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  • 1
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    Double PIK3CA mutations in cis increase oncogenicity and sensitivity to PI3Kα inhibitors
    American Association for the Advancement of Science (AAAS) ; 2019
    In:  Science Vol. 366, No. 6466 ( 2019-11-08), p. 714-723
    Details
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 366, No. 6466 ( 2019-11-08), p. 714-723
    Abstract: Some breast cancers harbor not one—but two— PIK3CA mutations, and this enhances their response to certain drugs.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
    URL: Article
    DOI: 10.1126/science.aaw9032
    RVK:
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    RVK:
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2019
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  • 2
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    ER +, HER2 − advanced breast cancer treated with taselisib and fulvestrant: genomic landscape and associated clinical outcomes
    Wiley ; 2023
    In:  Molecular Oncology Vol. 17, No. 10 ( 2023-10), p. 2000-2016
    Details
    In: Molecular Oncology, Wiley, Vol. 17, No. 10 ( 2023-10), p. 2000-2016
    Abstract: Taselisib is a potent β‐sparing phosphatidylinositol 3‐kinase (PI3K) inhibitor that, with endocrine therapy, improves outcomes in phosphatidylinositol‐4,5‐bisphosphate 3‐kinase catalytic subunit alpha ( PIK3CA )‐mutated ( PIK3CA mut) advanced breast cancer. To understand alterations associated with response to PI3K inhibition, we analysed circulating tumour DNA (ctDNA) from participants enrolled in the SANDPIPER trial. Participants were designated as either PIK3CA mut or PIK3CA no mutation was detected (NMD) per baseline ctDNA. The top mutated genes and tumour fraction estimates identified were analysed for their association with outcomes. In participants with PIK3CA mut ctDNA treated with taselisib + fulvestrant, tumour protein p53 ( TP53 ; encoding p53) and fibroblast growth factor receptor 1 ( FGFR1 ) alterations were associated with shorter progression‐free survival (PFS) compared to participants with NMD in these genes. Conversely, participants with PIK3CA mut ctDNA harbouring a neurofibromin 1 ( NF1 ) alteration or high baseline tumour fraction estimate experienced improved PFS upon treatment with taselisib + fulvestrant compared to placebo + fulvestrant. Broadly, alterations in oestrogen receptor (ER), PI3K and p53 pathway genes were associated with resistance to taselisib + fulvestrant in participants with PIK3CA mut ctDNA. Altogether, we demonstrated the impact of genomic (co‐)alterations on outcomes with one of the largest clinico‐genomic datasets of ER+, HER2−, PIK3CA mut breast cancer patients treated with a PI3K inhibitor.
    Type of Medium: Online Resource
    ISSN: 1574-7891 , 1878-0261
    URL: Issue
    URL: Article
    DOI: 10.1002/mol2.v17.10
    DOI: 10.1002/1878-0261.13416
    Language: English
    Publisher: Wiley
    Publication Date: 2023
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  • 3
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    Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).
    American Society of Clinical Oncology (ASCO) ; 2012
    In:  Journal of Clinical Oncology Vol. 30, No. 15_suppl ( 2012-05-20), p. 8531-8531
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 30, No. 15_suppl ( 2012-05-20), p. 8531-8531
    Abstract: 8531 Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic melanoma cohort, including the ocular subtype. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). Results: Enrollment to this cohort is complete (n = 77); all pts are unblinded. Baseline characteristics: median age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 30%; known BRAF mutation 32%; LDH ≥ 1.1 x upper limit normal 35%; bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the open-label Lead-in stage with 25 pts randomized to continue cabo (n=12) or to placebo (n=13). Median PFS from randomization was 5.7 months for cabo vs. 3 months for placebo (HR=0.3, p =0.055). Median PFS from Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 44%. Evidence of objective tumor regression was observed in 39/65 pts (60%) with ≥ 1 post-baseline tumor assessment including 11/23 pts (48%) with ocular melanoma. Two bone scan evaluable pts demonstrated partial resolution of bone lesions at wk 6 accompanied by pain relief. Most common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), and diarrhea (3%); one related Grade 5 AE of diverticular perforation and peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo, and high rates of PFS6 and objective tumor regression. The safety profile of cabo was comparable to that of other VEGFR TKIs.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/jco.2012.30.15_suppl.8531
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2012
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  • 4
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    SANDPIPER: Phase III study of the PI3-kinase (PI3K) inhibitor taselisib (GDC-0032) plus fulvestrant in patients (pts) with estrogen receptor (ER)-positive, HER2-negative locally advanced or metastatic breast cancer (BC) enriched for pts with PIK3CA- mutant tumors.
