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| Profile Name | PIK3CA act mut |
| Gene Variant Detail | |
| Relevant Treatment Approaches | Akt Inhibitor (Pan) Akt1 Inhibitor Akt2 Inhibitor mTOR Inhibitor mTORC1 Inhibitor mTORC2 Inhibitor PI3K Inhibitor (Pan) PIK3CA inhibitor |
| Molecular Profile | Indication/Tumor Type | Response Type | Relevant Treatment Approaches | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
|---|---|---|---|---|---|---|---|---|
| PIK3CA act mut | lung non-small cell carcinoma | sensitive | PI3K Inhibitor (Pan) | Pictilisib | Preclinical - Cell line xenograft | Actionable | In preclinical studies, the PI3K inhibitor GDC-0941 demonstrated efficacy against NSCLC tumor cell lines in culture and in xenograft models harboring alterations in the PI3K pathway (PMID: 23136191). | 23136191 |
| PIK3CA act mut | Advanced Solid Tumor | conflicting | PIK3CA inhibitor | Taselisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Taselisib (GDC-0032) effectively suppressed growth of multiple tumor types in cell line xenograft models, with greater selectivity for PIK3CA activating mutants (PMID: 23662903). | 23662903 |
| PIK3CA act mut | breast cancer | sensitive | PIK3CA inhibitor | Copanlisib | Preclinical | Actionable | In a preclinical study, breast cancer cell lines with a PIK3CA activating mutation and/or ERBB2 (HER2) over expression demonstrated increased sensitivity to inhibition of proliferation by Aliqopa (copanlisib) in culture, compared to ERBB2 (HER2)-negative and wild-type PIK3CA cell lines (PMID: 24170767). | 24170767 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt1 Inhibitor Akt2 Inhibitor | BAY1125976 | Preclinical | Actionable | In a preclinical study, BAY1125976 demonstrated anti-tumor efficacy in multiple xenograft tumor models of different cancers with PIK3CA mutations or PTEN deletions and displayed synergy with other anti-cancer therapies (Cancer Res 2013;73(8 Suppl):Abstract nr 2050). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTORC1 Inhibitor | Everolimus | Preclinical - Cell line xenograft | Actionable | In a preclinical study, Afinitor (everolimus) demonstrated efficacy in multiple cancer cell lines in culture and xenograft models with PIK3CA activating mutations (PMID: 20664172). | 20664172 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTOR Inhibitor | Metformin | Preclinical | Actionable | In a preclinical study, Glucophage (metformin) demonstrated efficacy in treating dietary restriction-resistant human xenograft tumors harboring a PIK3CA-activating mutation (PMID: 23986086). | 23986086 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxol (paclitaxel) resulted in an objective response rate (ORR) of 8.0% (2/25, partial responses) in patients with advanced solid tumors (n=25), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (2/6) compared to patients without PIK3CA activating mutations (0/19) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | Akt Inhibitor (Pan) | Afuresertib | Preclinical | Actionable | In a preclinical study, various tumor cell lines harboring PI3KCA activating mutations demonstrated increased sensitivity to Afuresertib (GSK2110183) in cultured cells (PMID: 24978597). | 24978597 |
| PIK3CA act mut | breast cancer | sensitive | Akt Inhibitor (Pan) | MK2206 | Preclinical | Actionable | In a preclinical study, breast cancer cell lines harboring activating mutations in PIK3CA had increased sensitivity to MK2206 in cell culture (PMID: 22932669). | 22932669 |
| PIK3CA act mut | head and neck squamous cell carcinoma | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Gedatolisib | Preclinical | Actionable | In a preclinical study, PF-05212384 decreased viability of head and neck squamous carcinoma cells harboring a PIK3CA activating mutation in cell culture (PMID: 24823695). | 24823695 |
| PIK3CA act mut | ovarian clear cell adenocarcinoma | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib | Preclinical | Actionable | In a preclinical study, BEZ235 demonstrated efficacy in mouse xenograft models of ovarian clear cell adenocarcinoma with PIK3CA mutations (PMID: 24927217). | 24927217 |
