects

Conclusion • Docetaxel treatment results in an improved overall survival. At a dose of 75mg/m2 of docetaxel, the benefits outweigh the risks.

Other Comments

Other Important Published Data: (e.g. meta-analysis, retrospective analyses, phase II)

Meta-analysis studying platinum-doublet chemotherapy vs best supportive care in advanced NSCLC: NSCLC Meta-Analyses Collaborative Group. Chemotherapy in addition to supportive care improves survival in advanced non-small-cell lung cancer: a systematic review and meta-analysis of individual patient data from 16 randomized controlled trials. J Clin Oncol. 2008;26(28):4617.

BSC +/- Chemo; 16 RCT; n= 27149 % absolute improvement in SV at 12 months OS 1y 20à29%

Bevacizumab studies:

Reck M, von Pawel J, Zatloukal P, et al: Phase III Trial of Cisplatin Plus Gemcitabine With Either Placebo or Bevacizumab As First-Line Therapy for Nonsquamous Non-Small-Cell Lung Cancer: AVAiL. J Clin Oncol 27: 1227-1234, 2009.

Reck M, von Pawel J, Zatloukal P, et al: Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous non-small-cell lung cancer: results from a randomized phase III trial (AVAiL). Annals of Oncology 21: 1804-1809, 2010.

n=1043CDDP-Gemc x 6 cycles + Bev 7.5 mg/kg or Bev 15 mg/kg or Plac Endpoint= PFSHR 0.75 (s) Bev 7.5 mg/kg and HR 0.85 (ns) Bev 15 mg/kgNo difference in mOS in the 2 arms (all > 13 m)

Maintenance therapy:

1. Maintenance Pemetrexed - Paz-Ares LG, de Marinis F, Dediu M, et al:

PARAMOUNT: Final Overall Survival Results of the Phase III Study of Maintenance Pemetrexed Versus Placebo Immediately After Induction Treatment With Pemetrexed Plus Cisplatin for Advanced Nonsquamous Non-Small-Cell Lung Cancer. J Clin Oncol 31:2895-2902, 2013.

Advanced NSCLCPem-CDDP x 4àif not PDàmaintenance pem vs placebo N=939à539 pt without PD were randomized 2:1Mean number of maintenance cycles = 7.9mOS maint 13.0 vs 11mOS 1y 45à58% [NNT 8]OS 2y 21à32% [NNT 9]

2. Maintenance Erlotinib – Cappuzzo F et al. Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: a multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol. 2010 Jun;11(6):521-9.SATURN study

CDDP based chemo x 4àif not PDàerlotinib vs placebo any EGFR statusN= 1948ànot PD 889Endpoint PFS

mPFS 12.3 weeks erlo vs 11.1 weeks plac (s)!!!! irrespective of EGFR status AE Grade 3 or more: rash 9%, diarrhea 2%.

3. Coudert et al. SATURN investigators. Survival benefit with erlotinib maintenance therapy in patients with advanced non-small-cell lung cancer according to response to first-line chemotherapy. Ann Oncol 2012 23:388-394.N=889 (same patients as prior report)

Erlotinib increased PFS regardless of prior response but OS was prolonged in SD group only irrespective of EGFR mutation status.

Elderly patients:

The Elderly Lung Cancer Vinorelbine Italian Study Group: Effects of Vinorelbine on Quality of Life and Survival of Elderly Patients With Advanced Non-Small-Cell Lung Cancer. J Natl Cancer Inst 91:66-72, 1999.ELVIS study

Stabe IIIB and IV NSCLC 70 yo or older, ECOG 0-2 Vinorelbine monotherapy x 6 cyclesStopped early due to low enrollmentOS 1y 14à32% (s) [NNT 6]

HR: 0.65

Quoix E et al. Carboplatin and weekly paclitaxel doublet chemotherapy compared with monotherapy in elderly patients with advanced non-small-cell lung cancer: IFCT-0501 randomised, phase 3 trial. Lancet. 2011 Sep 17;378(9796):1079-88.IIIB or IV NSCLC, ECOG 0-2, 70-89 yo

Carbo-pacli x 4 cycles of 4w (weekly pacli) or vinorelbine monotherapy or gemc monotherapy (monotherapy was 2 weeks on one week off) x 5 cycles of 3w.N=451mOS 10.3 m for doublet vs 6.2m for monotherapy (s)

