PIKTOR 33% Response Masks Single-Arm Paclitaxel Confound and No OS Precedent

Faeth's PIKTOR Shows Positive Phase II Results in Refractory Endometrial Cancer

Faeth Therapeutics' PIKTOR, a combination of serabelisib and sapanisertib, alongside paclitaxel, demonstrated positive outcomes in a single-arm Phase II trial (NCT06463028) for 42 patients with advanced or recurrent endometrial cancer. These patients had a PI3K/AKT/mTOR (PAM) pathway mutation and had progressed after platinum-based chemotherapy and a checkpoint inhibitor. At the data cutoff, 33% of 36 evaluable patients achieved a confirmed objective response, with a median progression-free survival of 7.4 months. The combination was generally well-tolerated, with 7% discontinuing due to treatment-emergent adverse events and no drug-related deaths. Faeth plans to advance PIKTOR to Phase III, addressing a significant unmet need in this patient population.

• The Phase II trial demonstrated significant efficacy, with 33% (12 out of 36 evaluable patients) achieving a confirmed objective response. Furthermore, the median progression-free survival was 7.4 months across the entire cohort, and 62% of patients did not experience cancer progression at the six-month mark. These results suggest a meaningful clinical benefit for patients with advanced or recurrent endometrial cancer who have limited treatment options after prior therapies.
• PIKTOR, in combination with paclitaxel, exhibited a favorable safety profile. Only 7% of patients discontinued treatment due to treatment-emergent adverse events (TEAEs), and no drug-related deaths were reported. The most common TEAEs included nausea, fatigue, and diarrhoea, while neutropenia was the most frequent Grade 3 or higher TEAE. This tolerability profile supports the potential for continued development of the combination.
• The study focused on a challenging patient population: those with advanced or recurrent endometrial cancer harboring a PI3K/AKT/mTOR (PAM) pathway mutation, who had previously progressed on platinum-based chemotherapy and a checkpoint inhibitor. With a median of two prior treatments, these patients represent a group with significant unmet medical needs, highlighting the importance of new therapeutic strategies like PIKTOR in this refractory setting.
• Following these positive mid-stage results, Faeth Therapeutics intends to advance PIKTOR into a Phase III clinical trial. This progression underscores the company's confidence in the combination's potential to address the critical treatment gaps for patients with advanced endometrial cancer who have exhausted standard-of-care options. The move to late-stage development signals a commitment to bringing this therapy closer to patients.

Addressing Unmet Needs in Refractory Endometrial Cancer

Advanced or recurrent endometrial cancer encompasses biologically diverse subgroups with disparate prognosis and treatment responsiveness. Recent studies target populations with limited options after platinum-based chemotherapy, older or comorbid patients underrepresented in trials, and molecularly defined high-risk disease.

• Older and comorbid patients receiving suboptimal care: Patients aged ≥65 years and ≥75 years frequently present with myometrial invasion, non-endometrioid histology and high-grade tumors, and frequently receive suboptimal care. Post-operative radiotherapy was effective and well tolerated in patients ≥65 years, with 5-year cause-specific survival of 79.8% vs 74.3% and progression-free survival of 67.5% vs 57.8% for younger elderly (65-74 years) vs older elderly (≥75 years). Real-world data describe a median age of 71 years with 22.2% obese, 20.0% with cardiovascular disease and 20.2% with diabetes, and first-line systemic therapy use impacted by age and comorbidities.

• Mismatch repair proficient (pMMR) / microsatellite stable (MSS) / non-microsatellite instability-high disease after prior systemic therapy: Pembrolizumab plus lenvatinib is recommended for non-microsatellite instability-high/mismatch repair proficient advanced or recurrent endometrial cancer who have progressed following prior systemic therapy. Real-world comparisons showed objective response rate (41.6% vs 28.2%), progression-free survival (13.1 [9.0 to 15.4] vs 8.4 [5.8 to 11.1] months) and overall survival (19.6 [16.9 to 26.3] vs 13.5 [11.9 to 17.6] months) for lenvatinib+pembrolizumab versus single-agent chemotherapy. Research focuses on dose optimization, with lenvatinib starting dose ≤10 mg versus >10 mg showing ORR of 50% and 26%, and on biomarkers including baseline Systemic Immune-Inflammation Index ≤540 versus >540 with PFS of 12.5 months versus 5.5 months (HR 2.94).

• Mismatch repair deficient (dMMR) / microsatellite instability-high (MSI-H) disease: Pembrolizumab and dostarlimab are established for previously treated dMMR/MSI-H endometrial cancer, with KEYNOTE-158 reporting ORR of 50% (40%-61%) in MSI-H/dMMR versus 7% (3%-14%) in non-MSI-H/non-dMMR, median PFS of 13.1 months versus 2.1 months, and median OS of 65.4 months versus 11.1 months. Unmet need remains to stratify Lynch-like versus methylated subgroups, with ORR of 100% versus 44%, PFS unreached versus 14.6 months and OS unreached versus 32.6 months, and to confirm effectiveness of dostarlimab plus carboplatin-paclitaxel and dostarlimab monotherapy (objective response rate 53.6%) in routine practice.