    American Society of Clinical Oncology (ASCO) ; 2017
    In:  Journal of Clinical Oncology Vol. 35, No. 15_suppl ( 2017-05-20), p. TPS1119-TPS1119
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 35, No. 15_suppl ( 2017-05-20), p. TPS1119-TPS1119
    Abstract: TPS1119 Background: As one of the most frequent genomic alterations in BC, PIK3CA mutations occur in ~40% of ER-positive, HER2-negative breast tumors. PIK3CA mutations may mediate resistance to endocrine therapies and promote growth and proliferation of tumors in BC. Taselisib is a potent and selective PI3K inhibitor that preferentially degrades mutant versus wild-type PI3Kα via a unique mechanism not seen with alpelisib and pictilisib. In PIK3CA-mutant BC cell lines, taselisib had enhanced activity. Confirmed partial responses were reported in pts with PIK3CA-mutant BC treated with taselisib either as a single agent or in combination with fulvestrant. Methods: SANDPIPER is a double-blind, placebo-controlled, randomized, phase III study, designed to evaluate the efficacy and safety of taselisib plus fulvestrant in pts with ER-positive, HER2-negative, PIK3CA-mutant locally advanced or metastatic BC. Postmenopausal pts will be randomized 2:1 to receive either taselisib (4 mg qd) or placebo in combination with fulvestrant (500 mg intramuscular on Days 1 and 15 of Cycle 1, and on Day 1 of each subsequent 28-day cycle). Pts must have had disease recurrence or progression during or after aromatase inhibitor treatment. Randomization will be stratified by visceral disease, endocrine sensitivity, and geographic region. SANDPIPER enriches for pts with PIK3CA-mutant tumors and a centrally assessed, valid cobas PIK3CA Mutation Test result in tumor tissue is required prior to enrollment; pts with PIK3CA-mutant tumors are randomized separately from those with non-mutant tumors. The primary efficacy endpoint is investigator-assessed progression-free survival in pts with PIK3CA-mutant tumors (estimated by Kaplan–Meier methodology). Other endpoints include overall survival, objective response rate, clinical benefit rate, duration of objective response, safety, pharmacokinetics, and patient-reported outcomes. Enrollment is open for pts with PIK3CA-mutant tumors. Target enrollment is 600 pts and 〉 300 patients have been enrolled. Clinical trial information: NCT02340221.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2017.35.15_suppl.TPS1119
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2017
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  • 5
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    Cabozantinib in Chemotherapy-Pretreated Metastatic Castration-Resistant Prostate Cancer: Results of a Phase II Nonrandomized Expansion Study
    American Society of Clinical Oncology (ASCO) ; 2014
    In:  Journal of Clinical Oncology Vol. 32, No. 30 ( 2014-10-20), p. 3391-3399
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 32, No. 30 ( 2014-10-20), p. 3391-3399
    Abstract: Cabozantinib (XL184), an oral inhibitor of multiple receptor tyrosine kinases such as MET and VEGFR2, was evaluated in a phase II nonrandomized expansion study in castration-resistant prostate cancer (CRPC). Patients and Methods Patients received open-label cabozantinib at daily starting doses of 100 mg or 40 mg until disease progression or unacceptable toxicity. The primary end point was bone scan response, defined as ≥ 30% reduction in bone scan lesion area. Other efficacy end points included overall survival, pain, analgesic use, and biomarkers. Results One hundred forty-four patients sequentially enrolled in either a 100-mg (n = 93) or 40-mg (n = 51) study cohort. Ninety-one patients (63%) had a bone scan response, often by week 6. Treatment resulted in clinically meaningful pain relief (57% of patients) and reduction or discontinuation of narcotic analgesics (55% of patients), as well as improvements in measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Improvements in each of these outcomes were observed in both cohorts: bone scan response in 73% and 45%, respectively; reductions in measurable soft tissue disease in 80% and 79%, respectively. Median overall survival was 10.8 months for the entire population. Most common grade 3 or 4 adverse events were fatigue (22%) and hypertension (14%). Fewer dose reductions because of toxicity were required in the 40-mg group. Conclusion The evidence suggests that cabozantinib has clinically meaningful activity in CRPC. Cabozantinib resulted in improvements in bone scans, pain, analgesic use, measurable soft tissue disease, circulating tumor cells, and bone biomarkers. Taken together, these phase II observations warrant further development of cabozantinib in prostate cancer.