| PIK3CA act mut | breast cancer | predicted - sensitive | Akt Inhibitor (Pan) mTORC1 Inhibitor | MK2206 + Ridaforolimus | Phase I | Actionable | In a Phase I clinical trial, Ridaforolimus in combination with MK-2206 demonstrated clinical activity in breast cancer patients expressing a PI3K pathway dependent gene expression signature, with complete response in 14.3% (2/14), partial response in 12.5% (2/16), and 2 patients achieving stable disease (PMID: 26187616). | 26187616 |
| PIK3CA act mut | Advanced Solid Tumor | sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | GSK1059615 | Preclinical | Actionable | In a preclinical study, solid tumor cell lines harboring PIK3CA activating mutations demonstrated increased sensitivity to GSK1059615 in culture (Clin Cancer Res October 1, 2008 14; B37). | detail... |
| PIK3CA act mut | lung small cell carcinoma | predicted - sensitive | PI3K Inhibitor (Pan) | Navitoclax + Pictilisib | Preclinical - Cell line xenograft | Actionable | In a preclinical study, the combination of Navitoclax (ABT-263) and GDC-0941 resulted in increased tumor growth delay and apoptosis in a small cell lung cancer cell line xenograft model harboring a PIK3CA activating mutation compared to either drug alone (PMID: 27197306). | 27197306 |
| PIK3CA act mut | estrogen-receptor positive breast cancer | predicted - sensitive | Akt Inhibitor (Pan) | Capivasertib + Tamoxifen | Preclinical - Cell culture | Actionable | In a preclinical study, the combination of Truqap (capivasertib) and 4-hydroxytamoxifen (4-OHT) worked synergistically or additively to inhibit growth of several estrogen receptor-positive breast cancer cell lines in culture, including cell lines with PIK3CA activating mutations, and overcame tamoxifen resistance in a resistant cell line (PMID: 26116361). | 26116361 |
| PIK3CA act mut | breast cancer | no benefit | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib + Venetoclax | Preclinical - Cell culture | Actionable | In a preclinical study, inhibition of Pi3k signaling by BEZ235 did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to Venclexta (venetoclax) in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | Dactolisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, inhibition of Pi3k signaling by BEZ235 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | no benefit | PI3K Inhibitor (Pan) | Buparlisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, Buparlisib (BKM120) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | no benefit | PIK3CA inhibitor | Alpelisib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, Alpelisib (BYL719) did not sensitize breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Torin 1 + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Torin1 sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Sapanisertib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Sapanisertib (MLN0128) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | breast cancer | predicted - sensitive | mTOR Inhibitor | Vistusertib + WEHI-539 | Preclinical - Cell culture | Actionable | In a preclinical study, the ATP-competitive mTORC1/2 inhibitor Vistusertib (AZD2014) sensitized breast cancer cell lines harboring PIK3CA activating mutations to WEHI-539 in culture (PMID: 27974663). | 27974663 |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | mTORC1 Inhibitor | Bevacizumab + Doxorubicin + Everolimus | Phase I | Actionable | In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038). | 27893038 |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | mTORC1 Inhibitor | Bevacizumab + Doxorubicin + Temsirolimus | Phase I | Actionable | In a Phase I trial, triple-receptor negative breast cancer patients, including those with PIK3CA activating mutations, demonstrated an overall response rate of 21% (11/52) and clinical benefit rate of 40% (21/52) when treated with a combination of Avastin (bevacizumab), Adriamycin (doxorubicin), and either Afinitor (everolimus) or Torisel (temsirolimus) (PMID: 27893038). | 27893038 |
