FRACP teaching 2007

• 50 year old man with 50 pack year smoking. PS is normal (ECOG 1). Investigations show he has a non-small cell carcinoma stage T2N1M0. His exercise tolerance is unrestricted and his bloods are normal. What would be considered the most appropriate treatment for him?

• A. Surgery

• B. Radical radiotherapy

• C. Combined chemo/RT

• D. Surgery followed by adjuvant chemotherapy

• E. Downstaging with (neoadjuvant) chemo followed by surgery

NSCLC – Staging

NSCLC – Staging

• A. Surgery

• B. Radical radiotherapy

• C. Combined chemo/RT

• D. Surgery followed by adjuvant chemotherapy

• E. Downstaging with (neoadjuvant) chemo followed by surgery

Answer

• D. Resection followed by adjuvant chemotherapy

Chemotherapy in NSCLC: A Meta-analysis using updated data on individual patients from 52 randomised clinical trials.Early Disease: Surgery versus Surgery plus Chemotherapy

Alkylating agents

Other agents

Cisplatin-based

Overall

• 5% improvement in survival at 5 years (P=0.08) with cisplatin-based postoperative chemotherapy

NSCLC Collaborative Group BMJ 1995; 311: 899-909

Cisplatin-based

Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected NSCLC:

The IALT Trial

• 1867 pts

• Complete resection

• Pathological Stage I, II or IIIA NSCLC

• Observation

• (post-operative thoracic radiotherapy given to 28% of pts)

• Cisplatin 80-100 mg/m2 for 3-4 doses

• Given with etoposide (57% of pts) or vinorelbine (27% of pts)

• (post-operative thoracic radiotherapy given to 23% of pts)

The International Adjuvant Lung Cancer Trial Collaborative Group. New England Journal of Medicine 2004; 350:4 351-360.

Cisplatin-Based Adjuvant Chemotherapy in Patients with Completely Resected NSCLC:

The IALT Trial

• Absolute 5-year survival benefit was 4.1% (P = 0.03)

• RT given to <25% pts• Compliance achieved

in 74% pts• Chemo mortality <1%

The International Adjuvant Lung Cancer Trial Collaborative Group. New England Journal of Medicine 2004; 350:4 351-360.

Is this therapy proven?• Efficacy

– 5% improvement in 5 yr survival demonstrated in stage II and III by independent studies, JBR10 and ANITA (platinum and vineralbine) but also LACE metanalysis pooled data from 5 adjuvant cisplatin trials

– Evidence in stage I is lacking and not currently recommeded

• Safety– Treatment regimens are well established– <1% treatment-related mortality in postoperative

NSCLC patients• Statistics

– Conventional levels of significance now achieved

Are the benefits clinically significant?

• Cisplatin-based Postoperative Adjuvant Chemotherapy in NSCLC– Absolute survival increased by 5% at 5 years

– NNT, 25 pts treated to prevent 1 death

– Estimated to prevent >7,000 deaths/year worldwide

• Postoperative Adjuvant Breast Cancer Chemo– Absolute survival increased by 3.3% at 5 years and 6.3% at 10

years

• Thoracic radiotherapy and PCI for SCLC– Absolute survival benefit of 5.4% at 3 years

Review Sashidharan et al NZ Med J 2006 119 1245

• A 53 year with a 45 pack year smoking history presents with haemoptysis and wt loss of 2%. A CT scan shows a RLL tumour with mediastinal nodes and 2 lesions in the liver. ECOG PS = 0-1. The patient is offered palliative chemotherapy in the for of Carboplatin/paclitaxel. Which of the following statements about chemo in NSCLC are true.

• The likely response rate is 50% with median survival 18 months

• The likely response rate is 20-30% with median survival 7-9 months

• The response rate is in the order of 10-15% and med survival 5 months

• There is no role for chemotherapy for NSCLC (and all Oncologists who offer this type of therapy are mad).

