A Phase IB/II Multi-Cohort Study of Targeted Agents and/or Immunotherapy With Atezolizumab for Patients With Recurrent or Persistent Endometrial Cancer

This is a Phase IB/II multi-cohort study designed to evaluate the efficacy and safety of targeted agents with or without cancer immune checkpoint therapy with atezolizumab in participant with recurrent and/or persistent endometrial cancer. The main protocol provides a platform for genomic screening with homogeneous basic eligibility criteria in order to direct study participants into biomarker-matched study cohorts consisting of testing targeted agents.

More details:

This is a Phase IB/II multi-cohort study designed to evaluate the efficacy and safety of targeted agents with or without cancer immune checkpoint therapy with atezolizumab in participants with recurrent and/or persistent endometrial cancer. This biomarker-driven study provides a platform whereby participants with persistent/recurrent endometrial cancer will be placed into study cohorts evaluating targeted agents selected on the basis of the tumor's specific genomic profile. Prospective participants with persistent and/or recurrent endometrial cancer will be prescreened within 60 days of treatment assignment to have a tumor tissue sample submitted for next-generation sequencing (NGS) using FoundationOne® companion diagnostic (CDx) testing prior to entering screening. If a participant has FoundationOne® CDx testing within five years of enrollment, the previous tumor tissue may be re-analyzed for use in the study. Depending on the cohort assignment per the tumor's biomarker profile, participants will be assigned to the AFT-50A Protocol (atezolizumab+targeted agent) or the AFT-50B Protocol (non-atezolizumab targeted agents). The current study cohorts are as follows: AFT-50A Cohorts * Atezolizumab + Bevacizumab doublet - Closed to Accrual * Atezolizumab + Ipatasertib doublet - Closed to Accrual * Atezolizumab + Talazoparib doublet * Atezolizumab + Trastuzumab emtansine (TDM-1) doublet - Closed to Accrual * Atezolizumab + Tiragolumab doublet AFT-50B Cohorts * Inavolisib + Letrozole doublet * Giredestrant + Abemaciclib doublet It is anticipated that approximately 20 participants will be enrolled in each study cohort in AFT-50A and 24 participants in each study cohort in AFT-50B, unless otherwise specified for a given cohort due to statistical considerations. Each study cohort will open/close independently of other study cohorts. Once a study cohort reaches the prespecified number of participants, it will be closed to further enrollment, unless an expansion phase is planned. The study is structured to allow for additional cohorts to be added as the study progresses. These additional study cohorts may be proposed by investigators, but requires approval by the Steering Committee in order to be added to the protocol.

Overview

Tiragolumab (MTIG7192A, RG6058, RO7092284) is a human IgG1/k monoclonal antibody that targets the inhibitory receptor TIGIT. It has been studied mostly in combination with the PD‑L1 inhibitor atezolizumab across multiple tumor types. Early randomized phase 2 data in PD‑L1–positive NSCLC suggested activity, but several subsequent phase 3 trials in lung cancer did not meet primary endpoints. Positive phase 3 results have been reported in first‑line esophageal squamous cell carcinoma (ESCC) with chemo‑immunotherapy. (pubmed.ncbi.nlm.nih.gov)

Mechanism of action

• Target: TIGIT, an inhibitory receptor on activated T cells and NK cells; major ligand CD155 (PVR). Tiragolumab blocks TIGIT–CD155/CD112 interactions, aiming to restore antitumor immunity. (dctd.cancer.gov)
• Antibody features: Fc‑competent IgG1; emerging translational work indicates FcγR engagement may activate myeloid cells and modulate Treg biology, potentially enhancing PD‑L1 blockade. (pubmed.ncbi.nlm.nih.gov)

Efficacy

Non–small cell lung cancer (NSCLC) - Phase 2 (CITYSCAPE): In PD‑L1–positive, treatment‑naive metastatic NSCLC, tiragolumab + atezolizumab improved outcomes vs atezolizumab alone. Reported ORR 38.8% vs 20.6% (intent‑to‑treat), with pronounced effect in PD‑L1 TPS ≥50% (ORR 69% vs 24%); PFS HR 0.62 (overall) and 0.29 (PD‑L1‑high). (pubmed.ncbi.nlm.nih.gov)
- Phase 3 (SKYSCRAPER‑01, PD‑L1‑high): Did not meet the primary endpoint of overall survival at the final analysis vs atezolizumab alone; detailed data pending presentation. (reuters.com)