| PIK3CA act mut | head and neck squamous cell carcinoma | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | AZD8055 + Cetuximab | Preclinical - Pdx | Actionable | In a preclinical study, two head and neck squamous cell carcinoma patient-derived xenograft (PDX) models harboring a PIK3CA activating mutation demonstrated greater delayed tumor growth when treated with a combination of AZD8055 and Erbitux (cetuximab) compared to either agent alone (PMID: 28446642). | 28446642 |
| PIK3CA act mut | Advanced Solid Tumor | conflicting | PIK3CA inhibitor | Taselisib | Phase II | Actionable | In a Phase II trial (MATCH), Taselisib (GDC-0032) treatment resulted in limited efficacy in heavily pretreated patients with advanced solid tumors harboring PIK3CA activating mutations, with an objective response rate of 0% (0/61) after a median follow-up of 35.7 months, stable disease in 52% (32/61), a median progression-free survival of 3.1 months, and a median overall survival of 7.2 months (PMID: 35138919; NCT02465060). | 35138919 |
| PIK3CA act mut | breast cancer | sensitive | PIK3CA inhibitor | Copanlisib | Case Reports/Case Series | Actionable | In a Phase I clinical trial, treatment with Aliqopa (copanlisib) resulted in partial response in one and stable disease in another patient with breast cancer harboring activating PIK3CA mutations (PMID: 27672108; NCT00962611). | 27672108 |
| PIK3CA act mut | lung squamous cell carcinoma | predicted - sensitive | PI3K Inhibitor (Pan) | Buparlisib | Preclinical - Pdx | Actionable | In a preclinical study, Buparlisib (BKM120) treatment resulted in inhibition of AKT and S6 phosphorylation and durable responses in 4/5 lung squamous cell carcinoma patient-derived xenograft (PDX) models harboring PIK3CA E545K or E542K mutations, 3 that also had PIK3CA amplification and 1 with PTEN loss (PMID: 30093452). | 30093452 |
| PIK3CA act mut | lung squamous cell carcinoma | predicted - sensitive | PIK3CA inhibitor | Alpelisib | Preclinical - Pdx | Actionable | In a preclinical study, Alpelisib (BYL719) treatment resulted in responses in multiple lung squamous cell carcinoma patient-derived xenograft (PDX) models harboring PIK3CA E545K or E542K mutations, including models with PIK3CA amplification or PTEN loss (PMID: 30093452). | 30093452 |
| PIK3CA act mut | lung non-small cell carcinoma | predicted - resistant | Osimertinib | Case Reports/Case Series | Actionable | In a retrospective analysis, activating PIK3CA mutations were identified in 6 of 100 patients with non-small cell lung cancer at treatment discontinuation of Tagrisso (osimertinib) (PMID: 31839416). | 31839416 | |
| PIK3CA act mut | triple-receptor negative breast cancer | predicted - sensitive | Akt Inhibitor (Pan) | Capivasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (PAKT), addition of Truqap (capivasertib) to Taxol (paclitaxel) as first-line therapy significantly improved median progression-free survival (9.3 vs 3.7 months, HR=0.30, p=0.01) and reduced risk (66%, HR=0.34, p=0.04) compared to Taxol (paclitaxel) alone in patients with metastatic triple-negative breast cancer harboring activating mutations in AKT1 (E17K, n=1) or PIK3CA (n=17), or inactivating mutations or gene loss in PTEN (n=13) (PMID: 31841354; NCT02423603). | 31841354 |
| PIK3CA act mut | estrogen-receptor positive breast cancer | predicted - sensitive | PIK3CA inhibitor | Palbociclib + Taselisib | Phase I | Actionable | In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in estrogen-receptor negative breast cancer patients harboring PIK3CA activating mutations and resulted in an objective response rate of 10% (1/10), a clinical benefit rate of 30% (4/10), and a median progression-free survival of 3.6 months (PMID: 32958578; NCT02389842). | 32958578 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | Palbociclib + Taselisib | Phase I | Actionable | In a Phase Ib trial (PIPA), the combination of Ibrance (palbociclib) with Taselisib (GDC-0032) was well tolerated in patients with advanced solid tumors harboring PIK3CA activating mutations and resulted in an objective response rate of 0% (0/12), a clinical benefit rate of 16.7% (2/12), and a median progression-free survival of 3.8 months (PMID: 32958578; NCT02389842). | 32958578 |