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2013.54.5954
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2014
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  • 6
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    Abstract PD10-04: Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC)
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD10-04-PD10-04
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. PD10-04-PD10-04
    Abstract: Background: The MORPHEUS platform consists of multiple, global, open-label, randomized Phase Ib/II trials designed to gauge safety and identify early efficacy signals in treatment (tx) combinations across cancers. Within MORPHEUS, atezo (anti-PD-L1) was evaluated with ipat, an oral AKT inhibitor, with (M-HR+ BC) and without (M-TNBC) fulv. Methods: In 2 separate randomized trials, eligible immune checkpoint inhibitor naive pts with either 2L/3L HR+ chemotherapy-naive BC who had prior CDK4/6 inhibitor treatment or 2L TNBC, received atezo (840 mg D1, 15) with ipat (400 mg D1-21); pts with HR+ BC also received fulv monthly. Control tx for M-HR+ BC (NCT03280563) was fulv and for M-TNBC (NCT03424005) was capecitabine; given the adaptive nature of the MORPHEUS platform only some of the control arm pts were enrolled concurrently with pts in the ipat arms for M-HR+ BC. Primary endpoints were ORR (overall response rate; investigator-assessed RECIST 1.1) and safety. Progression-free survival (PFS) and overall survival (OS) were secondary endpoints. Results: Median duration of survival follow-up was 7.6 months for M-HR+ BC (data cutoff: Aug 2020) and 10.8 for M-TNBC (data cutoff: Mar 2021). In M-HR+ BC, none of whom received prior fulvestrant, 26 pts received atezo + ipat + fulv and 15 received fulv. Confirmed ORRs were 23.1% (95% CI: 9.0, 43.7) and 0% (95% CI: 0, 21.8), respectively. Median PFS was 4.4 mo (95% CI: 1.6, not evaluable) and 1.9 mo (95% CI: 1.6, 3.9), respectively. Updated survival data will be presented. Respectively, 61.5% and 20.0% of pts had Gr 3-4 AEs; no G5 AEs were observed; serious AEs (SAEs) occurred in 38.5% and 13.3% of pts; 7.7% and 0% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (73.0%), diarrhea (53.8%), nausea (42.3%), fatigue (26.9%), vomiting (23.1%), decreased appetite (19.2%), headache (15.4%), pyrexia (11.5%), hyperglycemia (11.5%), and aspartate aminotransferase (AST) increase (11.5%), in the combination arm; of these, rash (38.4%), diarrhea (7.7%), and AST increase (7.7%) included Grade 3-4 tx-related AEs. In M-TNBC, 29 pts received atezo + ipat and 24 received capecitabine. Confirmed ORRs were 3.4% (95% CI: 0.1, 17.8) and 20.8% (95% CI: 7.1, 42.2), respectively. Median PFS was 1.7 mo (95% CI: 1.5, 2.8) and 4.1 mo (95% CI: 2.3, 5.7), respectively. Median OS was 10.8 mo (95% CI: 7.0, 18.1) and 15.2 mo (95% CI: 14.4, 20.8). Gr 3-4 AEs were seen in 51.7% and 37.5% of pts, respectively; Gr 5 AEs were seen in 1 pt in the combination arm (encephalitis due to atezo). SAEs occurred in 51.7% and 16.7% of pts, respectively; 6.9% and 4.2% of pts had tx-related AEs leading to tx withdrawal. The most common tx-related AEs were rash (55.2%), diarrhea (48.3%), nausea (37.9%), pyrexia (31.0%), and fatigue (24.1%) in the combination arm; of these, rash (24.1%), fatigue (3.4%), and pyrexia (3.4%) included Gr 3-4 tx-related AEs. Biomarker data, including PI3K pathway status, PD-L1 and CD8-panCK expression, will also be presented. Conclusion: Atezo + ipat + fulv was tolerable with a preliminary efficacy signal in HR+ BC. Atezo + ipat had limited efficacy in biomarker unselected TNBC. Citation Format: Sara A. Hurvitz, Valentina Boni, Elizabeth Comen, Seock-Ah Im, Kyung Hae Jung, Sung-Bae Kim, Keun Seok Lee, Sherene Loi, Hope S. Rugo, Amir Sonnenblick, Melinda L. Telli, Kelly DuPree, Marcella Fasso, Ya-Chen Lin, Mina Nikanjam, Frauke Schimmoller, Xiaosong Zhang, Jing Zhu, Peter Schmid. Phase Ib/II open-label, randomized trial of atezolizumab (atezo) with ipatasertib (ipat) and fulvestrant (fulv) vs control in MORPHEUS-HR+ breast cancer (M-HR+ BC) and atezo with ipat vs control in MORPHEUS triple negative breast cancer (M-TNBC) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD10-04.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-PD10-04
