Reading our newsletter will keep you up to date with last month’s news items on oncology drug development!

NEWS AND PUBLICATIONS

Immunotherapy combinations overcome resistance to bispecific T cell engager treatment in T cell–cold solid tumors

Bispecific T cell engagers (BiTE) therapies represent a promising off-the-shelf treatment for cancer. It remains unclear why some tumors are resistant to BiTE treatment. To address this, Belmontes et al. evaluated pharmacokinetics, pharmacodynamics, and immune correlates for response to BiTE treatment. Therapeutic approaches are needed to promote T cell–mediated destruction of poorly immunogenic, “cold” tumors typically associated with minimal response to immune checkpoint blockade (ICB) therapy. Bispecific T cell engager (BiTE) molecules induce redirected lysis of cancer cells by polyclonal T cells and demonstrated initial clinical benefit against some solid tumors. Little is understood about the factors that underly clinical responses. Using an immunocompetent mouse model expressing a humanized CD3ε chain and BiTE molecules directed against mouse CD19, mouse CLDN18.2, or human EPCAM antigens, the pharmacokinetic and pharmacodynamic parameters and immune correlates associated with BiTE efficacy across multiple syngeneic solid-tumor models were investigated. The results show that pretreatment tumor-associated T cell density is a critical determinant of response to BiTE therapy, identified CD8+ T cells as important targets and mediators of BiTE activity, and revealed an antagonistic role for CD4+ T cells in BiTE efficacy. Therapeutic combinations, including ICB and 4-1BB agonism, that synergized with BiTE treatment in poorly T cell–infiltrated, immunotherapy-refractory tumors were identified. In the tested models, BiTE efficacy was dependent on local expansion of tumor-associated CD8+ T cells, and not  their recruitment from circulation. The data highlight the relative contributions of baseline T cell infiltration, local T cell proliferation, and peripheral T cell trafficking for BiTE molecule–mediated efficacy, identify combination strategies capable of overcoming resistance to BiTE therapy, with direct clinical relevance for the development of BiTE and other T cell engager therapies.

Neural stem cell delivery of an oncolytic adenovirus in newly diagnosed malignant glioma: a first-in-human, phase 1, dose-escalation trial

Data from a first-in-human, open-label, phase 1, dose-escalation trial to determine the maximal tolerated dose of NSC-CRAd-S-pk7, following a 3 + 3 design was published. Patients with newly diagnosed, histologically confirmed, high-grade gliomas (WHO grade III or IV) were recruited. After neurosurgical resection, NSC-CRAd-S-pk7 was injected into the walls of the resection cavity. Within 10–14 days, treatment with temozolomide and radiotherapy was initiated. Primary endpoints were safety and toxicity profile and the maximum tolerated dose for a future phase 2 trial (NCT03072134). Histopathological evaluation identified 11 (92%) of 12 patients with glioblastoma and one (8%) patient with anaplastic astrocytoma. The median follow-up was 18 months. Overall, treatment was safe without dose-limiting toxicity and 1·50 × 108 NSCs loading 1·875 × 1011 viral particles was recommended as a phase 2 trial dose. There were no treatment-related deaths. The median progression-free survival was 9·1 months (95% CI 8·5–not reached) and median overall survival was 18·4 months (15·7–not reached), which are encouraging initial signs for the further development in this high unmet need population.

INDUSTRY

Pfizer to acquire Trillium Therapeutics

Pfizer has signed a deal with a familiar CD47 player to solidify its next-generation game plans. Pfizer and Trillium Therapeutics Inc., a clinical stage immuno-oncology company developing innovative therapies for the treatment of cancer, announced that the companies have entered into a definitive agreement under which Pfizer will acquire Trillium. Under the terms of the agreement, Pfizer will acquire all outstanding shares of Trillium not already owned by Pfizer for an implied equity value of $2.26 billion. Trillium’s portfolio includes biologics that are designed to enhance the ability of patients’ innate immune system to detect and destroy cancer cells. Its two lead molecules, TTI-622 (NCT03530683) and TTI-621 (NCT02663518), block the signal-regulatory protein α (SIRPα)–CD47 axis, which is emerging as a key immune checkpoint in hematological malignancies. TTI-622 and TTI-621 are novel, potentially best-in-class SIRPα-Fc fusion proteins that are currently in Phase 1b/2 development across several indications, with a focus on hematological malignancies. Accumulating data suggest that the SIRPα–CD47 axis is a key immune checkpoint in hematologic malignancies, similar to the PD-L1 / PD-1 checkpoint for solid tumors. CD47 is a protein that is overexpressed in numerous cancer cells, and in general, high CD47 expression correlates with more aggressive disease and poorer clinical outcomes. SIRPα is an inhibitory receptor expressed on myeloid cells that binds to CD47, preventing the immune system from destroying cancer cells. Disruption of the CD47-SIRPα interaction has been proven to elicit tumor destruction through triggering of an innate immune response.

EMA

In August the CHMP met (written procedure) without any new drug approvals posted at the time of this newsletter’s release.