Small‑cell lung cancer (ES‑SCLC) - Phase 3 (SKYSCRAPER‑02): Adding tiragolumab to atezolizumab + carboplatin/etoposide did not improve PFS (median 5.4 vs 5.6 months; HR 1.11) or OS (median 13.1 months both arms; HR 1.14). (pubmed.ncbi.nlm.nih.gov)

Non‑squamous NSCLC vs pembrolizumab‑chemo - Phase 2/3 (SKYSCRAPER‑06): The tiragolumab + atezolizumab + chemotherapy arm showed reduced efficacy vs pembrolizumab + chemotherapy; primary PFS and interim OS endpoints were not met; trial discontinued. (businesswire.com)

Esophageal squamous cell carcinoma (ESCC) - Phase 3 (SKYSCRAPER‑08): First‑line tiragolumab + atezolizumab + chemotherapy improved PFS (IRF median 6.2 vs 5.4 months; HR 0.56; p<0.0001), OS (median 15.7 vs 11.1 months; HR 0.70; p=0.0024), and ORR (59.7% vs 45.5%). (ascopubs.org)

Head and neck cancer - A dedicated randomized phase 2 of atezolizumab ± tiragolumab in PD‑L1–positive recurrent/metastatic HNSCC is ongoing/registered; peer‑reviewed efficacy results were not identified. (clinicaltrials.ucbraid.org)

Safety

Across randomized studies, tiragolumab combinations showed toxicity profiles generally consistent with PD‑L1 inhibitors and background chemotherapy, with no new safety signals noted.

• ES‑SCLC (SKYSCRAPER‑02): Immune‑mediated AEs in 54.4% vs 49.2% (grade 3/4: 7.9% vs 7.7%); treatment withdrawal 8.4% vs 9.3% (tiragolumab vs control). (pubmed.ncbi.nlm.nih.gov)
• ESCC (SKYSCRAPER‑08): Grade 3/4 treatment‑related AEs 59.6% vs 56.4%; grade 5 2.6% vs 0.9% (tiragolumab combo vs control). (ascopubs.org)
• PD‑L1‑high NSCLC (SKYSCRAPER‑01): Sponsor reports indicate no new safety signals at final analysis. (reuters.com)

Further reading

• CITYSCAPE phase 2 NSCLC primary and follow‑up analyses (Lancet Oncology 2022). (pubmed.ncbi.nlm.nih.gov)
• SKYSCRAPER‑02 phase 3 ES‑SCLC (J Clin Oncol 2024, full text). (ascopubs.org)
• SKYSCRAPER‑08 phase 3 ESCC (ASCO GI 2024 abstract). (ascopubs.org)
• Mechanistic study on Fc‑dependent myeloid/Treg modulation by tiragolumab (Nat Immunol‑adjacent/PMID 38418879; J Immunol 2024 abstract). (pubmed.ncbi.nlm.nih.gov)
• NCI drug page for tiragolumab (target and mechanism overview). (dctd.cancer.gov)
• Updates on SKYSCRAPER‑01 OS outcome and program changes. (reuters.com)

Notes: As of October 7, 2025, phase 3 lung cancer trials with tiragolumab (SKYSCRAPER‑01 and ‑06) have not demonstrated survival benefit, while SKYSCRAPER‑08 in ESCC reported statistically significant improvements in both PFS and OS. Pending detailed publications may further clarify benefit–risk in specific subgroups. (reuters.com)

Last updated: Oct 2025

Overview

Ipatasertib (GDC-0068; RG7440) is an oral, ATP-competitive pan-AKT inhibitor (AKT1/2/3) developed to target tumors with PI3K/AKT pathway activation (e.g., PTEN loss, PIK3CA or AKT1 alterations). It has been studied across solid tumors, with the most advanced data in metastatic castration‑resistant prostate cancer (mCRPC) and triple‑negative breast cancer (TNBC). (aacrjournals.org)

