SITC 2021 - AIPAC Poster

Hans Wildiers1, Anne Armstrong2, Eveline Cuypere3, Florence Dalenc4, Luc Dirix5, Steve Chan6, Frederik Marme7, Carolina Pia Schröder8, Jens Huober9, Jill Wagemans10, Peter Vuylsteke11, Jean-PhilippeJacquin12, Etienne Brain13, Sherko Kümmel14, Zsuzsanna Pápai15, Christian Mueller16, Chrystelle Brignone17 and Frederic Triebel17

Final results from AIPAC: A phase IIb trial comparing eftilagimod alpha (soluble LAG-3 protein) in combination with weekly paclitaxel in HR+ HER2- MBC

Abstract # 948

1Department of General Medical Oncology and Multidisciplinary Breast Centre, Leuven, Belgium, 2The Christie NHS Foundation Trust, Manchester, UK, 3AZ Sint-JanBurgge-Oostende AV, Ruddershove, Belgium, 4Institut Claudius Regaud, Toulouse, France,5GZA ziekenhuizen campus Sint-Augustinus, Oosterveldlaan, Belgium, 6Nottingham Cancer Clinical Trials Team (NCCTT), Nottingham, UK, 7National Center for Tumor Diseases (NCT) Heidelberg, Heidelberg, DE, 8University Medical Center Groningen, Groningen, Netherlands, 9Universitätsfrauenklinik Ulm, Ulm, Germany 10AZ Sint-Maarten, Mechelen, Belgium, 11Clinique Sainte-Elisabeth, Uccle, Belgium, 12Institut de Cancérologie de la Loire (ICO) Lucien Neuwirth, Saint Priest en Jarez, France, 13 Institut Curie -Hôpital René Huguenin, Saint-Cloud, France, 14KEM | Evang. Kliniken Essen-Mitte, Essen, Germany, 15MH Egészségügyi Központ Onkológiai Osztály, Budapest, Hungary, 16Clinical Development, Immutep, Berlin, Germany, 17Research & Development, Immutep, Paris, France

BACKGROUND

PATIENT DISPOSITION & EXPOSURE

EFFICACY - OVERALL POPULATION

Figure 1. efti's mechanism of action	Eftilagimod alpha (efti) is a soluble LAG-3
	protein targeting a subset of MHC class II
	molecules, thus mediating antigen
	presenting cell (APC) and CD8 T-cell
	activation (Figure 1). Such stimulation of
	the dendritic cell network and resulting T
	cell recruitment may lead to stronger anti-
	tumor responses in combination with
	paclitaxel than observed with paclitaxel
	alone. We report the final results from the
	randomized part of the AIPAC (Active
	Immunotherapy PAClitaxel NCT02614833)
	study in metastatic breast carcinoma
	(MBC) patients.

METHODS

Study Design and Patients

Multicenter, placebo-controlled,double-blind, 1:1 randomized Phase IIb study in female hormone receptor-positive metastatic breast cancer patients.

The randomized stage consisted of a chemo-immunotherapy phase followed by a maintenance phase. Patients received 80 mg/m2 paclitaxel i.v. days 1, 8, 15 plus efti/placebo s.c. days 2 and 16 up to 24 weeks and then efti/placebo s.c. every 4 weeks (Figure 2).

Figure 2. Study design

• 227 patients were randomized to efti (N=114) or to placebo (N=113) between January 2017- July 2019. All except one patient received at least 1 dose of study medication and were included in the full analysis and safety populations.

Table 1. Baseline disease characteristics and prior therapy

	Efti + Paclitaxel	Placebo + Paclitaxel	Overall
	N=114	N=112	N=226
Baseline characteristics, n (%)
Age, median (range), years	58 (24-87)	61 (35-79)	60 (24-87)
<65 years	76 (66.7)	71 (63.4)	147 (65.1)
Body mass index, median (range)	24.7 (18.1-48.1)	24.9 (15.4-44.5)	24.7 (15.4-48.1)
ECOG 0	69 (60.5)	70 (62.5)	139 (61.5)
Visceral disease	103 (90.4)	104 (92.9)	207 (91.6)
Luminal A / B / Other¶, %	34.1 / 48.8 / 17.1	36.7 / 49.4 / 13.8	35.5 / 49.1 / 15.4
Monocytes <0.25/nl	25 (21.9)	22 (19.8)	47 (20.9)
Elevated (>250 U/L) LDH	74 (65.5)	81 (73.0)	155 (69.2)
Prior therapy, n (%)
Prior surgery	92 (80.7)	94 (83.9)	186 (82.3)
Prior radiotherapy	87 (76.3)	84 (77.7)	174 (77.0)
Prior systemic therapy	106 (93.0)	108 (96.4)	214 (94.7)
Prior adjuvant therapy	85 (74.6)	81 (72.3)	166 (73.5)
Prior therapy for metastatic disease	78 (68.4)	80 (71.4)	158 (69.9)
Prior taxanes (adjuvant)	51 (44.7)	43 (38.4)	94 (41.6)
Prior CDK4/6	50 (44.6)	50 (43.9)	100 (44.2)
Prior endocrine therapy	103 (90.4)	104 (92.9)	207 (91.6)
Endocrine resistant	85 (82.5)	89 (85.6)	174 (84.1)
Last therapy prior to inclusion, n (%)