OS 1y 25% monotherapyà44.5% with doublet (s)

Second line and beyond:

1. Hanna N, Shepherd FA, Fossella FV, et al: Randomized Phase III Trial of

Pemetrexed Versus Docetaxel in Patients With Non-Small-Cell Lung Cancer Previously Treated With Chemotherapy. J Clin Oncol 22: 1589-1597, 2004.2nd

line N=571Pem (vit B12 and folic acid) vs DocetBoth OS 1y 29%Equivalent efficacy outcomes but pemetrexed was better tolerated

2. Garassino MC, Martelli O, Broggini M, et al: Erlotinib versus docetaxel as second-line treatment of patients with advanced non-small-cell lung cancer and wild-type EGFR tumours (TAILOR): a randomized controlled trial. Lancet

Oncology 14: 981-988, 2013.2nd linestage IV wild-type EGFR after platinum based chemoErlo po vs docet (q 21 d or weekly plan)N=222mOS 8.2 Docet vs 5.4 erlotinib (ns) [Note: HR included 1.0 and p=0.05 à it was ns but the

authors conclude that chemo is more effective then erlo in 2nd line NSCLC wild type EGFR tumors]

3. Shepherd FA et al. Erlotinib in previously treated non-small-cell lung cancer. N

Engl J Med. 2005;353(2):123.2nd lineIIIB or IV NSCLC N=731 pt randomized 2:1 vs placebo PFS 1.8 mà2.2 m (s)OR 8.9% erlotinibmOS 4.7à6.7 m (m) HR 0.7

5% d/c erlotinib due to AEsMore responses were associated with: Non smokers, adenocarcinoma, EGFR+In multivariate analysis OS was associated with treatment with erlotinib, adenocarcinoma and never smoked.EGFR was not predictive of better OS

4. Brahmer J et al. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(2):123. CheckMate 0172nd

line Nivolumab 3mg/kg q2w vs docet 75mg/m2 q3wn=272 mOS 6 m docetaxel vs 9.2 m with nivolumab HR 0.59 (s)OS 1 year 24% docetà42% Nivo (s)PFS 2.8 m docet vs 3.5 m Nivo (s)Expression of PD-1 ligand (PD-L1) was neither prognostic nor predictive of benefit Nivo was better tolerated than docetaxel. All histology was included and also brain mets

5. Borghaei H et al. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015;373(17):1627. CheckMate 0572nd

line Non squamous NSCLCNivo vs docet (similar doses to CheckMate 017) N=582mOS 9.4m docet vs 12.2m Nivo OS 1y 39% docet vs 51% NivoOR 12% docet vs 19% NivoNo difference in PFS (2.3 vs 4.2 m)

METASTATIC NSCLC DRIVER MUTATION POSITIVE


Epidermal growth factor receptor (EGFR) gene mutation positive patients:

First line therapy: Epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) therapy until disease progression or intolerable toxicity. Osimertinib (third generation) is the front line choice of therapy. Either gefitinib or afatinib are also EGFR TKI’s frequently used. Recently published data of second generation TKI Dacomitnib shows improved PFS compared to Gefitinib (it was not compared to osimertinib) however it is not approved by Health Canada and is still a submission under review (June 2018)

Resistance to EGFR TKI’s/Second-line therapy: Resistance to EGFR TKI’s (first and second generation) generally develops 9 to 18 months after an initial dramatic response. About 60% of these cases of resistance are due to development of a secondary T790M mutation, which inhibits EGFR TKI binding. Osimertinib is an irreversible EGFR TKI selective for both EGFR and T790M resistance mutations. Osimertinib is the preferred approach to treatment in T790M mutation positive patients with resistance to EGFR TKI.

Third-line therapy: Refer to Section on “METASTATIC NSCLC DRIVER MUTATION NEGATIVE, first-line therapy”.

Anaplastic lymphoma kinase (ALK) gene mutation positive patients (2-7%):

First-line therapy: Alectinib (an ALK inhibitor) therapy until disease progression or intolerable toxicity2. However, crizotinib is frequently used as alectinib is not funded in all provinces first line at this time.