Mechanism of action

• Selective, ATP-competitive inhibitor that preferentially binds active, phosphorylated AKT; pharmacodynamic studies in first‑in‑human biopsies confirmed inhibition of downstream targets (PRAS40, GSK3β, mTOR). (aacrjournals.org)

Efficacy

Prostate cancer (mCRPC) - Phase II (ipatasertib + abiraterone vs placebo + abiraterone, post‑docetaxel): rPFS improved numerically overall; greater effect in PTEN‑loss tumors. (pubmed.ncbi.nlm.nih.gov) - Phase III IPATential150 (first‑line mCRPC): in the prespecified PTEN‑loss (IHC) subgroup, ipatasertib + abiraterone improved radiographic PFS vs placebo + abiraterone (median 18.5 vs 16.5 months; HR 0.77, 95% CI 0.61–0.98; P=0.0335). No rPFS benefit in PTEN‑intact tumors. Exploratory NGS suggested larger benefit in tumors with PIK3CA/AKT1/PTEN alterations. Final overall survival (OS) analysis (median follow‑up 33.9 months) showed no OS improvement in PTEN‑loss or intention‑to‑treat populations. Selected exploratory NGS subsets (e.g., PIK3CA/AKT1/PTEN‑altered) showed signals but require validation. (ascopubs.org)

Triple‑negative breast cancer (TNBC) - Phase II LOTUS (first‑line ipatasertib + paclitaxel vs placebo + paclitaxel): improved PFS in the ITT population (median 6.2 vs 4.9 months; HR 0.60, 95% CI 0.37–0.98) with a larger effect in PIK3CA/AKT1/PTEN‑altered tumors; OS showed a numerical but not statistically significant trend at final reporting. (mdanderson.elsevierpure.com) - Phase III IPATunity130 Cohort A (biomarker‑selected, PIK3CA/AKT1/PTEN‑altered advanced TNBC): negative for PFS (HR 1.02; median 7.4 vs 6.1 months) and OS (HR 1.08). (aacrjournals.org)

Neoadjuvant TNBC (early disease) - Phase II FAIRLANE (ipatasertib + paclitaxel vs placebo + paclitaxel, 12 weeks): no significant improvement in pathologic complete response in the ITT (17% vs 13%), PTEN‑low, or PIK3CA/AKT1/PTEN‑altered subgroups. (pubmed.ncbi.nlm.nih.gov)

Safety

• Class‑consistent adverse events include diarrhea, rash, and hyperglycemia; most were grade 1–2 in early studies, with dose‑dependent increases at higher exposures. (aacrjournals.org)
• In combinations:
• With abiraterone (IPATential150): higher rates of grade 3/4 AEs and drug discontinuations vs placebo; diarrhea, hyperglycemia, rash, and transaminase elevations were more frequent and tended to occur early (median onset 8–43 days). Overall safety considered tolerable with supportive care. (pubmed.ncbi.nlm.nih.gov)
• With paclitaxel (LOTUS): grade ≥3 diarrhea occurred in 23% with ipatasertib vs 0% with placebo; other grade ≥3 events included neutropenia/neutrophil count decreased. (mdanderson.elsevierpure.com)
• Phase I combination work corroborated diarrhea, hyperglycemia, and rash as ipatasertib‑associated events; recommended phase II doses in combinations were 400 mg with paclitaxel and 600 mg with mFOLFOX6. (pubmed.ncbi.nlm.nih.gov)

Development status (as of October 2025)

• In mCRPC, phase III rPFS benefit was limited to the PTEN‑loss subgroup by IHC, but final OS was negative; exploratory genomics may refine selection. (sciencedirect.com)
• In TNBC, the biomarker‑selected phase III study was negative, tempering earlier phase II signals. (aacrjournals.org)