| PIK3CA act mut | triple-receptor negative breast cancer | no benefit | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase II | Actionable | In a Phase II trial (LOTUS), Ipatasertib (GDC-0068) in combination with Abraxane (paclitaxel) resulted a median progression free survival of 6.2 vs 4.9 months with placebo in triple-receptor negative breast cancer patients harboring activating mutations in PIK3CA or AKT1, or inactivating mutations in PTEN (PMID: 28800861; NCT02162719). | 28800861 |
| PIK3CA act mut | triple-receptor negative breast cancer | no benefit | Akt Inhibitor (Pan) | Ipatasertib + Paclitaxel | Phase III | Actionable | In a Phase III trial (IPATunity 130), the addition of Ipatasertib (GDC-0068) to treatment with Abraxane (paclitaxel) did not result in improved progression-free survival in patients with triple-negative breast cancer harboring PIK3CA and/or AKT activating mutations or PTEN alterations, with a median PFS of 7.4 months with Ipatasertib (GDC-0068) plus Abraxane (paclitaxel) vs. 6.1 months with placebo plus Abraxane (paclitaxel) (SABCS Meeting 2020, Abstract GS3-04; NCT03337724). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | no benefit | Akt Inhibitor (Pan) | TAS-117 | Phase II | Actionable | In a Phase II trial, TAS-117 treatment in advanced solid tumor patients with PIK3CA activating mutations (n=12) or AKT1 E17K (n=1) refractory to standard treatment had minimal activity, and led to an overall response rate of 8% (1/13), disease control rate of 23% (3/13), median progression-free survival of 1.4 months (mo), and a median overall survival of 4.8 mo, however due to poor accrual and lack of durable response to TAS-117 early termination of study was recommended (PMID: 33723724; NCT03017521). | 33723724 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | mTOR Inhibitor PI3K Inhibitor (Pan) | LY3023414 + Prexasertib | Phase I | Actionable | In a Phase Ib trial, the combination therapy of Samotolisib (LY3023414) and Prexasertib (LY2606368) resulted in an overall response rate of 13.3% (2/15; 2 partial responses) in patients with an advanced solid tumor harboring a PIK3CA activating mutation of either H1047R, H1047L, E542K, or E545K (PMID: 33495309; NCT02124148). | 33495309 |
| PIK3CA act mut | endometrial cancer | no benefit | mTOR Inhibitor PI3K Inhibitor (Pan) | LY3023414 | Phase II | Actionable | In a Phase II trial, patients with advanced endometrial cancer harboring a PI3K pathway mutation, including PIK3CA activating mutations, demonstrated only a modest clinical benefit with an overall response rate of 16% (4/25), a clinical benefit rate of 28% (7/25) at 12 weeks, a progression-free survival of 2.5 months, and overall survival of 9.2 months when treated with LY3023414 (PMID: 31880826; NCT01775072). | 31880826 |
| PIK3CA act mut | Her2-receptor negative breast cancer | predicted - sensitive | PIK3CA inhibitor | Alpelisib + Nab-paclitaxel | Clinical Study - Cohort | Actionable | In a Phase I/II trial, Piqray (Alpelisib) and Abraxane (nab-paclitaxel) combination treatment resulted in improved clinical benefit rate (100% vs 68%; OR=1.47, P=0.013) and median progression-free survival (11.9 vs 7.5 mo.; HR=0.44, P=0.027) and longer median overall survival (26.7 vs. 14.9 mo.; HR=0.59, P=0.19) in patients with ERBB2 (HER2)-negative metastatic breast cancer harboring activating PIK3CA mutations compared to patients without PIK3CA mutations (PMID: 33602685; NCT02379247). | 33602685 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | Akt Inhibitor (Pan) | Docetaxel + Ipatasertib | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and Taxotere (docetaxel) resulted in an objective response rate (ORR) of 