FDA

In August, the FDA granted approval for:

  • The combination of lenvatinib (multi-kinase inhibitor, Lenvima, Eisai) plus pembrolizumab (Keytruda, Merck) for first-line treatment of adult patients with advanced renal cell carcinoma (RCC). The efficacy of this combination was investigated in CLEAR (Study 307/KEYNOTE-581; NCT02811861). Progression-free survival (PFS), assessed by independent radiologic review according to RECIST 1.1, and overall survival (OS) were the major efficacy endpoints. Patients receiving pembrolizumab with lenvatinib had a median PFS of 23.9 months (95% CI: 20.8, 27.7) compared with 9.2 months (95% CI: 6.0, 11.0) for those receiving sunitinib (HR 0.39; 95% CI: 0.32, 0.49; p<0.0001).
  • Belzutifan (Welireg, Merck), a hypoxia-inducible factor inhibitor for adult patients with von Hippel-Lindau (VHL) disease who require therapy for associated renal cell carcinoma (RCC), central nervous system (CNS) hemangioblastomas, or pancreatic neuroendocrine tumors (pNET), not requiring immediate surgery. Belzutifan was investigated in the ongoing Study 004 (NCT03401788), an open-label clinical trial in 61 patients with VHL-associated RCC (VHL-RCC) diagnosed based on a VHL germline alteration and with at least one measurable solid tumor localized to the kidney. Enrolled patients had other VHL-associated tumors, including CNS hemangioblastomas and pNET.
  • Dostarlimab-gxly (anti-PD-1 antibody, Jemperli, GlaxoSmithKline LLC) for adult patients with mismatch repair deficient (dMMR) recurrent or advanced solid tumors, as determined by an FDA-approved test, that have progressed on or following prior treatment and who have no satisfactory alternative treatment options. This is an accelerated approval based on ORR results. The efficacy of dostarlimab was evaluated in the GARNET Trial (NCT02715284), a non-randomized, multicenter, open-label, multi-cohort trial. The efficacy population consisted of 209 patients with dMMR recurrent or advanced solid tumors who progressed following systemic therapy and had no satisfactory alternative treatment. The primary efficacy endpoints were overall response rate (ORR) and duration of response (DoR) as determined by blinded independent central review according to RECIST 1.1. The ORR was 41.6% (95% CI: 34.9, 48.6), with 9.1% complete response rate and 32.5% partial response rate. Median DOR was 34.7 months (range 2.6, 35.8+), with 95.4% of patients with duration ≥6 months.
  • VENTANA MMR RxDx Panel as a companion diagnostic device to select patients with dMMR solid tumors for treatment with dostarlimab-gxly.
  • Nivolumab (Opdivo, Bristol-Myers Squibb Co.) for the adjuvant treatment of patients with urothelial carcinoma (UC) who are at high risk of recurrence after undergoing radical resection. This is the first FDA approval for adjuvant treatment of patients with high-risk UC. The results supporting this approval also supported the conversion of nivolumab’s accelerated approval for advanced/metastatic UC to a regular approval. Nivolumab was investigated in CHECKMATE-274 (NCT02632409), a randomized, double-blind, placebo-controlled trial. The primary efficacy endpoint was investigator-assessed disease-free survival (DFS) in the intent-to-treat (ITT) population and in patients with tumors expressing PD-L1 ≥1%. At a prespecified interim analysis, the median DFS was 20.8 months (95% CI: 16.5, 27.6) in patients who received nivolumab compared with 10.8 months (95% CI: 8.3, 13.9) in patients who received placebo (HR 0.70; 95% CI: 0.57, 0.86; p=0.0008). For patients with tumors expressing PD-L1 ≥1%, median DFS was not reached (95% CI: 21.2, not estimable) in those who received nivolumab vs. 8.4 months (95% CI: 5.6, 21.2) for patients who received placebo (HR 0.55; 95% CI: 0.39, 0.77; p=0.0005).
  • Ivosidenib (IDH inhibitor, Tibsovo, Servier Pharmaceuticals LLC) for adult patients with previously treated, locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation as detected by an FDA-approved test. Ivosidenib was investigated in a randomized (2:1), multicenter, double-blind, placebo-controlled clinical trial (Study AG120-C-005, NCT02989857) of 185 adult patients with locally advanced or metastatic cholangiocarcinoma with an IDH1 mutation. The patient’s  disease must have progressed following at least one, but not more than two prior regimens, including at least one gemcitabine- or 5-flurouracil-containing regimen. The primary efficacy endpoint was PFS as determined by independent review committee according to RECIST 1.1. The trial demonstrated a statistically significant improvement in PFS for patients randomized to ivosidenib (HR 0.37; 95% CI: 0.25, 0.54; p<0.0001). The analysis of OS was not significant (0.79; 95% CI: 0.56, 1.12; p=0.093); 70% of patients randomized to placebo had crossed over to receive ivosidenib after radiographic disease progression.
  • Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to aid in selecting patients with cholangiocarcinoma for treatment with ivosidenib.

FDA guidance documents of interest:

Nonmetastatic Castration-Resistant Prostate Cancer: Considerations for Metastasis-Free Survival Endpoint in Clinical Trials

This guidance provides recommendations to sponsors about using metastasis-free survival (MFS) as an endpoint in clinical trials for nonmetastatic castration-resistant prostate cancer (nmCRPC) development programs for drug or biological products regulated by FDA.

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