Further reading

• First‑in‑human pharmacology and mechanism: Cancer Discovery 2016. (aacrjournals.org)
• Phase II mCRPC (ipatasertib + abiraterone) with PTEN biomarker analyses: Clinical Cancer Research 2018/2019. (aacrjournals.org)
• IPATential150 biomarker and outcome analyses (ASCO/ESMO abstracts and final OS in European Urology 2025). (ascopubs.org)
• LOTUS phase II TNBC (Lancet Oncology 2017) and final OS update (Breast Cancer Research and Treatment 2021). (mdanderson.elsevierpure.com)
• IPATunity130 phase III TNBC (Clinical Cancer Research 2024). (aacrjournals.org)
• FAIRLANE neoadjuvant TNBC (Annals of Oncology 2019). (pubmed.ncbi.nlm.nih.gov)

Notes: Key quantitative results and safety data above come from peer‑reviewed journals and major conference abstracts. Where exploratory biomarker findings are noted, these require prospective validation.

Last updated: Oct 2025

Overview

Giredestrant (GDC‑9545) is an investigational, oral selective estrogen receptor degrader (SERD) and full ER antagonist being developed for ER‑positive/HER2‑negative breast cancer across early and advanced disease settings. It has shown antiproliferative activity in neoadjuvant early breast cancer and has mixed results in metastatic disease to date, including one negative phase II trial versus physician’s‑choice endocrine therapy and a positive phase III combination trial reported by press release in the post‑CDK4/6 inhibitor setting. (pubs.acs.org)

Mechanism of action

• Potent, non‑steroidal oral SERD that competitively binds ERα, induces receptor degradation via the proteasome, and fully antagonizes ER signaling, leading to suppression of ER‑dependent transcription and tumor cell proliferation. Preclinical studies showed activity in both ESR1 wild‑type and ESR1‑mutant models. (pubs.acs.org)

Efficacy

Early breast cancer (neoadjuvant, coopERA BC; phase II) - In a randomized neoadjuvant study (n=221), giredestrant produced a greater relative geometric mean reduction in Ki‑67 at 2 weeks than anastrozole (−75% vs −67%; p=0.043). With added palbociclib for 16 weeks, Ki‑67 suppression at surgery remained greater (−81% vs −74%), while objective response rates were similar (50% vs 49%); pathologic complete response was ~4–5% in both arms. (thelancet.com)

Previously treated advanced/metastatic disease (acelERA BC; phase II) - Randomized, open‑label study (n=303) comparing giredestrant vs physician’s‑choice endocrine therapy (mostly fulvestrant) did not meet the primary endpoint: investigator‑assessed PFS HR 0.81 (95% CI, 0.60–1.10; P=0.176); median PFS 5.6 vs 5.4 months. Prespecified subgroup analysis suggested a larger, non‑significant effect in ESR1‑mutated tumors (HR 0.60; 95% CI, 0.35–1.03). (ascopubs.org)

Post‑CDK4/6 inhibitor advanced/metastatic disease (evERA BC; phase III, combination with everolimus) - Company press release (Sept 22, 2025) reported evERA met both co‑primary endpoints, with statistically significant and clinically meaningful PFS improvement for giredestrant + everolimus vs standard endocrine therapy + everolimus in the intention‑to‑treat and ESR1‑mutated populations; OS data immature. Full peer‑reviewed results are pending. (globenewswire.com)

Other ongoing phase III programs - First‑line metastatic with palbociclib (persevERA; NCT04546009) and adjuvant early disease (lidERA; NCT04961996) are ongoing; results not yet published in peer‑reviewed venues as of October 7, 2025. (inclinicaltrials.com)

Safety

• Across studies to date, giredestrant has been generally well tolerated with a safety profile comparable to endocrine therapy controls.
• In acelERA BC (phase II), treatment‑related grade 3–4 AEs occurred in 4.0% with giredestrant vs 2.6% with control; treatment‑related serious AEs 2.0% vs 0.7%; discontinuations due to AEs 1.3% vs 2.0%. (ascopost.com)
• In coopERA BC, endocrine therapy–related AEs and grade ≥3 events were similar between giredestrant and anastrozole arms (both 6% grade ≥3 in final analysis). Patient‑reported outcomes showed manageable symptom burden. (ascopubs.org)
• Phase Ib experience (monotherapy and with palbociclib) described giredestrant as well‑tolerated; common AEs (≥10%) with monotherapy included fatigue, cough, back pain, pain in extremity, and arthralgia. (ascopubs.org)
• Press release for evERA reported the combination with everolimus was well tolerated with no new safety signals; detailed rates await full presentation/publication. (globenewswire.com)