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 7
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    Abstract A233: Cabozantinib (XL184), a dual MET-VEGFR2 inhibitor, blocks osteoblastic and osteolytic progression of human prostate cancer xenografts in mouse bone.
    American Association for Cancer Research (AACR) ; 2011
    In:  Molecular Cancer Therapeutics Vol. 10, No. 11_Supplement ( 2011-11-12), p. A233-A233
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 10, No. 11_Supplement ( 2011-11-12), p. A233-A233
    Abstract: Background: Prostate cancer bone metastases are associated with high levels of MET expression, and both HGF, the only known ligand for MET, and VEGF appear to direct crosstalk between tumor cells, osteoblasts (OBs), and osteoclasts (OCs). Cabozantinib (cabo), a dual MET-VEGFR2 inhibitor, has shown clinical activity in patients with metastatic castration-resistant prostate cancer (CRPC), where a complete or partial resolution of lesions on bone scans, reduced pain, and soft tissue tumor regression were observed in the majority of patients studied. Therefore, the preclinical effects of cabo were studied in the human CRPC bone xenograft model ARCaPM, which expresses both MET and the VEGF co-receptor neuropilin-1. In addition, the effects of cabo on the differentiation and activity of human OCs and mouse OBs were studied in vitro. Methods: ARCaPM cells were injected bilaterally into the tibiae of nude mice on Day 1, and on Day 31 animals received either cabo at 10 or 30 mg/kg (mpk) or vehicle once-daily for 7 weeks (wks). Animals (n=10 for each dose group) were sacrificed at the end of the treatment period and X-ray images of the tibiae were taken. Five representative tibiae per group were also scanned and analyzed by a Scanco 40 micro-CT instrument. In addition, one tibia from each mouse was fixed, decalcified and embedded for histology and histomorphometry analyzes. The OC culture system consisted of CD34+ cells derived from human bone marrow that were cultured on bovine bone slices in the presence of growth factors including M-CSF and RANK-L. The OB culture system used mouse KS483 cells that differentiate into OBs capable of forming mineralized bone nodules. Results: X-ray and micro-CT imaging of tibiae harvested after the 7 wk treatment period indicated that cabo treatment blocked both the osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone, with concomitant increases in bone mineral density. Histomorphometry data indicated that tumors were present in 70% (7/10) of the tibiae in the control group but only 30% (3/10) and 20% (2/10) in the 10 mpk and 30 mpk cabo groups, respectively. Consistent with its anti-tumor effect in the bone, cabo treatment decreased the ratio of tumor to tissue area and increased the bone area relative to the tissue area in the analyzed tibia sections compared to vehicle. Histological analyzes indicated an increase in the number of OBs and no change in the number of OCs along the trabecular bone perimeter of tibiae from cabo-treated animals relative to vehicle controls. In the in vitro studies, cabo treatment resulted in reduced OC differentiation in a dose dependent manner but did not affect the ability of mature OCs to resorb bone. In contrast, in the OB studies cabo treatment resulted in a biphasic effect inducing OB differentiation and bone forming activity at the lower doses while reducing these parameters at higher doses. Conclusions: Cabo treatment resulted in diverse effects on the differentiation and function of OBs and OCs in vitro, and blocked both osteoblastic and osteolytic progression of ARCaPM xenograft tumors in bone. These data demonstrate a substantial impact of cabo on tumor cells, OBs, and OCs consistent with the observed clinical results in patients with CRPC. Studies to characterize the molecular mechanisms underlying these effects are underway. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2011 Nov 12-16; San Francisco, CA. Philadelphia (PA): AACR; Mol Cancer Ther 2011;10(11 Suppl):Abstract nr A233.
