On November 11, 2024 NuCana plc (NASDAQ: NCNA) reported that initial data from the ongoing Phase 1b/2 modular study (NuTide:303) investigating NUC-3373 in combination with the PD-1 inhibitor pembrolizumab for patients with advanced solid tumors (Module 1) and in combination with docetaxel for patients with lung cancer (Module 2) have been published in MedRxiv, the preprint server for Health Sciences (Press release, Nucana, NOV 11, 2024, View Source [SID1234648195]).
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Module 1 included 12 patients with a variety of solid tumors who had exhausted all other treatment options. The majority of patients (n=9) had received prior PD-(L)1 based therapy. Encouraging signals of anti-cancer activity were observed with confirmed Partial Responses in 2 patients and Stable Disease in a further four patients, resulting in an objective response rate of 22% and a disease control rate of 67% in the efficacy evaluable population. The combination of NUC-3373 plus pembrolizumab was generally well tolerated.
Module 1 Selected Case Studies: NUC-3373 plus pembrolizumab in patients with advanced solid tumors
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72-year-old patient with urothelial bladder cancer (Lynch syndrome) who had previously received gemcitabine plus cisplatin followed by the PD-L1 inhibitor atezolizumab (achieved a Partial Response and remained on therapy for 23 months). Following treatment with NUC-3373 plus pembrolizumab, the patient achieved 100% reduction in the target lesion (considered a confirmed Partial Response due to the presence of non-target lesions) and remains on treatment for over 10 months.
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75-year-old patient with BRAF mutant metastatic cutaneous melanoma who had previously received pembrolizumab (best response of Progressive Disease within 5 months) followed by dabrafenib plus trametinib (discontinued trametinib after 1 month due to toxicity and achieved Stable Disease before progressing after seven years on dabrafenib). Following treatment with NUC-3373 plus pembrolizumab, this patient achieved a confirmed Partial Response with an 81% reduction in the target lesion and remains on treatment for over 12 months.
Module 2 included 4 patients with non-small cell lung cancer (NSCLC) or pleural mesothelioma who had disease progression on, or were unable to tolerate, prior chemotherapy-containing regimens. Docetaxel is the current standard of care for NSCLC patients without targetable alterations who progress on PD-(L)1 inhibitor-based therapy, however, it is associated with modest clinical benefit (median PFS of 3-4 months) and substantial toxicity. Following treatment of the first 4 patients in this module, enrollment was put on hold due to toxicity challenges with docetaxel. Despite this, 2 patients achieved prolonged Stable Disease. Protocol modifications to include the use of a different taxane in this combination are currently being considered.
Module 2 Selected Case Studies: NUC-3373 plus docetaxel in patients with lung cancer
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60-year-old patient with pleural mesothelioma who had previously received carboplatin plus pemetrexed (progressed within 4 months), the PD-1 inhibitor nivolumab (progressed within 4 months), and carboplatin plus pemetrexed (progressed within 1 month). Following treatment with NUC-3373 plus docetaxel, the patient achieved Stable Disease for more than 13 months (ongoing).
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77-year-old patient with squamous NSCLC who had previously received carboplatin plus paclitaxel plus pembrolizumab (Stable Disease for 2 months) followed by maintenance pembrolizumab (progressed within 21 months). Following treatment with NUC-3373 plus docetaxel, the patient achieved Stable Disease for 7 months.
Full details can be found in the publication: Link
Professor David Harrison, NuCana’s Head of Translational Medicine stated: "We previously presented data on NUC-3373’s ability to elicit the release of Damage Associated Molecular Patterns (DAMPs), promote an anti-tumor immune response, and potentiate the activity of PD-1 inhibitors in human cancer cell lines. These data led us to investigate the combination of NUC-3373 plus pembrolizumab so we are very excited to observe these encouraging clinical findings in PD-(L)1 inhibitor experienced patients."
Professor Harrison continued: "We have also demonstrated that NUC-3373 is a very potent thymidylate synthase inhibitor and causes DNA damage, leading us to hypothesize that NUC-3373 may be an attractive alternative to pemetrexed in patients with NSCLC and mesothelioma. Observing that NUC-3373 in combination with docetaxel is stabilizing disease in these hard-to-treat patient populations provides further evidence supporting this hypothesis."
Hugh S. Griffith, NuCana’s Founder and Chief Executive Officer said: "We are very excited that these NUC-3373 combinations have been observed to provide a meaningful clinical benefit to patients who had exhausted all other treatment options. We recently presented encouraging efficacy and safety data at ESMO (Free ESMO Whitepaper) on NUC-7738 plus pembrolizumab in patients with metastatic melanoma who were refractory or resistant to PD-1 inhibitors. We are pleased to have two Phase 2 product candidates in our portfolio, each with a distinct mechanism of action, that can potentiate PD-1 inhibitors in PD-(L)1 resistant patients. We look forward to sharing additional data from the NuTide:303 study and our clinical development plans for both NUC-3373 and NUC-7738 in the near future."