7.7% (2/26, partial responses) in patients with advanced solid tumors (n=26), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to patients without PIK3CA activating mutations (1/22) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | Akt Inhibitor (Pan) | Fluorouracil + Ipatasertib + Leucovorin + Oxaliplatin | Phase I | Actionable | In a Phase Ib trial, the combination of Ipatasertib (GDC-0068) and mFOLFOX6 resulted in an objective response rate (ORR) of 6.1% (2/33, partial responses) in patients with advanced solid tumors (n=33), and ORR was proportionally higher in patients harboring activating PIK3CA mutations (1/4) compared to in patients without PIK3CA activating mutations (1/29) (PMID: 32205017; NCT01362374). | 32205017 |
| PIK3CA act mut | castration-resistant prostate carcinoma | predicted - sensitive | mTOR Inhibitor | CC-115 + Enzalutamide | Phase I | Actionable | In a Phase Ib trial, combination of Xtandi (enzalutamide) and CC-115 was safe and resulted in a PSA reduction >= 50% (PSA50) in 80% and >=90% (PSA90) in 58% of patients with metastatic castration-resistant prostate cancer at 12 weeks, patients harboring PIK3CA activating mutations or TSC1/2 loss (n=16) achieved superior PSA50, PSA90, and median time on treatment (94%, 63%, 57 wks) compared to PI3K pathway wild-type (n=24) patients (71%, 54%, 44 wks) (Ann Oncol (2021) 32 (suppl_5): S626-S677; NCT02833883). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | RLY-2608 | Preclinical - Cell line xenograft | Actionable | In a preclinical study, RLY-2608 treatment led to inhibition of cell viability in a panel of cancer cell lines harboring PIK3CA hotspot mutations, and led to tumor regression or stasis in cell line xenograft models (Mol Cancer Ther 2021;20(12 Suppl):Abstract nr P251). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | mTORC1 Inhibitor | Temsirolimus | Phase II | Actionable | In a Phase II trial (TAPUR), Torisel (temsirolimus) treatment resulted in an objective response rate of 11% (3/28, 3 partial responses) and a disease control rate of 29% in patients with advanced solid tumors other than breast cancer harboring PIK3CA mutations, with PIK3CA H1047R/L (n=3), E545K (n=2), and E542K (n=2) as the most common mutation in patients achieved disease control (J Clin Oncol 41, 2023 (suppl 16; abstr 3117); NCT02693535). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | Copanlisib | Phase II | Actionable | In a Phase II trial (NCI MATCH EAY131-Z1F), Aliqopa (copanlisib) treatment resulted in an objective response rate of 16% (4/25, all partial response), a clinical benefit rate of 36% (9/25), a median progression-free survival of 3.4 months, and a median overall survival of 5.9 months in patients with advanced solid tumors harboring activating PIK3CA mutations (PMID: 35133871; NCT02465060). | 35133871 |
| PIK3CA act mut | Advanced Solid Tumor | no benefit | Akt Inhibitor (Pan) | Atezolizumab + Ipatasertib | Phase II | Actionable | In a Phase II trial (CRAFT), treatment with Ipatasertib (GDC-0068) plus Tecentriq (atezolizumab) demonstrated safety but limited clinical benefit in advanced solid tumor patients harboring PI3K-AKT pathway mutations (n=13), including PTEN deletion/inactivating mutations or activating mutations in PIK3CA or AKT1, with a partial response in a breast cancer patient with AKT1 E17K and stable disease in a prostate cancer patient with PTEN loss (Ann Oncol (2023) 34 (suppl_2): S256-S257;NCT04551521). | detail... |
| PIK3CA act mut | Advanced Solid Tumor | predicted - sensitive | PIK3CA inhibitor | Copanlisib + Nivolumab | Phase II | Actionable | In a Phase II trial (BaCoN), treatment with the combination of Aliqopa (copanlisib) and Opdivo (nivolumab) was well tolerated in patients with advanced solid tumors harboring an activating mutation in PIK3CA, and resulted in a complete response/partial response (CR/PR) in 27% (4/15, 1 cPR, 3 uCR/PR) and a clinical benefit rate (CR or PR or stable disease > 4 months) of 40% (Ann Oncol 34 (2023): S487-S488; NCT04317105). | detail... |