Environmental stresses lower the efficiency of photosynthesis and sometimes cause irreversible damage to plant functions. When spinach thylakoids and Photosystem II membranes were illuminated with excessive visible light (100–1,000 µmol photons m−1 s−1) for 10 min at either 20°C or 30°C, the optimum quantum yield of Photosystem II decreased as the light intensity and temperature increased. Reactive oxygen species and endogenous cationic radicals produced through a photochemical reaction at and/or near the reaction center have been implicated in the damage to the D1 protein. Here we present evidence that lipid peroxidation induced by the illumination is involved in the damage to the D1 protein and the subunits of the light-harvesting complex of Photosystem II. This is reasoned from the results that considerable lipid peroxidation occurred in the thylakoids in the light, and that lipoxygenase externally added in the dark induced inhibition of Photosystem II activity in the thylakoids, production of singlet oxygen, which was monitored by electron paramagnetic resonance spin trapping, and damage to the D1 protein, in parallel with lipid peroxidation. Modification of the subunits of the light-harvesting complex of Photosystem II by malondialdehyde as well as oxidation of the subunits was also observed. We suggest that mainly singlet oxygen formed through lipid peroxidation under light stress participates in damaging the Photosystem II subunits.

1026 Background: In CLEOPATRA (NCT00567190), adding P to H + D significantly improved progression-free and overall survival (PFS/OS) v Pla + H + D in patients (pts) with previously untreated HER2-positive LR/MBC. PUFFIN (NCT02896855) is a China bridging study; the objective being to assess consistency of efficacy with CLEOPATRA. Methods: Pts with previously untreated HER2-positive LR/MBC were randomized 1:1 to P + H + D or Pla + H + D, stratified by visceral v non-visceral disease and hormone receptor status. The primary endpoint was investigator-assessed PFS. Secondary endpoints included objective response rate (ORR in pts with measurable baseline disease), OS, and safety. The target sample size (240) was determined based on the consistency threshold for PFS, defined as hazard ratio (HR) < 0.81, which maintains ≥ 50% of the risk reduction determined in CLEOPATRA (HR 0.62). Results: Two hundred forty-three pts were randomized. Baseline/disease characteristics and prior therapies were generally balanced between arms. For PFS, the HR was 0.69 (95% CI 0.49, 0.99) in the ITT population. No cases of heart failure or symptomatic left ventricular ejection fraction decline were reported. Efficacy/safety are shown in the table. Conclusions: PUFFIN met its primary endpoint. Overall, efficacy data were consistent with CLEOPATRA (ITT population and Asian subgroup). Safety was also consistent and in line with the known P safety profile, with no new or unexpected signals reported. PUFFIN adds to the totality of data with P in previously untreated HER2-positive LR/MBC, and supports the favorable benefit–risk profile of P in Chinese pts. Clinical trial information: NCT02896855. [Table: see text]

