Pimitespib for the Treatment of Advanced Gastrointestinal Stromal tumors and Other Tumors

Figures & data

Infographic: A PDF version of this infographic is available as supplemental material.

Table 1. Cancer-associated proteins that are clients of heat shock protein 90 chaperones.

Function	Client proteins
Receptor tyrosine kinases	Human epidermal growth factor receptor (HER) 2 Mutant epidermal growth factor receptor (EGFR) v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue (KIT) Fms-related tyrosine kinase 3 (FLT3) Vascular endothelial growth factor receptor (VEGFR) Insulin-like growth factor-1 receptor (IGF1R) MET proto-oncogene (MET) Platelet-derived growth factor receptor-α (PDGFRA)
Signal transduction proteins	v-raf-1 murine leukemia viral oncogene homolog 1 (RAF1) Mutant v-Raf murine sarcoma viral oncogene homologue B1 (BRAF) v-akt murine thymoma viral oncogene homolog (AKT) IκB kinase (IKK) v-src avian sarcoma (Schmidt-Ruppin A-2) viral oncogene homolog (SRC)
Transcription factors	Hypoxia-inducible factor (HIF) 1 α Oestrogen receptor-α (ER-α) Androgen receptor (AR)
Cell-cycle proteins	Cyclin-dependent kinase (CDK) 4 CDK6 Cyclin D
Others	Human telomerase reverse transcriptase (hTERT) Matrix metalloproteinase (MMP) 2

Figure 1. The chemical structure of pimitespib.

Figure 2. Inhibition of HSP90 prevents the correct folding of client proteins and leads to their degradation.

ATP: Adenosine triphosphate; CDK: Cyclin-dependent kinase; EGFR: Epidermal growth factor receptor; HER2: Human epidermal growth factor receptor 2; HIF-1: Hypoxia-inducible factor 1; HSP 90: Heat shock protein 90; KIT: V-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homologue; PDGFR: Platelet-derived growth factor receptor.

Table 2. Binding affinity of HSP90 inhibitors for proteins in the HSP90 family.

Compound	Binding affinity (Ki, nmol/l)
	HSP90α	HSP90β	GRP94	TRAP-1
Pimitespib	34.7 ± 8.4	21.3 ± 3.0	>50,000	>50,000
Tanespimycin	10.0 ± 1.3	6.6 ± 0.3	19.9 ± 4.2	968.4 ± 405.0
Alvespimycin	5.8 ± 0.5	4.8 ± 0.4	12.6 ± 1.0	110.7 ± 14.7
Luminespib	4.5 ± 0.1	3.2 ± 0.1	27.0 ± 2.6	71.8 ± 4.8
BIIB021	6.1 ± 0.9	5.5 ± 0.3	117.6 ± 23.7	101.9 ± 5.1
SNX-2112	11.5 ± 1.8	9.0 ± 0.5	720.2 ± 22.1	533.1 ± 58.0

GRP94: 94-kDa glucose-regulated protein; HSP90: Heat shock protein 90; Ki: Inhibition constant; TRAP-1: Tumour necrosis factor receptor-associated protein 1.

Reused from [29] copyright holder: The American Association for Cancer Research.

Figure 3. Mean ± standard deviation levels of pimitespib or luminespib in rat xenograft models after administration of pimitespib 12.0 mg/kg PO or luminespib 20.0 mg/kg iv.

iv.: Intravenously; PO: Orally.

Table 3. Key patient characteristics, study end points and treatment-related adverse events seen in the phase II and III studies with pimitespib.

	Phase II study [41]	Phase III study [44]
	Pimitespib (n = 40)	Placebo (n = 28)	Pimitespib (n = 58)
Patient characteristics
Age, years, median (IQR)	62 (51–70 ^† )	61.5 (51.0–68.5)	62.0 (55.0–70.0)
ECOG performance status, n (%)
0	28 (70.0)	24 (85.7)	49 (84.5)
1	12 (30.0)	4 (14.3)	9 (15.5)
Previous treatments, n (%)
3	19 (47.5)	15 (53.6)	40 (69.0)
≥4	21 (52.5)	13 (46.4)	18 (31.0)
Primary tumour site, n (%)
Small intestine	21 (52.5)	18 (64.3)	33 (56.9)
Stomach	15 (37.5)	9 (32.1)	19 (32.8)
Other	4 (10.0)	1 (3.6)	6 (10.3)
Dose intensity, %, median (IQR)	71.9 (55.9–89.4)	98.6 (92.8–100.0)	83.3 (63.2–99.0)
Major end points
PFS, months, median (95% CI)	4.4 (2.8–6.0)	1.4 (0.9–1.8)	2.8 (1.6–2.9)
HR for PFS (95% CI)	–	0.51 (0.30–0.87) ^¶
OS, months, median (95% CI)	11.5 (7.0–NR)	9.6 (5.5–NR)	13.8 (9.2–NR)
HR for OS (95% CI)	–	0.63 (0.32–1.21)
OS using RPSFT model, months, median (95% CI)	–	7.6 (5.3–14.9)	13.8 (9.2–NR)
HR for OS using RPSFT model (95% CI)		0.42 (0.21–0.85) ^#
DCR ^‡ , % (95% CI)	85.0 (70.2–94.3)	35.7 (18.6–55.9)	62.1 (48.4–74.5)
Treatment-related AEs occurring in ≥10% of patients
Diarrhoea	32 (80.0)	4 (14.3)	43 (74.1)
Decreased appetite	18 (45.0)	2 (7.1)	18 (31.0)
Creatinine increased	17 (42.5)	2 (7.1)	15 (25.9)
Nausea	16 (40.0)	3 (10.7)	14 (24.1)
Eye disorders	8 (20.0)	0	8 (13.8) ^§
Anaemia	5 (12.5)	0	5 (8.6)
Malaise	5 (12.5)	3 (10.7)	15 (25.9)

† Range.

‡ Stable disease lasting ≥6 weeks.

§ Night blindness.

¶ p = 0.006.

# p = 0.007.

AE: Adverse events; DCR: Disease control rate; ECOG: Eastern Cooperative Oncology Group; HR: Hazard ratio; IQR: Interquartile range; NR: Not reached; OS: Overall survival; PFS: Progression-free survival; RPSFT: Rank-preserving structural failure time.

Doi T, Kurokawa Y, Sawaki A et al. Efficacy and safety of TAS-116, an oral inhibitor of heat shock protein 90, in patients with metastatic or unresectable gastrointestinal stromal tumour refractory to imatinib, sunitinib and regorafenib: a phase II, single-arm trial. Eur. J. Cancer 121, 29–39 (2019).

 PubMed Web of Science ®Google Scholar

Kurokawa Y, Honma Y, Sawaki A et al. Pimitespib in patients with advanced gastrointestinal stromal tumor (CHAPTER-GIST-301): a randomized, double-blind, placebo-controlled Phase III trial. Ann. Oncol. 33(9), 959–967 (2022).

 PubMed Web of Science ®Google Scholar