Can contemporary trials of chemotherapy for HER2-negative metastatic breast cancer detect overall survival benefit?

Figures & data

Table 1 Overview of trials included in the analysis. Trials are ordered according to date enrollment began (earliest first)

Trial	Recruitment period	Control arm (A)	Experimental arm (B)	Missing information for retrospective sample size calculation	Reported sample size calculation			Primary endpoint	Data cutoff for primary analysis	HR for PFS/TTP (95% CI)	HR for OS (95% CI)	Median duration of follow-up, months
					Assumed HR	Power, %	Events/patients
HEPI 013^Citation10	Sep 1990–Nov 1992	Cyclophosphamide, methotrexate, fluorouracil	Cyclophosphamide, epirubicin, fluorouracil	Yesa	0.73	80	155/420	TTP	NR	0.73 (0.59–0.92)	0.87 (0.70–1.10)	>20
SBG 9403^Citation11	Feb 1995–Jan 1999	Epirubicin	Vinorelbine + epirubicin	Yes	NR	NR	NR	PFS	NR	0.75 (0.61–0.92)	NR	42 (A)/43 (B)
Jassem et al 2001^Citation12	Nov 1996–Apr 1998	Fluorouracil, doxorubicin, cyclophosphamide	Doxorubicin + paclitaxel	Yesa	0.67	80	192/260	TTP	NR	0.74 (0.56–0.98)	0.68 (0.51–0.93)	29
von Minckwitz et al 2005^Citation13	Nov 1996–Sep 2001	Cyclophosphamide, methotrexate, fluorouracil	Bendamustine, methotrexate, fluorouracil	Yes	NR	NR	NR/296	TTP	NR	NR	NR	NR
Bontenbal et al 2005^Citation14	Mar 1997–Apr 2002	Fluorouracil, doxorubicin, cyclophosphamide	Doxorubicin + docetaxel	No	0.67	80	201/260	TTP	NR	0.67 (0.51–0.88)	0.70 (0.52–0.94)	27 (OS)/14 (TTP)
Albain et al 2008^Citation15	Aug 1999–Apr 2002	Paclitaxel	Gemcitabine + paclitaxel	No	0.75	80	377/526	OS	NR	0.70 (0.59–0.85)	0.82 (0.67–1.00)	NR
E2100^Citation16^–^Citation18	Dec 2001–May 2004	Paclitaxel	Bevacizumab + paclitaxel	No	0.75	85	546/685	PFS	Feb 9, 2005 (PFS)/Oct 21, 2006 (OS)	0.48 (0.40–0.61)	0.87 (NR)	NR
Sparano et al 2009^Citation19	Sep 2004–Nov 2006	Docetaxel	Pegylated liposomal doxorubicin + docetaxel	No	0.77	>80	485/720	TTP	NR	0.65 (0.55–0.77)	1.02 (0.86–1.22)	NR
RIBBON-1b,^Citation20,Citation21	Dec 2005–Aug 2007	Capecitabine	Bevacizumab + capecitabine	No	0.75	80	405/600	PFS	Jul 31, 2008	0.69 (0.56–0.84)	0.88 (0.69–1.13)	16 (PFS)/23 (OS)
AVADOc,^Citation22	Mar 2006–Apr 2007	Docetaxel	Bevacizumab + docetaxel	No	0.70	80	430/669	PFS	NR	0.77 (0.64–0.93)	1.03 (0.70–1.33)	25
ATX (BOOG 2006-06)^Citation23	Jun 2007–Dec 2010	Paclitaxel + bevacizumab induction, then bevacizumab maintenance	Paclitaxel + bevacizumab + capecitabine induction, then bevacizumab and capecitabine maintenance	No	0.81	80	NR/303	PFS	Apr 26, 2013	0.52 (0.41–0.67)	0.92 (0.72–1.19)	41
IMELDA^Citation24	Jul 2009–Mar 2011	Docetaxel + bevacizumab induction, then bevacizumab maintenance	Docetaxel + bevacizumab induction, then capecitabine + bevacizumab maintenance	No	0.70	80	244/290	PFS	Oct 4, 2013	0.38 (0.27–0.55)	0.43 (0.26–0.69)	30 (A)/32 (B)
MERiDiAN^Citation25,Citation26	Aug 2012–Dec 2013	Paclitaxel	Paclitaxel + bevacizumab	No	0.67	85	326/480	PFS	Nov 30, 2014 (PFS)/Apr 28, 2017 (OS)	0.68 (99% CI 0.51–0.91)	0.94 (0.75–1.18)	15 (PFS)/24 (A) and 23 (B) (OS)

Notes:

a Total study duration missing.

b Data reported for capecitabine cohort (anthracycline/taxane cohort not included because of heterogeneity of chemotherapy backbone).

c Data reported for comparison of bevacizumab 15 mg/kg vs placebo (bevacizumab 7.5 mg/kg not included in this analysis as there was no significant improvement in the primary endpoint) but events/patients for reported sample size calculations include all three treatment arms as reported in the statistical design section of the publication.

