# Presentation: 709176

## ASCO/FDA Workshopon Lung Cancer EndpointsAlexandria, VAApril 15, 2003

- Renzo Canetta, M.D.
- Vice President
- Life Cycle Management and Clinical Design & Evaluation Oncology
- Bristol-Myers Squibb
- Pharmaceutical Research InstituteWallingford, CT, USA

## Worldwide Endpointsfor Approval in Lung Cancer

- US
- Europe
- Japan

- Overall survival in randomized trials is the accepted standard for all recent approvals
- An intermediate position:  randomized trials usually required, but other endpoints (i.e. RR, TTP and QoL) and/or methodologies (i.e. meta-analyses) utilized
- Objective response rate in non-randomized trials (with independent committee assessment) for all recent approvals

## Drugs Specifically Approved for NSCLC

## Drugs Specifically Approved for SCLC

## Drugs Generically Approved for Lung Cancer (or Bronchogenic Carcinoma)

## Registrational Trials for Taxol in NSCLC: Classical EndpointsCombinations with Cisplatin

**Study #****	****Design****	****RR (%)****	****TTP (mos.)****	****OS (mos).**
- -165	HD-Taxol/cisplatin	30	4.9	10.0
- ECOG	vs.	**p<0.001**	**p=0.0042**	p=0.0785*
- (n=599)	Etoposide/cisplatin	14	2.7	7.4
- 		LD-Taxol/cisplatin	26	4.3	9.3
- 		vs.	**p=0.003**	**p=0.0504**	p=0.1253*
- 		Etoposide/cisplatin	14	2.7	7.4
- -103	Taxol/cisplatin	36	5.0	9.9
- EORTC	vs.	**p=0.031**	p=0.7229	p=0.8024
- (n=332)	Teniposide/cisplatin	25	5.1	9.5
- -208	Taxol/cisplatin	24	4.3	8.1
- Gatzemeier	vs.	**p=0.047**	p=0.085**	p=0.862
- (n=414)	Cisplatin	16	3.2	8.6
**When Taxol arms were pooled:  9.7 vs. 7.4 mos., ****p=0.0492***
***********When secondary therapy considered progression:  4.1 vs. 2.7 mos., ****p=0.0259***

## Study #	Design	Superior Outcome*

-165	HD Taxol/cisplatin	
ECOG	vs.
(n=599)	Etoposide/cisplatin

		LD Taxol/cisplatin	Lung cancer symptoms (p=0.027)
		vs.
		Etoposide/cisplatin

-103	Taxol/cisplatin	Functioning:  physical (p=0.002), role (p=0.021), social (p=0.030); 
EORTC	vs.	global health status (p=0.022); fatigue (p=0.017)
(n=332)	Teniposide/cisplatin	Peripheral neuropathy (p=0.008)

-208	Taxol/cisplatin	Functioning:  physical (p=0.054); nausea & vomiting (p=0.0003);
Gatzemeier	vs.	appetite loss (p=0.020); constipation (p=0.032)
(n=414)	Cisplatin	Peripheral neuropathy (p=0.0001); hair loss (p=0.0001)

*For ECOG:  FACT-L; for EORTC and Gatzemeier:  EORTC QLQ-30, LC-13

- -165	HD Taxol/cisplatin
- ECOG	vs.
- (n=599)	Etoposide/cisplatin
- 		LD Taxol/cisplatin	Lung cancer symptoms **(p=0.027)**
- 		vs.
- 		Etoposide/cisplatin
- -103	Taxol/cisplatin	Functioning:  physical **(p=0.002),** role **(p=0.021)**, social **(p=0.030)**;
- EORTC	vs.	global health status **(p=0.022)**; fatigue **(p=0.017)**
- (n=332)	Teniposide/cisplatin	Peripheral neuropathy **(p=0.008)**
- -208	Taxol/cisplatin	Functioning:  physical (p=0.054); nausea & vomiting **(p=0.0003)**;
- Gatzemeier	vs.	appetite loss **(p=0.020)**; constipation **(p=0.032)**
- (n=414)	Cisplatin	Peripheral neuropathy **(p=0.0001)**; hair loss **(p=0.0001)**
**For ECOG:  FACT-L; for EORTC and Gatzemeier:  EORTC QLQ-30, LC-13*

***Registrational Trials for Taxol in NSCLC: Quality of Life******Combinations with Cisplatin***

## Registrational Trials for Taxol in NSCLC: Classical EndpointsSingle Agent

**Study #****	****Design****	****RR (%)****	****TTP (mos.)****	****OS (mos).****	****% 1-yr.**
- -224**	Taxol	15	3.9	6.8	31
- Thatcher	vs.		**p=0.0001*****	****p=0.0373**
- (n=157)	BSC	--	0.5	4.8	28
- -029	Taxol	17	2.1	4.4	40
- ECOG	vs.
- (n=118)	Merbarone	2	1.2	4.4	18
- 		vs.
- 		Piroxantrone	2	1.5	5.9	21
- 			**p=0.034****	****p=0.021**	p=n.s.
- -123	Taxol	20	--	--	--
- Yoneda (n=15)
- -186 A	Taxol	32	--	7.5	22
- Furuse (n=60)
- -186 B	Taxol	38	--	11.2	48
- Sekine (n=61)
**When censoring for secondary therapy: 4.0 vs. 1.2 months, ****p=0.0001***
***Quality of Life (Rotterdam Symptom Checklist) favored Taxol for functional activity ****(p=0.043)**** *
*   **and BSC for physical score (p=0.060)*

## Japan:Examples of Registrational Trials (1990-2000) in NSCLC*

**Agent****	****Author****	****Pts.****	****RR%****	****OS (wks.)**
- Docetaxel	Kunitoh	75	18.6	42	Kudoh	72	25.0	-
- Gemcitabine	Takada	73	26.0	44	Yokoyama	67	20.9	39
- Paclitaxel	Furuse	60	31.6	30	Sekine	61	38.0	49
- Vinorelbine	Furuse	79	29.1	40
- Irinotecan	Fukuoka	72	31.9	41
**From Fukuoka, IASLC 2001*

## Japan:  Examples of Phase IV Commitments in NSCLC

**Study #****	****Design****	****RR (%)****	****TTP (mos.)****	****% 1-yr.**
- A		Vindesine/cisplatin	21.8	49.6	47.6
- (n=203)	vs.		p=0.586
- 		Irinotecan/cisplatin	28.6	44.7	42.6
- B		Vindesine/cisplatin	31.7	45.6	38.3
- (n=380)	vs.
- 		Irinotecan/cisplatin	43.7	50.0	46.5
- 		vs.
- 		Irinotecan	20.5	46.0	41.8
- 				p=0.115*
- C		Irinotecan/cisplatin
- (n=602)	vs.
- 		Gemcitabine/cisplatin
- 		vs.
- 		Vinorelbine/cisplatin
- 		vs.
- 		Paclitaxel/carboplatin
**For stage IV subset:  36.4 vs. 50.0 vs. 42.1 weeks, ****p=0.004***

- RESULTS TO BE PRESENTED
- AT ASCO (JUNE 2003)
- AND IASLC (AUGUST 2003)