Second-line therapy/Resistance to crizotinib: Ceritinib is an ALK inhibitor that is more potent than crizotinib3. Alectinib can also be used.

c-ROS oncogene 1 mutation positive patients:

Treatment with crizotinib is recommended for patients with a ROS mutation4. Further investigation is being done on other second generation inhibitors.


• FLAURA Osimertinib in Untreated EGFR-Mutated Advanced Non–Small-

Cell Lung Cancer • N Engl J Med 2018; 378:113-125 DOI: 10.1056/NEJMoa1713137

Regimen Front line Osimertinib vs Investigators choice Gefitinib or

Erlotinib Mechanism of Action of Experimental Drug

• Osimertinib: Irreversible epidermal growth factor receptor

tyrosine kinase inhibitor

Primary Endpoint • Primary endpoint PFS


•Included: adenocarcinoma, exon 19 del or L858R

Excluded: ILD, cord compression, unstable brain mets

Size (N) • 556 patients, 1:1 randomization

Results Median PFS with osimertinib was 18.9 months vs. 10.2 months with first generation EGFR TKIs

Toxicity Adverse events of grade 3 or higher were less frequent with osimertinib than with standard EGFR-TKIs (34% vs. 45%)

Conclusion Front osimertinib improves PFS with reduced g3/g4 adverse events

Other Comments

Crossover allowed

Iressa Pan-Asian Study (IPASS): Gefitinib or Carboplatin–Paclitaxel in Pulmonary AdenocarcinomaMok T et al. N Engl J Med 2009; 361:947-957

Regimen

• Gefitinib 250mg po per day vs carboplatin AUC 5-6mg/mL/min iv and paclitaxel 200mg/m2 D1 q3w x 6 cycles


• Gefitinib: inhibits EGFR TKI

• Carboplatin: attaches an alkyl group to DNA bases to interrupt DNA/RNA synthesis and forms crosslinks

• Paclitaxel: inhibits depolymerization of tubulin therefore inhibiting DNA, RNA and protein synthesis.

Primary Endpoint

• PFS


• Previously untreated Asian patients with advanced lung adenocarcinoma who were nonsmokers or former light smokers

Size (N)

• 1217 patients

Results

• PFS/TTP: 12 month PFS 24.9% in gefitinib group vs 6.7% in carboplatin-paclitaxel group; subgroup analysis showed longer PFS ONLY for EGFR mutation positive patients.

• No difference in median OS (22 months for both) likely

secondary to significant crossover.

• RR: 43% in gefitinib group vs 32% in carbo-paclitaxel group, RR was much different for gefitinib in the EGFR positive

vs EGFR negative groups (71% vs 1.1%)

• QOL: There was a clinically relevant improvement in QOL in the gefitinib group when compared to the carbo-paclitaxel group.

Toxicity

• Rash, Acne, Diarrhea in gefitinib group

• Neurotoxicitiy, neutropenia, alopecia in carbo-paclitaxel group

Conclusion • Gefitinib prolongs PFS over chemo especially in EGFR positive patients.

Other Comments • (e.g. criticisms about the study)

EURTAC: Erlotinib versus standard chemotherapy as first-line treatment for European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a multicentre, open-label, randomised phase 3 trial.Rosell R. Lancet Oncol. 2012 Mar;13(3):239-46.

Regimen

• Erlotinib 150mg per day vs. standard chemo (either cisplatin plus docetaxel or cisplatin plus gemcitabine. Carboplatin was allowed in patients who could not have cisplatin).


• Erlotinib: inhibits EGFR TKI

• Cisplatin/carboplatin: attaches an alkyl group to DNA bases to interrupt DNA/RNA synthesis and prevents formation of crosslinks

• Docetaxel: inhibits depolymerization of tubulin therefore inhibiting DNA, RNA and protein synthesis.

• Gemcitabine: arrests DNA replication by replacing cytidine, a

nucleic acid

Primary Endpoint • PFS


• Non-Asian patients with NSCLC and EGFR mutations, no prior history of chemotherapy for metastatic disease, ECOG < 3


Results

• Survival: mOS 19.3 vs 19.5 (ns)

• PFS: 9.7 mos in erlotinib groups vs 5.2 mos in standard chemo group (s)

• Response Rate: 18% vs 64%

• Quality of Life: not done.