• All patients were HR+ and HER/neu- as per local assessment with majority as luminal B1 (49.1%) and luminal A (35.5%) as per central assessment (Table 1).
• Subjects were heavily pre-treated with a median of 2 prior systemic anticancer regimens. Patients were predominantly endocrine resistant (84%), while 44.2% were pre-treated with CDK4/6 inhibitors and received prior palliative therapy (74.8%)
• Treatment exposure for paclitaxel was similar between arms with mean dose intensity of 93%. A total of 60 (52.6%) efti and 54 (48.2%) placebo patients completed the chemo-immunotherapy phase (Figure 3).

Figure 3. Subject disposition

Figure 5. Kaplan-Meier curve for OS in the overall population

Table 3. Post-study treatments

Post-study anticancer	Efti + Paclitaxel	Placebo + Paclitaxel
systemic treatment	N=114	N=112
Any	95 (83.3)	100 (89.3)
Chemotherapy based	80 (70.2)	86 (76.8)
Endocrine therapy based	54 (47.4)	40 (35.7)

Figure 6. Global Health Status/ QoL QLQC30-B23

10

baseline	5

	0		*
from
Change	-5
	-10
		3 months	6 months
	Number of subjects
	107	75	48
	107	79	52

Figure 7. Mean ± SEM of absolute count of CD8 T cells* prior next dosing

blood)of	P-value 0.006	0.047
400	✱	✱
cells/L	300
(million	200
cellsT	100
CD8	0
	Baseline	3 months	6 months

At database cut-off (14 May 2021) for final analysis(73% events), minimum follow-up was 22 months:

• Numerical increase in OS: +2.9 months from median of 17.5 (95%
  CI: 12.9-21.9) in placebo to 20.4 (95% CI: 14.3 -25.1) in the efti group (Figure 5).
• HR 0.88 for OS overall (95% CI: 0.64-1.19; p=0.197).
• ORR and PFS by BICR was not updated during final analysis.
• Post-studytreatment similar: patients received chemotherapy 70.2% (efti) vs. 76.8% (placebo) or endocrine therapy 47.4 % (efti) vs. 35.7 % (placebo) (Table 3)
• Significant deterioration of QoL (QLQ-C30-B23) observed in the placebo group at 6 months. No deterioration with efti (Figure 6).
• Efti significantly increased CD8 T cells compared to placebo

(Figure 7). (Note: Blood samples were taken 2 weeks after last dosing and prior to next dosing, showing the minimal residual effect.)

• Increase in pre-dose CD8 T cells is significantly correlated to increased overall survival (Figure 8).

Figure 8. Correlation between cytotoxic CD8 T cells and OS

months		900	Placebo	Rho= -0.2; p= 0.5
6 )	700	30 mg efti	Rho= 0.6; p= 0.007
at blood	500
countcell	of
(10
	/L
6
		300
T
CD8		100
		10	20	30	40	50

Overall survival (months )

None	6	(5.3)	4	(3.6)	10 (4.4)
Adjuvant/curative	25	(21.9)	22	(19.6)	47 (20.8)

EFFICACY - UNIVARIATE/MULTIVARIATE ANALYSIS

EFFICACY - SUBGROUP <65 YEARS

Assessments and Statistical Analyses

Palliative

83 (72.8)

86 (76.8)

169 (74.8)

• Central assessment performed on available and evaluable primary or metastatic tissues (n=169). Classified using PgR and Ki67 index according to St Gallen International Expert Consensus guidelines1.
  Defined according to ESMO Internal Consensus Guidelines (Advanced Breast Cancer 4)2.

• Through exploratory multivariate analyses, poor prognostic markers using baseline characteristics were analyzed in a Cox model using backward selection (p<0.15). Prior CDK4/6 and higher BMI at baseline were found to be independent significant poor prognostic markers for both PFS and OS. Other markers were found solely for PFS or OS.
• Median OS for patients pre-treated with CDK4/6 was reduced to 14.9 months in the placebo group and remained at 20.2 months for the efti group.

• Cut off <65 years was defined prior to unblinding and showed significant (p=0.017, one-sided) improvement in OS with a HR of 0.66 (95% CI: 0.45-0.97) and median increase of 7.5 months (Figure 10). Within this subgroup, all poor prognostic markers from multivariate analyses were equally distributed between the placebo and efti groups.

Figure 10. Kaplan-Meier curve for OS in patients <65 years of age

• The effect of age upon survival was investigated through exploratory analysis in 10-year increments. Age had an

• Primary Endpoint: Progression-free survival (PFS) based on blinded independent central review (BICR) - RECIST1.1.

• Secondary Endpoints: Overall survival (OS), safety and tolerability, PFS based on investigator review, overall response rate (ORR), time to next treatment (TTNT), duration of response

(DOR), quality of life (QoL), presence of antidrug antibodies (ADAs).