• High-grade, p53-abnormal, serous and carcinosarcoma subtypes with racial disparities: Uterine serous carcinoma and uterine carcinosarcoma account for 15% of all cases, and are responsible for more than 50% of related deaths, distinguished by high likelihood of metastasis and multisite recurrence. HER2 gastric-score 2+/3+ expression (22.5% vs 8.9%) and folate receptor alpha positivity (20.1% vs 4.4%) were enriched in serous versus endometrioid carcinoma, restricted to FIGO grade 3 tumors and concentrated in p53-abnormal disease. Risk of aggressive histology diagnosis varied by race, ethnicity and country of origin, with odds ratio of 3.07 (3.01-3.13) for non-Hispanic Black versus non-Hispanic White patients.

• Platinum-resistant, heavily pretreated and recurrent disease requiring novel targets and tolerability: In cohorts with 85% high-grade histology, 75% platinum-resistant and 67.8% p53 mutations, pembrolizumab and lenvatinib showed overall ORR of 37%, with p53 mutation and ECOG <2 independently associated with improved PFS. Investigational approaches include pembrolizumab, radiotherapy and an immunomodulatory five-drug cocktail with irORR of 11.1% in cervical and 12.0% in endometrial cancer, LAG-3 as a potential target for MSS PD-L1-positive endometrioid disease, and antibody-drug conjugates against TROP2, HER2 and FRα, with triple-negative TROP2/HER2/FRα tumors in 6/308 (1.9%).

PIKTOR's Phase II Efficacy and Safety in Endometrial Cancer

Recent studies in advanced or recurrent endometrial cancer have focused on adding immune checkpoint inhibitors to chemotherapy or evaluating immunotherapy alone and in novel combinations. Efficacy outcomes vary by mismatch repair and microsatellite status, with safety profiles reflecting both chemotherapy and immune-related toxicities.

• MITO END-3 compared carboplatin (area under the curve [AUC] 5 mg/mL × min) and paclitaxel (175 mg/m) versus avelumab (10 mg/kg intravenously) added to carboplatin and paclitaxel, with avelumab then every 2 weeks as single maintenance treatment. Median progression-free survival was 9·9 months (95% CI 6·7-12·1) in the standard group and 9·6 months (7·2-17·7) in the experimental group (HR of progression or death 0·78 [60% CI 0·65-0·93]; one-tailed p=0·085). Serious adverse events were reported more frequently in the experimental group (24 vs seven events in the standard group); neutrophil count decrease was the most frequent grade 3-4 adverse event (19 [31%] of 61 patients in the experimental group vs 26 [43%] of 61 patients in the standard group), with two deaths in the experimental group during treatment.

• KEYNOTE-158 evaluated pembrolizumab 200 mg Q3W for ≥35 cycles in MSI-H/dMMR (n = 94) and non-MSI-H/non-dMMR (n = 96) advanced endometrial cancer. The ORR (95% CI) was 50% (40%-61%) in the MSI-H/dMMR group and 7% (3%-14%) in the non-MSI-H/non-dMMR group, with median PFS of 13.1 (95% CI, 4.3-25.7) months and 2.1 (95% CI, 2.1-2.2) months, respectively, and median OS of 65.4 (95% CI, 29.5-not reached) and 11.1 (95% CI, 8.1-15.3) months, respectively.

• GARNET evaluated dostarlimab 500 mg every 3 weeks for four cycles, then 1,000 mg every 6 weeks until progression in 143 patients with dMMR/MSI-H EC and 156 patients with MMRp/MSS EC. ORR was 45.5% (n = 65) and 15.4% (n = 24) for dMMR/MSI-H EC and MMRp/MSS EC, respectively, with median DOR not met (median follow-up, 27.6 months) for dMMR/MSI-H EC and 19.4 months for MMRp/MSS EC.

• Lenvatinib plus pembrolizumab was evaluated at 20 mg oral lenvatinib daily plus 200 mg intravenous pembrolizumab every 3 weeks in 108 patients with previously treated endometrial carcinoma. The ORR was 38.0% (95% CI, 28.8% to 47.8%), with median DOR of 21.2 months (95% CI, 7.6 months to not estimable), median PFS of 7.4 months (95% CI, 5.3 to 8.7 months), and median OS of 16.7 months (15.0 months to not estimable); grade 3 or 4 treatment-related adverse events occurred in 83/124 (66.9%) patients.