Abbreviations: NR, not reported; OS, overall survival; PFS, progression-free survival; TTP, time to disease progression.

Figure 1 Summary of PFS/TTP and OS HRs across trials. Vertical bars represent 95% CIs, except for MERiDiAN, which shows the 99% CI reported for this coprimary endpoint.

Abbreviations: OS, overall survival; PFS, progression-free survival; TTP, time to progression.

Table 2 Summary of trial outcomes

Trial	Total no of patients in trial	Observed median, months (arm A vs arm B)			Retrospectively calculated sample size		Factor (x)
		PFS	TTP	OS	PFS/TTP	OS	OS sample size/N	OS/(PFS/TTP) sample size
HEPI 013^Citation10	460	–	6.3 vs 8.7	18.2 vs 20.1	360	5,906	12.8	16.4
SBG 9403^Citation11	387	8.2 vs 10.1	–	18.0 vs 19.1	788	11,988	31.0	15.2
Jassem et al 2001^Citation12	267	–	6.2 vs 8.3	18.3 vs 23.3	506	1,402	5.3	2.8
von Minckwitz et al 2005^Citation13	345	–	6.7 vs 8.2	–	792	–	–	–
Bontenbal et al 2005^Citation14	216	–	6.6 vs 8.0	16.2 vs 22.6	1,022	476	2.2	0.5
Albain et al 2008^Citation15	529	–	4.0 vs 6.1	15.8 vs 18.6	168	1,404	2.7	8.4
E2100^Citation16,Citation17	722	5.8 vs 11.3	–	24.8 vs 26.5	74	10,396	14.4	140.5
Sparano et al 2009^Citation19	751	–	7.0 vs 9.8	20.6 vs 20.5	294	1,847,626	2460.2	6284.4
RIBBON-1^Citation20,Citation21	615	5.7 vs 8.6	–	22.8 vs 25.7	264	6,000	9.8	22.7
AVADOa,^Citation22	488	8.2 vs 10.1	–	31.9 vs 30.2	806	21,136	43.3	26.2
ATX (BOOG 2006-06)^Citation23	312	8.4 vs 11.2	–	23.1 vs 24.2	440	24,178	77.5	55.0
IMELDA^Citation24	185	4.3a vs 11.9a	–	23.7a vs 39.0a	32	214	1.2	6.7
MERiDiAN^Citation25,Citation26	481	8.8 vs 11.0	–	25.8 vs 28.8	866	6,728	14.0	7.8

Notes:

a Median values are not comparable with the other trials, first because PFS and OS were calculated from the time of randomization to maintenance therapy rather than the start of first-line therapy, and second because only patients with response or stable disease after induction therapy were included in the randomized population.

Abbreviations: OS, overall survival; PFS, progression-free survival; TTP, time to disease progression.

Figure 2 Additional patients required to show an OS benefit^a.

Note: ^aOne study¹⁹ is not shown on the figure as the numbers are so large (x=2,460.2, retrospectively calculated increase in sample size =1,846,875).

Abbreviation: OS, overall survival.

Table S1 Search strategy for identification of eligible trials

Set#	Searched for	Results
S1	MESH.EXACT.EXPLODE(“Breast Neoplasms”)	260,430
S2	ti,ab((breast OR mamma*) NEAR/2 (cancer* OR carcinoma* OR tumo* OR neoplasm* or neoplasm* or malignanc*)) AND dstat.exact(“Publisher” OR “In Process” OR “PubMed not MEDLINE” OR “In Data Review”)	32,411
S3	s1 or s2	292,808
S4	ti,ab(metasta* or mBC or dissemin* or spread or advanced) AND s3	66,764
S5	MESH.EXACT.EXPLODE(“Neoplasm Metastasis”) AND s3	31,899
S6	s4 or s5	78,519
S7	s6 AND rtype.exact(“Randomized Controlled Trial”)	2,832
S8	all(randomized) AND s6	5,803
S9	all(placebo) AND s6	475
S10	s7 or s8 or s9	5,920
S11	(s7 or s8 or s9) AND rtype.exact(“Clinical Trial, Phase III” OR “Clinical Trial, Phase II”)	969
S12	(ti,ab(phase p/2 III[*1] or phase p/2 3[*1] or phase p/2 II[*4] or phase p/2 2[*4]) AND s10)	1,468
S13	(s12) and (dstat.exact(“Publisher” OR “In Process” OR “PubMed not MEDLINE” OR “In Data Review”))	126
S14	(s11 or s13)	1,095
S15	((s11 or s13)) and (pd(2014-2018))	348

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Data availability

All data used for the analyses reported in this paper are taken from the cited publications.