Toxicity

• Rash, Acne, Diarrhea in gefitinib group

• Neurotoxicitiy, neutropenia, alopecia in carbo-paclitaxel group

Conclusion

• This study further strengthened the rationale for routine baseline tissue-based assessment of EGFR mutations in patients with NSCLC and for treatment of mutation-positive patients with EGFR tyrosine-kinase inhibitors.

Other Comments

• Insufficient patient response to QOL assessment.

Alectinib versus Crizotinib in Untreated ALK-Positive Non–Small-Cell Lung Cancer

Peters et al. NEJM June 6, 2017

Regimen • Either alectinib (600 mg twice daily) or crizotinib (250 mg twice daily) until progression or intolerable toxicity


• Alectinib, a highly selective inhibitor of anaplastic lymphoma kinase (ALK), has shown systemic and central nervous system (CNS) efficacy in the treatment of ALK-positive non–small-cell lung cancer (NSCLC).

Primary Endpoint • Investigator assessed PFS


• Patients with previously untreated, advanced ALK-positive NSCLC

Size (N) • N=303

Results

• During a median follow-up of 17.6 months (crizotinib) and 18.6 months (alectinib), an event of disease progression or death occurred in 62 of 152 patients (41%) in the alectinib group and 102 of 151 patients (68%) in the crizotinib group.

• The rate of investigator-assessed progression-free survival was significantly higher with alectinib than with crizotinib (12-month event-free survival rate, 68.4% [95% confidence interval (CI), 61.0 to 75.9] with alectinib vs. 48.7% [95% CI, 40.4 to 56.9] with crizotinib; hazard ratio for disease progression or death, 0.47 [95% CI, 0.34 to 0.65]; P<0.001); the median progression-free survival with alectinib was not reached.

• The results for independent review committee–assessed progression-free survival were consistent with those for the primary end point. A total of 18 patients (12%) in the alectinib group had an event of CNS progression, as compared with 68 patients (45%) in the crizotinib group (cause-specific hazard ratio, 0.16; 95% CI, 0.10 to 0.28;

P<0.001).

• A response occurred in 126 patients in the alectinib group (response rate, 82.9%; 95% CI, 76.0 to 88.5) and in 114 patients in the crizotinib group (response rate, 75.5%; 95% CI, 67.8 to 82.1) (P=0.09).

Toxicity • Grade 3 to 5 adverse events were less frequent with alectinib (41% vs. 50% with crizotinib) – better tolerated esp. with eye symptoms and other GI S/E

Conclusion • As compared with crizotinib, alectinib showed superior efficacy and lower toxicity in primary treatment of ALK-positive NSCLC

AURA3: Osimertinib or Platinum-Pemetrexed in EGFR T790M-Positive Lung Cancer

Mok T et al. NEJM December 6, 2016.

Regimen

• Randomized 2:1 to Osimertinib 80 mg daily vs. platinum-pemetrexed (Pemetrexed 500mg/m2 plus either Carboplatin AUC 5 or Cisplatin 75mg/m2 q 3 weeks for up to 6 cycles).


• Osimertinib: TKI that inhibits T790M and EGFR

• Cisplatin/carboplatin: attaches an alkyl group to DNA bases to interrupt DNA/RNA synthesis and prevents formation of crosslinks

• Pemetrexed: antifolate as above.

Primary Endpoint • PFS


• Advanced or metastatic NSCLC

• Disease progression on first-line EGFR TKI

• Presence of an EGFR mutation AND T790M mutation

• CNS mets were included


Results

• Overall survival: not mature yet.

• PFS: 10.1 mos in osimertinib group vs 4.4 mos in platinum-pem group; HR PFS 0.30 (s)

• Response Rate: 71% vs 31%

• Quality of Life: patient-reported outcomes were reported as better in the osimertinib group.

Toxicity

• Rash, Diarrhea, decreased appetite, cough in osimertinib

group

• Neurotoxicitiy, nausea, cytopenia in platinum-pem group

Conclusion

• Osimertinib improves PFS in patients with T790M mutation who have progressed on first-line EGFR TKI. This includes patients with CNS mets.