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.TARG-11-A233
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
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  • 8
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    Abstract P3-03-01: Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P3-03-01-P3-03-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P3-03-01-P3-03-01
    Abstract: Activating mutations in PIK3CA, the gene coding for the catalytic subunit (p110α) of phosphoinositide-3-kinase (PI3K), are the most frequent oncogenic alterations in estrogen receptor-positive (ER+) breast cancer and are also prevalent in other tumor types. PI3Kα inhibitors including alpelisib have recently been shown to be clinically active in ER+ PIK3CA mutant breast cancer. To characterize determinants of sensitivity to these agents, we undertook a comprehensive analysis of PIK3CA mutant cancer genomes and observed the presence of double PIK3CA mutations in 12-15% of breast cancer and other tumor types. These double PIK3CA mutations are clonal, located in cis on the same allele, and are composed of a single hotspot mutation combined with a recurrent second-site mutation. Double PIK3CA mutations in cis result in increased PI3K activity and downstream signaling together with enhanced cell proliferation and tumor growth compared to single hotspot mutations. The biochemical mechanisms underlying this increased oncogenicity include increased disruption of p110α binding to the inhibitory subunit p85α, which relieves its catalytic inhibition, and increased membrane lipid binding. Finally, these double PIK3CA mutations predict for increased sensitivity to PI3Kα inhibitors compared to single hotspot mutations (e.g. E545K or H1047R) in experimental models and in patients with ER+ PIK3CA mutant metastatic breast cancer from the SANDPIPER randomized phase III clinical trial. These findings implicate double PIK3CA mutations in cis as a novel mechanism of oncogene addiction relative to single hotspot mutations, providing a rationale to develop PI3Kα inhibitors for the therapy of double PIK3CA mutant cancers. Citation Format: Neil Vasan, Pedram Razavi, Jared L Johnson, Hong Shao, Timothy Wilson, Frauke Schimmoller, Hardik Shah, Alesia Antoine, Erik Ladewig, Alexander Gorelick, Ting-Yu Lin, Eneda Toska, Guotai Xu, Abiha Kazmi, Matthew T Chang, Barry S. Taylor, Maura N. Dickler, Komal Jhaveri, Sarat Chandarlapaty, Raul Rabadan, Ed Reznik, Melissa L Smith, Robert Sebra, Lori Friedman, Lewis C Cantley, Maurizio Scaltriti, José Baselga. Double PIK3CA mutations in cis drive oncogene addiction and enhance sensitivity to PI3K alpha inhibitors in breast cancer [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-03-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P3-03-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 9
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    Multiple PIK3CA mutation clonality correlates with outcomes in taselisib + fulvestrant-treated ER+/HER2–, PIK3CA-mutated breast cancers
    Springer Science and Business Media LLC ; 2023
    In:  Genome Medicine Vol. 15, No. 1 ( 2023-04-26)
    Details
    In: Genome Medicine, Springer Science and Business Media LLC, Vol. 15, No. 1 ( 2023-04-26)
    Abstract: Mutations in the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), encoded by the PIK3CA gene, cause dysregulation of the PI3K pathway in 35–40% of patients with HR+/HER2– breast cancer. Preclinically, cancer cells harboring double or multiple PIK3CA mutations (mut) elicit hyperactivation of the PI3K pathway leading to enhanced sensitivity to p110α inhibitors. Methods To understand the role of multiple PIK3CA mut in predicting response to p110α inhibition, we estimated the clonality of multiple PIK3CA mut in circulating tumor DNA (ctDNA) from patients with HR+/HER2– metastatic breast cancer enrolled to a prospectively registered clinical trial of fulvestrant ± taselisib, and analyzed the subgroups against co-altered genes, pathways, and outcomes. Results ctDNA samples with clonal multiple PIK3CA mut had fewer co-alterations in receptor tyrosine kinase (RTK) or non- PIK3CA PI3K pathway genes compared to samples with subclonal multiple PIK3CA mut indicating a strong reliance on the PI3K pathway. This was validated in an independent cohort of breast cancer tumor specimens that underwent comprehensive genomic profiling. Furthermore, patients whose ctDNA harbored clonal multiple PIK3CA mut exhibited a significantly higher response rate and longer progression-free survival vs subclonal multiple PIK3CA mut. Conclusions Our study establishes clonal multiple PIK3CA mut as an important molecular determinant of response to p110α inhibition and provides rationale for further clinical investigation of p110α inhibitors alone or with rationally-selected therapies in breast cancer and potentially other solid tumor types.