Further reading

• Journal of Medicinal Chemistry paper describing discovery and preclinical profile of giredestrant. (pubs.acs.org)
• Lancet Oncology publication of coopERA BC neoadjuvant trial. (thelancet.com)
• Journal of Clinical Oncology publication of the phase II acelERA BC trial. (ascopubs.org)
• ASCO Meeting Abstracts for coopERA BC final analysis and PROs. (ascopubs.org)
• Phase Ib combination/monotherapy experience (ASCO abstract). (ascopubs.org)
• Company press release summarizing positive phase III evERA results (pending peer‑reviewed presentation). (globenewswire.com)

Notes: Giredestrant remains investigational; no regulatory approvals are documented as of October 7, 2025. Where only press releases are available (evERA), conclusions should be considered preliminary until peer‑reviewed data are published. (globenewswire.com)

Last updated: Oct 2025

Key Inclusion Criteria:

* Recurrent or persistent endometrial carcinoma which has progressed or recurred after at least 1, but no more than 2, prior lines of therapy. Prior hormonal therapies (e.g., tamoxifen, aromatase inhibitors) will not count toward the prior regimen limit. Chemotherapy given in conjunction with radiotherapy as a radiosensitizer will be counted as a systemic therapeutic regimen.

* Measurable disease per RECIST 1.1

* Availability of a representative tumor specimen that is suitable for determination of biomarker status via central testing (F1CDx) OR If a patient has a prior F1CDx report from 1 September 2019 or later, those NGS results can be used to determine biomarker status as long as the tumor tissue used in the report was obtained within 5 years prior to prescreening and appropriate signed consent is obtained from the patient.

* Life expectancy \> 12 weeks

* Recovery from effects of recent radiotherapy, surgery, or chemotherapy

Key Exclusion Criteria:

* Endometrial tumors with the following histologies: squamous carcinomas, sarcomas

* Other invasive malignancies within the last 5 years, except for non-melanoma skin cancer with no evidence of disease within the past 5 years AND localized breast cancer with previous adjuvant chemotherapy treatment for breast cancer completed \> 5 years ago

* Synchronous primary invasive ovarian or cervical cancer

* Have an active or history of autoimmune disease or immune deficiency

* Have a history of idiopathic pulmonary fibrosis, organizing pneumonia, drug-induced pneumonitis, idiopathic pneumonitis, or evidence of active pneumonitis based on a screening chest computed tomography (CT) scan

* Active tuberculosis

* Severe infections within 4 weeks

* Have received therapeutic oral or IV antibiotic medication within 2 weeks, except prophylactic antibiotic medication

* Have significant cardiovascular disease

* Are administered treatment with a live attenuated vaccine within 4 weeks, or anticipation of need for such a vaccine during the course of the study

* Have prior allogeneic bone marrow transplantation or solid organ transplant

* History of treatment with systemic immunostimulatory agents (including but not limited to interferons, interleukin-2) within 4 weeks or 5 half-lives of the drug, whichever is longer, prior to initiation of study treatment

* History of treatment with systemic immunosuppressive medications within 2 weeks except acute, low-dose, systemic immunosuppressant medications, corticosteroids for chronic obstructive pulmonary disease and asthma, or mineralocorticoids and low-dose corticosteroids for participants with orthostatic hypotension or adrenocortical insufficiency

* Have a history or clinical evidence of any untreated CNS disease, seizures not controlled with standard medical therapy, or history of cerebrovascular accident (stroke), transient ischemic attack or subarachnoid hemorrhage within 6 months

AFT-50A Specific Exclusion Criteria:

● Prior treatment with T-cell costimulating or immune checkpoint blockade therapies including, but not limited to, CD137 agonists, anti-PD-1, anti-PD-L1, and anti-CTLA-4 therapeutic antibodies

Note: Additional study cohort specific inclusion and exclusion criteria may apply based on cohort assignment.