• Exploratory Endpoints: Blood immune cell phenotypes (CD8 T cells) and circulating Th1 biomarkers.

• Safety was analyzed in all patients who received at least one dose of study medication.

Figure 9. Forest plot for OS/PFS from univariate analysis (defined prior unblinding) significant for OS or significant predictive in multivariate analysis

almost linear effect on HR for OS. Figure 11 displays HR point estimates for different age groups. Point estimate of HR for OS flips to >1 in the age group ≥65 and <75 years.

• Efficacy was analyzed in all patients with measurable disease at baseline who received at least one dose of any study medication.

• Database cut-off date was May 14, 2021.

SAFETY

• 2 (1.8%) patients in the efti group and 3 (2.7%) patients in the placebo group had fatal

TEAEs - no fatal TEAE related to efti (see Table 2).

Figure 4. Most common TEAEs (≥15%)

• 3 patients discontinued due to hypersensitivity reactions developing after efti injections and 4 patients due to paclitaxel-induced hypersensitivity.
• Most common efti-related adverse event was any kind of local injection-related reaction (grade 1-3), reported in 75 (65.8%) patients in the efti arm compared to 13 (11.6%) in the placebo arm (Figure 4).

Figure 11. OS HR point estimates for different age groups

Table 2. Summary of treatment-emergent adverse events
Summary of treatment-emergent adverse events	Efti + Paclitaxel	Placebo + Paclitaxel
(N=114);	(N=112);
(TEAEs)
	N (%)	N (%)
≥1 TEAE		113	(99.1)	112	(100)
TEAE leading to death	2	(1.8)	3	(2.7)
≥1 TEAE leading to efti/placebo discontinuation	6	(5.3)	7	(6.3)
≥1 TEAE ≥3 Grade	78	(68.4)	73	(65.2)
ADA…anti-drug antibodies	CTCAE…Criteria for Adverse Events	GGT… gamma-glutamyltransferase	PgR… progesterone receptor	1. Goldhirsch A, Winer EP, Coates AS, et al. 2013;24(9):2206-2223. doi:10.1093/annonc/mdt303
APC… antigen-presenting cell	DCR … disease control rate		HR+… hormone receptor-positive	PFS… progression free survival	2. Cardoso F, et al. 2018;29(8):1634-1657. doi: 10.1093/annonc/mdy192.
AST… aspartate aminotransferase	DOR… duration of response		i.v… intravenous		QoL… quality of life	*Pre-dose blood samples (selected patients) were collected prior to paclitaxel administration (i.e., 13 days
BICR… blinded independent central review ECOG… Eastern Cooperative Oncology	MBC…metastatic breast cancer	s.c… subcutaneous	after 6th/12th injection of placebo/efti) to monitor absolute counts of CD45+CD3+CD8+CD4- cytotoxic T cells by
CI… confidence interval	Group		ORR…overall response		TEAE…treatment-emergent adverse event	flow cytometry. Mean (±SEM, n=36/31 in placebo/efti group) is presented in the 2 arms at each timepoints.
CMH … Cochran Mantel-Haenszel	efti… eftilagimod alpha		OS…overall survival		TTNT… time to next treatment	Difference between two groups was tested by Wilcoxon rank sum tests.

• Exploratory univariate analysis (analysis groups defined prior unblinding) showed that younger patients (<65 years), those with low baseline monocytes (<0.25/nL) or breast cancer subtype luminal B had significant and clinical meaningful improvement in median OS compared to placebo (Figure 9).
• No prior taxanes and low monocytes were found to be significant (p<0.15) in an exploratory multivariate analysis using the multivariate prognostic model.

The AIPAC trial protocol has been published, see	First Author COI Hans Wildiers: Roche, TRM Oncology, Lilly, Pfizer, Sirtex,
Dirix, L. & Triebel, F. Future Oncol. 2019	AstraZeneca, PUMA Biotechnology, Vifor Pharma, ORION Corpora, Abbvie, Daiichi
Jun;15(17):1963-1973. The trial identifiers are	Sankyo, EISAI, KCE, Novartis, PSI Cro AG, MSD, Ariez, DNA Prime, The planning shop.
IMP321-P011 (code for sponsor), 2015-002541-63	This presentation is the intellectual property of the author/presenter. Contact
(EudraCT) and NCT02614833 (ClinicalTrials.gov).	[e-mail] for permission to reprint and/or distribute.

CONCLUSION

•	Efti added to paclitaxel led to a non-significant 2.9	•	Efti significantly increased circulating CD8 T cells,
	months median OS increase in predominantly		further significantly correlating to improved OS.
	endocrine-resistant HR+ HER2- MBC patients.	•	The overall safety profile remained consistent with
•	Effects were significant and clinically-meaningful		previous results with no new safety signals.
	(median improved between 4.2 and 19.6 months) for
	OS in younger patients (<65 years), those with low	→ Weekly paclitaxel + efti should be further investigated
	monocytes (<0.25/nl) or more aggressive disease	in a phase III HR+ MBC setting.
	(luminal B).