Chemotherapy in NSCLC: A Meta-analysis using data from 52 RCTs. Extensive disease. Chemotherapy v Best

Supportive Care

Cisplatin based Chemotherapy

overall

Cisplatin

Alkylating agents

Other agents

Median survival improvement 6 weeks p < 0.001

NSCLC Collaborative Group BMJ 1995; 311: 899-908

ECOG 1594: A randomised, phase III four arm trial in advanced NSCLC

(Shepard et al ASCO 2000)

RR(%) Med 1 yr(%)

Pac/Cis 21 7.8 31

Gem/Cis 21 8.1 36

Doc/Cis 17.3 7.4 31

Pac/Carbo 15.3 8.2 35

Ist law of Oncology

“Tumour must shrink faster than patient”

All studies tend to be in “fit” patients PS 0-1 with generally improvement in survival and QOL

PS > 2 very few trials

Elderly patients only single agent vineralbine assessed and tolerated well “ELVIS” study

Role second and 3rd line chemo

NSCLC response rates decrease with subsequent regimens of chemotherapy

0

5

10

15

20

25

1st 2nd 3rd 4th Last

Objective response rate (%)

Massarelli et al 2003

Line of therapy

20.9

16.3

2.30.0

2.3

Lung Cancer Screening

• Which of the following statements on screening for lung cancer in an at risk smoking group is correct

A. CT screening is no more sensitive than CXR or sputum analysis

B. CT screening shown to improve survival and reduce mortality from lung cancer in smokers

C. CT screening shown to improve survival but not mortality

D. Screening for lung cancer is now well established and recommended

Answer

• B CT screening has been shown to improve survival but not evidence reduce mortality from lung cancer in smokers

Lung Cancer Screening

• CT screening more sensitive than CXR (ELCAP I) detection rate 2.7% v 0.7% Henscke et al lancet 1999;345:99-105

• Improved survival but not mortality (ELCAP I)• Result however may be due to over diagnosis and lead

time bias• ELCAP II international study screened 31,567 at risk

individuals NEJM 2006: 355:1763-71

• Estimated 10 yr survival of 302 who were resected 92% compared with 80% for all 484 patients

ELCAP CT screening

Henschke et al NEMJ 2006; 355:1763-71

Copyright restrictions may apply.

Bach, P. B. et al. JAMA 2007;297:953-961.

Combined Results from 3 centres of Lung Cancer Screening With Computed Tomography

• Screening not currently standard practice• Early detection may alter survival but not

mortality• Mayo data suggests good survival of screened

individuals may be due to over diagnosis (picking up good prognosis tumours) and lead time bias (earlier detection but not alter outcome)

• Awaiting results of large RCTs of CT v CXR

• A 42 non smoking asian woman presents with wt loss and coughing a CXR shows a 4 cm RUL lesion and liver mets. An FNA shows a NSCLC with the profile of a lung primary

Which of the following are correct?

1) The cytological profile is likely to be that of an adenocarcinoma

2) The tumour is likely to respond to an EGFRI (erlotinib, gefitinib) if there is evidence of EGFR mutation

3) The correct treatment would be a combination of EGFR and chemo concurrently

4) Standard treatment would be platinum based chemo (and consider 2nd line EGFRI)

• Correct answers are 1 ,2 and 4

Responsiveness to EGFR inhibitors (gefitinb (Iressa) and erlotinib (tarceva) correlates with

– female gender,

– non smoker,

– adenocarcinoma histology,

– Asian ethnicity

– Mutations in the EGFR genePaez et al, Science. 2004 304: 1497-1500

Franklin et al, ASCO 2004

• 8/9 (89%) of patients with striking responses to IRESSA (>50% tumour shrinkage) had tumours with EGFR-TK mutations compared to none in 7 who did not respond

• Over 30 somatic mutations in the EGFR-TK domain (exons 18-24) have been observed in primary tumour biopsies from patients with NSCLC

Lynch et al, NEJM 2004 Paez et al, Science 2004

EGFR-TK mutations and response to gefitinib (IRESSA)

Activating Mutations in the Epidermal Growth Factor Receptor Underlies the Responsiveness of NSCLC to Gefitinib

Lynch TJ et al. New England Journal of Medical 2004 350; 21 (20 May 2004)Paez et al Science 2004 online; Marx J Science 2004 ; 304: 658-9

EGFR mutations

• Activation Mutated EGFR is more intense and prolonged than wild type

• stabilise interaction between EGFR-TK and ATP (or competitive inhibitor gefitinib)

• Lower concentration gefitinib will completely inhibit mutant receptor cf wild type

Paez et al, science 2004; 304, 1497-1500

Lynch et al, NEJM; 2004; 101, 2129-2139

Combination therapies

Phase III RCT

Chemo ± EGFR TKI stage III or stage IV disease• INTACT I Gefitinib ± Gem/cis• INTACT II Gefitinib ± Carbo/taxol• TRIBUTE Erlotinib ±Carbo/taxol• TALENT Erlotinib ± Gem/cis

• Conclusion: no increase in survival in patients receiving combination treatment

Combination therapy

Why did the combination (INTACT) trials fail?