• Other Important Published Data: (e.g. meta-analysis, retrospective analyses, phase II)

Afatanib: Sequist LV, Yang JC-H, Yamamoto N, et al: Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations. JCO 31: 3327-3334, 2013 LUX-Lung 3 studyIIIB/IV adenocarcinoma EGFR mutatedAfatinib 40 mg po vs CDDP-pem x 6 cyclesEndpoint

PFSN=345mPFS 6.9m chemo vs 11.1 m afatinib (s)mPFS with exon 19 del and L858R EGFR mutations was 13.6m afatinib vs 6.9 m chemo (s)AES: diarrhea, rash/acne, stomatitisOS ns65% cross over

ALK positive trials:

1. ALK positive patients: 16. Shaw A, Kim D-W, Nakagawa K, et al: Crizotinib versus Chemotherapy in Advanced ALK-Positive Lung Cancer. NEJM 368: 2385-2394, 2013Locally advanced or IV ALK positive lung cancer2nd line after CDDP plan Critotinib 250 mg bid po vs cheo (pem or docet) Endpoint PFSmPFS 3m chemo 7.7. m crizotinib (s)OR chemo 20% vs 65% crizotinib

2. First line Crizotinib vs chemo in advanced ALK-positive Lung Cancer . Solomon et al. PROFILE 1014 trial. NEJM 2014; 371: 2167.Phase 3AlK positive advanced nonsquamous NSCLC

1st linen=343crizotinib 250 mg bid vs chemo (pem-CDDP or pem- carbo) x 6 cycles. Endpoint PFSPFS 7m chemo vs 10.9 m crizotinibOR 45% chemo vs 74% crizo. Median OS not reached in crizotinib group, 45.8 to 47.5mos in the cheme group. OS at 4 years 56.5% vs 49.1% in favor of crizotinib.

3. Ceritinib: Kim DW, Mehra R, Tan DS, et al. Ceritinib in advanced anaplastic

lymphoma kinase (ALK)- rearranged (ALK+) non-small cell lung cancer (NSCLC): Results of the ASCEND-1 trial (abstract 8003). 2014 American Society of Clinical Oncology (ASCO) meeting. Published: NEJM 2014; 370: 1189 Phase 1

N=59 ALK + NSCLCMaximum tolerated dose was 750 mg/dDLT: diarrhea, vomiting, dehydration, elevated liver enzymes, hypophosphatemiaThen expanded with additional 71 pts114 pts that received at least 400 mg ceritinib/dàOR 56% and mPFS 7m.Authors conclude ceritinib is highly active in pts with advanced ALK-rearranged NSCLC including those that progressed during crizotinib treatment.

4. ASCEND-2: Crino et al. JCO 2016; 34: 2866-2873. Multicenter Phase II study of whole-body and intracranial activity with ceritinib in patients with ALK-rearranged NSCLC previously treated with chemotherapy and crizotinib: results from ASCEND-2.N=140 ALK+ mets NSCLC, inc brain mets . Max dose 750mg/d of ceritinibORR 38.6%, median duration of response = 9.7mos, PFS 5.7mos Intracranial response rate = 45%.

5. Brigatinib in Patients With Crizotinib-Refractory Anaplastic Lymphoma Kinase–Positive Non–Small-Cell Lung Cancer: A Randomized, Multicenter Phase II Trial;

DOI: 10.1200/JCO.2016.71.5904 Journal of Clinical Oncology 35, no. 22 (August 1 2017) 2490-2498.Results: Investigator-assessed median progression-free survival was 9.2 months and 12.9 months in arms A (90mg brigatinib) and B (180mg Brigatinib), respectively. Brigatinib yielded substantial whole-body and intracranial responses as well as robust progression-free survival;

ROS1 positive trials:

Crizotinib for ROS mutation positive patients: Mazières J et al. Crizotinib therapy for advanced lung adenocarcinoma and a ROS1 rearrangement: results from the EUROS1 cohort. J Clin Oncol. 2015;33(9):992.1% lung adenocarcinomas are driven by ROS1 rearrangement Retrospective study of stabe IV lung adenocarcinoma that had ROS1 rearrangement according to FISH and had received crizotinib (off-label us)N=3265% women

68% never-smokersOR 80%mPFS 9.1mPFS at 1y 44%Authors conclude crizotinib was highly active in treating lung cancer with ROS1 rearrangement.

nsclc updated august 2017 by dr. kirstin...

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