PIKTOR's Role in the Evolving Endometrial Cancer Landscape

For patients with advanced stage or recurrent endometrial cancer, first-line therapy historically centered on paclitaxel plus carboplatin, with carboplatin plus paclitaxel (TC) established as the global first-line standard after demonstrating noninferiority to paclitaxel-doxorubicin-cisplatin (TAP) for overall survival (median, 37 v 41 months, respectively; hazard ratio [HR], 1.002; 90% CI, 0.9 to 1.12) and progression-free survival (median, 13 v 14 months; HR, 1.032; 90% CI, 0.93 to 1.15) in GOG0209. That paradigm was transformed by the ENGOT-EN-6-NSGO/GOG-3031/RUBY trial and the phase 3 NRG-GY018 study (NCT03914612), which investigated combining chemotherapy with immunotherapy. In RUBY, the addition of dostarlimab to standard chemotherapy with carboplatin and paclitaxel resulted in a significant and clinically relevant improvement of progression-free survival and overall survival in the overall population and in the subgroup with dMMR/MSI-high tumors, and a significant and clinically relevant improvement of progression-free survival in the subgroup with pMMR/MSI-low tumors. In NRG-GY018, patients (n = 810) were randomized (1:1) to pembrolizumab or placebo plus paclitaxel-carboplatin followed by maintenance pembrolizumab or placebo for up to 24 months, and the addition of pembrolizumab resulted in a significant and clinically relevant improvement of progression-free survival in the group with dMMR tumors and in the group with pMMR tumors, with hazard ratios for PFS per blinded independent central review of 0.45 (0.27-0.73); P = 0.0005 and 0.64 (0.49-0.85); P = 0.0008, respectively, while overall survival data were immature with hazard ratios favoring pembrolizumab of 0.55 (0.25-1.19); 1-sided nominal P = 0.0617 and 0.79 (0.53-1.17); 1-sided nominal P = 0.1157.

The effect in both trials was much more pronounced in the group of patients with dMMR/MSI-high tumors, a pattern confirmed in a meta-analysis of five studies comprising 2456 patients (1308 received ICIs with chemotherapy and 1148 treated with chemotherapy alone) where the addition of ICIs to chemotherapy improved PFS in the overall population (pooled HR, 0.63; 95% CI, 0.52-0.76; P <.001) with more pronounced benefit in the dMMR subgroup (pooled HR, 0.34; 95% CI, 0.27-0.44; P <.001), while for pMMR patients a statistically significant benefit was confirmed only when anti-PD1 were used (anti-PD-1: HR 0.64, 95% CI: 0.46-0.90, P =.010 vs anti-PD-L1: HR 0.87, 95% CI: 0.73-1.03, P =.104). For mismatch repair proficient disease, which makes up the majority of cases and remains difficult to treat due to an immune-cold microenvironment, combination strategies have defined the evolving standard. The updated results of KEYNOTE-775 showed that pembrolizumab plus lenvatinib led to significantly longer progression-free and overall survival than chemotherapy among patients with advanced endometrial cancer, irrespective of MMR status, supporting pembrolizumab plus lenvatinib as second-line treatment. Intensification with poly(adenosine diphosphate-ribose) polymerase inhibitors has improved PFS without overall survival benefit to date: in Part 2 of RUBY (291 patients randomized 2:1 to dostarlimab+chemotherapy followed by niraparib+dostarlimab maintenance or placebo+chemotherapy followed by placebo maintenance), the risk of progression or death was reduced by 40% (hazard ratio 0.60, 95% confidence interval 0.43 to 0.82, p <.001) overall and 37% (hazard ratio 0.63, 95% confidence interval 0.44 to 0.91, p =.006) in the mismatch repair-proficient/microsatellite stable population, with no overall survival benefit at 36.2 months of follow-up (hazard ratio 1.2, 95% confidence interval 0.81 to 1.78). Safety analyses show a manageable profile for chemo-immunotherapy, with doublet therapy significantly increasing grade ≥3 adverse events (risk ratio 1.12, 95% confidence interval 1.02 to 1.24) without increasing serious adverse events (risk ratio 2.20, 95% confidence interval 1.74 to 2.78 with triplet therapy), fatal adverse events, or treatment discontinuations, while triplet therapy was associated with significantly higher risk of grade ≥3 anemia (risk ratio 1.66, 95% confidence interval 1.14 to 2.42).

Treatment consideration by molecular subtype is now recommended under the Cancer Genome Atlas (TCGA) classification, which distinguishes four validated and highly prognostic subtypes — mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H), copy number high (CNH)/p53abn, copy number low (CNL)/no specific molecular profile (NSMP), and POLEmut — refined in ProMisE and TransPORTEC and integrated with FIGO for personalized treatment. FDA-approved immune checkpoint inhibitors include pembrolizumab and dostarlimab for previously treated dMMR/MSI-H endometrial cancer, and pembrolizumab/lenvatinib for mismatch repair-proficient/microsatellite-stable endometrial cancer, including CNH/p53abn and CNL/NSMP, with pembrolizumab fully approved and dostarlimab receiving accelerated approval in March and April 2022, respectively, for advanced/recurrent dMMR/MSI-H disease which has progressed on or following a platinum-containing therapy. Within subtypes, trastuzumab is NCCN compendium listed for HER2-positive serous endometrial cancer, which are primarily p53-abnormal, while antibody-drug conjugates targeting HER2, TROP2, and other tumor-specific antigens, PI3K/AKT/mTOR inhibitors, hormonal combinations with cyclin-dependent kinase 4/6 inhibitors and letrozole, and maintenance therapy with selinexor (XPO1-inhibitor/exportin-1 inhibitor) showing potential benefit in p53-wildtype cases are being investigated prospectively, and multiple prospective trials are evaluating de-escalation of care for POLEmut endometrial cancer given favorable survival regardless of adjuvant therapy.