9506 Background: MCC is a rare, aggressive, neuroendocrine skin cancer with a high risk of recurrence and metastases. A median survival of about 4 mo for pts with metastatic MCC who failed anti-PD-1/L1 therapy highlights an urgent need for novel therapies. In TP53WT MCC, oncoproteins from the Merkel cell polyomavirus (MCPyV) inhibit p53 tumor suppressor functions by activating murine double minute 2 (MDM2). Navtemadlin is a potent, selective, orally available MDM2 inhibitor that overcomes MDM2 dysregulation by restoring p53 activity and inducing apoptosis of TP53WT tumors. Methods: The dose-finding, phase 1b/2 KRT-232-103 study (NCT03787602) evaluated navtemadlin in adult TP53WT MCC pts who failed anti-PD-1/L1 therapy. Pts were randomly assigned to oral navtemadlin once daily in 21- or 28-day cycles: 240 mg 7 days (D) on/14D off or 5D on/23D off, 180 mg 5D on/23 D off or 7D on/21D off, or 120 mg 7D on/14D off, until disease progression or unacceptable toxicity. The primary endpoint was Recommended Phase 2 Dose (RP2D); objective response rate (ORR) was assessed per RECIST v1.1. Results: As of Nov 30, 2021, 31 pts were enrolled with median age 66 y (range, 25-82); 52% had visceral disease and 71% had received ≥2 lines of prior therapy. Baseline tumor profiling of available samples showed low tumor mutation burden, MCPyV-positivity, and nonamplified MDM2 gene in 100%, 92%, and 100% of pts, respectively. Treatment-emergent adverse events (TEAEs) were observed in 100% (68% grade 3/4) of pts. The most common Grade 3/4 TEAEs were hematologic: 32% anemia, 32% lymphopenia, and 19% thrombocytopenia. Navtemadlin doses ≤180 mg were well tolerated with fewer dose reductions and longer treatment durations; subsequently the 240 mg arms were closed to further enrollment. Evaluable pts receiving 180 mg 5D on/23D off showed a 25% confirmed ORR, a 38% unconfirmed + confirmed ORR, and a 63% disease control rate (Table); median duration of response was not reached (range, 6-16.2+ mo) and median time to treatment response was 4.1 mo (range, 1.2-7). Notably, one responder, following a prolonged partial response, achieved complete metabolic remission by PET/CT after 2 y on treatment. The 120 mg arm was closed due to a low response rate. The 180 mg dose has been selected for further evaluation. Conclusions: Navtemadlin is the first targeted agent to show promising single-agent activity in heavily pretreated MCC pts who failed anti-PD-1/L1 therapy. This study demonstrates that upregulation of the p53 pathway is a viable therapeutic strategy in MCC. Clinical trial information: NCT03787602. [Table: see text]

TPS7063 Background: Patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) secondary to myeloproliferative neoplasms (MPN) have limited treatment options, resulting in poor prognosis with median overall survival < 6 months (Dunbar 2020). Although conventional AML therapy can induce responses in a subset of patients, it does not prolong survival in AML secondary to MPN (Khan 2017). Navtemadlin is a potent, selective, orally available murine double minute 2 (MDM2) inhibitor that restores p53 activity to drive apoptosis in TP53 wild-type ( TP53WT) malignancies. MDM2 is frequently overexpressed in AML with the majority being TP53WT, suggesting that MDM2 inhibition may be a rational approach for the treatment of AML secondary to MPN (Rampal 2014; Carvajal 2018). Preclinically, navtemadlin had dose-dependent activity reducing leukemic cell burden and significantly prolonging survival in a murine MPN-blast phase, patient-derived xenograft model (Wang 2021). Evidence of clinical activity of navtemadlin monotherapy in R/R AML was observed among TP53WT patients in a Phase 1b dose-escalation study (Erba 2019). In a Phase 2 study of intermediate-high risk R/R myelofibrosis patients, navtemadlin demonstrated clinical activity that correlated with disease-modifying effects (Al-Ali 2020; Vachhani 2021). Together, these studies provide biological and clinical support for evaluating navtemadlin in patients with R/R AML secondary to MPN. Methods: The open-label, multicenter Phase 1b/2 KRT-232-104 study (NCT04113616) is evaluating TP53WT patients with R/R AML secondary to MPN (myelofibrosis, polycythemia vera, or essential thrombocythemia). Eligible patients are aged ≥18 years with ECOG performance status of 0-2 and adequate hepatic and renal function. Patients must have received ≥1 prior lines of therapy for AML secondary to MPN; prior treatment with a FLT3 or IDH1/IDH2 inhibitor is required if appropriate and available. Patients who have undergone allogeneic or autologous stem cell transplantation within 3 months or have active graft-versus-host disease prior to first study dose will be excluded. Patients (n = 12/arm) will be randomly assigned to receive oral navtemadlin once daily in Arm 1: 360 mg 7 days (D) on/21D off, Arm 2: 360 mg 7D on/21D off in Cycle 1 followed by 240 mg 7D on/21D off in subsequent cycles, or Arm 3: 180 mg 7D on/14D off until disease progression or unacceptable toxicity. The primary endpoint is Recommended Phase 2 Dose of navtemadlin. Secondary endpoints include rates of complete remission (CR; per modified 2017 European LeukemiaNet response criteria), CR with partial hematologic improvement, CR with incomplete hematologic recovery, overall response rate, duration of response, progression-free survival, overall survival, and safety. This trial is ongoing and will enroll patients at 65 global sites. Clinical trial information: NCT04113616.

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