• Chemo and EGFR-TKI may be antagonistic (Similar to antagonism demonstrated with tamoxifen and chemo in breast cancer)

• EGFR-TKI have antiproliferative effects with p27-mediated G1 cell-cycle arrest of EGFR which could render tumour cells less sensitive to cytotoxic agents

BR.21 Study Design

RANDOM I SE

Erlotinib* 150 mg daily

Placebo “150 mg”

daily

*2:1 Randomization

Previously Treated NSCLC

Stratified by:Centre

PS, 0/1 vs 2/3Response to prior Rx (CR/PR:SD:PD)

Prior regimens, (1 vs 2)

Prior platinum, (Yes vs no)

BR.21 Study Endpoints and Statistical Considerations

• Primary endpoint survival• Median survival of untreated patients was estimated

to be 4 months• Goal: detect an improvement in median survival of

33% (HR 0.75) • 90% power and a 2-sided 5% level test• 700 patients required to enter the study over 14

months with 6 months follow-up; 582 events required

BR.21 Overall Survival

*HR and p-value adjusted for stratification factors at randomisation + HER1/EGFR status

42.5% improvement in median survival

Su

rviv

al d

istr

ibu

tio

n f

un

ctio

n

Survival time (months)

erlotinb

Placebo

HR* = 0.73, p<0.001

TarcevaTM (n=488)

Placebo (n=243)

Median survival (months) 6.7 4.7

1-year survival (%) 31 21

1.00

0.75

0.50

0.25

00 5 10 15 20 25 30

Survival benefit with Tarceva according to EGFR biomarker status

n HR CI p value* p value†

EGFR mutation status

Wild-type‡ 177 0.75 0.53–1.07 0.110.45

Mutant§ 24 0.52 0.21–1.31 0.16

EGFR expression (IHC)

IHC +ve 184 0.68 0.49–0.95 0.020.25

IHC –ve 141 0.93 0.63–1.36 0.70

Gene copy number (FISH)

Low 69 0.86 0.48–1.51 0.590.10

High 56 0.44 0.2–0.82 0.008

*p value for subgroup compared with placebo†p value for interaction‡Includes indeterminate variants§Exon 19 deletions and L858R

Tsao M-S, et al. N Engl J Med 2005;353:133–44Tsao M-S, et al. N Engl J Med 2006;354:527–8

Responsiveness to EGFR inhibitors (gefitinb (Iressa) and erlotinib (tarceva) correlates with

– female gender, non smoker, adenocarcinoma histology, Asian ethnicity, Mutations in the EGFR gene

– Effective following chemotherapy as 2nd line therapy and no benefit concurrently

Paez et al, Science. 2004 304: 1497-1500

Franklin et al, ASCO 2004

Which of the following is not correct

1. This CT is most compatible with mesothelioma?

2. This could represent other pleural malignancy such as metastatic adenocarcinoma

3. The cells are cytokeratin and EMA positive but TTF-1 negative is this compatible with the diagnosis?

4. There is no standard treatment for this tumour5. Treatment requires the addition of B12 and

folate

The Gemcitabine/Cisplatin Combination in Mesothelioma

Author Byrne1 Nowak2 Van Haarst3

SWOG4

Patients

21 53 25 44

Gemcitabine 1000 1000 1250 1000

mg/m2 d 1,8,15 d 1,8,15 d 1,8 d 1,8,15

CDDP mg/m2 100d1 100 d1 q21D q28D

Schedule q28D q28D q21D q28D

Response 48% 33% 16% 9%

Survival 9.5 mo 11.2 mo 9.6 mo NA

1Byrne, JCO 1999; 17:25 2Nowak, Br J Ca 2002; 87:491 3van Harrst, Br J Ca 2002: 86:342 4K Antman, personal communication

Phase II Trial of Pemetrexed in MM

Dose 500mg/m²Patients: 64Partial Response Rate: 14%Median time to progression: 4.7 monthsMedian survival: 10.7 months1 year survival: 47.8%Grade 3/4 neutopenia: 23%

Scagliotti JOC 2003

pemetrexed and platinum

• Pemetrexed 600mg/m²and cisplatin 75mg/m²

• 11 patients

• RR 5/11 45%

• 7 gd 3/4 neutropenia

Calvert et al, 2000

Treatment for MM

• Largest contolled study in treatment of MM• Cis/pemetrexed currently the most active

combination trialed for MMshowing a survival advantage

• Cis/pemetrexed new standard treatment for MM in many countries

• Needs addition folate and B12 in view toxicity