    Type of Medium: Online Resource
    ISSN: 1756-994X
    URL: Article
    DOI: 10.1186/s13073-023-01181-8
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 10
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    Phase III study of taselisib (GDC-0032) + fulvestrant (FULV) v FULV in patients (pts) with estrogen receptor (ER)-positive, PIK3CA -mutant (MUT), locally advanced or metastatic breast cancer (MBC): Primary analysis from SANDPIPER.
    American Society of Clinical Oncology (ASCO) ; 2018
    In:  Journal of Clinical Oncology Vol. 36, No. 18_suppl ( 2018-06-20), p. LBA1006-LBA1006
    Details
    In: Journal of Clinical Oncology, American Society of Clinical Oncology (ASCO), Vol. 36, No. 18_suppl ( 2018-06-20), p. LBA1006-LBA1006
    Abstract: LBA1006 Background: Taselisib, a potent, selective PI3K inhibitor, has enhanced activity in PIK3CA-MUT BC cell lines and confirmed partial responses in PIK3CA-MUT BC as a single-agent or with FULV. We assessed taselisib + FULV in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. Methods: SANDPIPER (NCT02340221) is a double-blind, placebo (PBO)-controlled, randomized, phase III study. Postmenopausal pts with disease recurrence or progression during or after an aromatase inhibitor were randomized 2:1 to receive taselisib (4 mg oral, qd) or PBO + FULV (500 mg). Stratification factors were: visceral disease, endocrine sensitivity, and geographic region. Pts with PIK3CA-MUT tumors, assessed by central cobas PIK3CA Mutation Test, were randomized separately from non-MUT tumors. The primary endpoint was investigator-assessed progression-free survival (INV-PFS) in pts with PIK3CA-MUT tumors. Secondary endpoints included objective response rate (ORR), overall survival (OS), clinical benefit rate (CBR), duration of objective response (DoR), PFS by blinded independent central review (BICR-PFS), and safety. Results: 516 pts were randomized in the PIK3CA-MUT intention-to-treat (ITT) population. Efficacy is shown in the Table. Taselisib + FULV significantly improved INV-PFS (hazard ratio [HR] 0.70) as confirmed by BICR-PFS (HR 0.66). OS is immature. The most common grade ≥3 adverse events (AEs; preferred terms) in the taselisib + FULV arm in safety-evaluable pts who received ≥ 1 dose of treatment were diarrhea (12%), hyperglycemia (10%), colitis (3%), and stomatitis (2%). AEs led to more taselisib discontinuations (17% v 2%) and dose reductions (37% v 2%), v PBO. Conclusions: Taselisib + FULV significantly improved INV-PFS, v PBO + FULV, in pts with ER-positive, HER2-negative, PIK3CA-MUT locally advanced or MBC. The safety profile is largely consistent with previous studies. Clinical trial information: NCT02340221. [Table: see text]
    Type of Medium: Online Resource
    ISSN: 0732-183X , 1527-7755
    URL: Article
    DOI: 10.1200/JCO.2018.36.18_suppl.LBA1006
    RVK:
    XA 52760
    RVK:
    XA 10000
    Language: English
    Publisher: American Society of Clinical Oncology (ASCO)
    Publication Date: 2018
    detail.hit.zdb_id: 2005181-5
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