P53 is a tumor suppressor gene that pauses cell division to allow for repair of gene damage, and triggers apoptosis if the damage is not reparable. Loss of p53 is a critical step in the evolution of cancer. Most frequently, p53 is mutated at its DNA binding domain; since p53 is a transcription factor, a diminished ability to bind to DNA significantly disrupts its functioning. Continue reading
This week, the FDA Oncology Drug Advisory Committee provided a unanimous recommendation to Novartis’ tisagenlecleucel, a CAR (chimeric antigen receptor) T-cell therapy directed against CD19 for the treatment of relapsed or refractory (r/r) pediatric and young adult patients with B-cell acute lymphoblastic leukemia (ALL). In addition, the FDA granted full approval to Amgen for Blincyto (blinatumomab), a bispecific monoclonal antibody that targets CD19, for indicated for the treatment of relapsed or refractory B-cell precursor acute lymphoblastic leukemia (ALL) in adults and children. Blincyto received conditional approval in 2015 for this claim. Continue reading
Two companies – Biontech, RNA vaccine and Neon Therapeutics, peptide vaccine – reported very positive results of neo-antigen vaccines in patients with refractory metastatic melanoma. Continue reading
We have written previously about the Warburg Effect, the observation that cancer cells “bypass normal cellular respiration, that is, glucose converted to pyruvate through glycolysis, and the sequential oxidation of pyruvate through the Krebs Cycle in the mitochondria. Instead, tumor cells divert pyruvate to lactate dehydrogenase (LDH), which reduces pyruvate into lactate.” Continue reading
The last twenty years has been an unprecedented time in biology – in sequencing the genome and studying the functions of proteins, as well as in unraveling signal transduction pathways, the fundamental biology of normal and diseased cells has been elucidated to a great extent. Although many druggable targets have been identified, it has largely been impossible to target protein-protein interactions (PPI) in drug development. In fact, only ONE drug that targets a PPI has been approved. Continue reading
Olaparib (Lynparza) is a PARP (poly-ADP ribose polymerase) inhibitor that was approved by the FDA in 2014 for the treatment of patients with advanced ovarian cancer who have mutated BRCA1,2 gene. Recently, the drug showed a 70% reduction in risk of progression in patients with less-advanced disease in the maintenance therapy setting:
The Phase III SOLO-2 trial demonstrated a significant improvement in progression-free survival (PFS) in germline BRCA-mutated (gBRCA), platinum-sensitive, relapsed ovarian cancer patients treated with Lynparza (olaparib) tablets (300mg twice daily) compared with placebo in the maintenance setting. The trial met its primary endpoint of investigator assessed PFS (HR 0.30; 95% CI 0.22 to 0.41; P<0.0001; median 19.1 months vs 5.5 months).
PARP inhibitors act in a counter-intuitive manner – by blocking PARP in the context of mutated BRCA1, the cell becomes overwhelmed with double strand breaks, leading to crisis and cell death. BRCA1 mutations, alone, predispose the cell to the accumulation of mutations in protooncogenes and tumor suppressor genes – a few double strand breaks are tumorigenic, whereas a massive number of double strand breaks, as occurs in the context of PARP inhibition, leads to apoptosis.
The use of PARP inhibitors for breast cancer makes great sense, However, in a Phase 3 trial of velparib, an experimental PARP inhibitor, failed to achieve better rates of complete pathogenic response in patients with triple negative breast cancer (TNBC – lack of HER-2, estrogen, and progesterone receptor up-regulation) versus chemotherapy, alone.
At the ASCO conference last week, AstraZeneca presented data on the use of olaparib in 302 patients with BRCA1,2 mutated breast cancer from its OlympiAD trial that compares olaparib against physician’s choice of chemotherapy (capecitabine 2500 mg/m2 d1-14 q 21, or vinorelbine 30 mg/m2 d1,8 q 21, or eribulin 1.4 mg/m2 d1,8 q 21):
OlympiAD Inclusion Criteria:
- Germline mutation in BRCA1 or BRCA2 that is predicted to be deleterious or suspected deleterious.
- Histologically or cytologically confirmed breast cancer with evidence of metastatic disease.
- Prior therapy with an anthracycline and a taxane in either an adjuvant or metastatic setting.
- Prior platinum allowed as long as no breast cancer progression occurred on treatment or if given in adjuvant/neoadjuvant setting at least 12 months from last dose to study entry elapsed.
- ER/PR breast cancer positive patients must have received and progressed on at least one endocrine therapy (adjuvant or metastatic), or have disease that the treating physician believes to be inappropriate for endocrine therapy.
- ECOG performance status 0-1.
- Adequate bone marrow, kidney and liver function.
OlympiAD Exclusion Criteria:
- Prior treatment with PARP inhibitor.
- Patients with HER2 positive disease.
- More than 2 prior lines of chemotherapy for metastatic breast cancer.
- Untreated and/or uncontrolled brain metastases.
Results were quite impressive – this was the first study that demonstrated PARP inhibition is effective in breast cancer:
- About 60% of patients saw their tumors shrink, a hair more than double the 29% objective response rate seen in those patients on chemotherapy.
- Lynparza showed efficacy in patients with TNBC, which is more difficult to treat. AbbVie, which is developing its own PARP inhibitor called veliparib, recentlyannounced a study specifically geared to look at veliparib’s activity in triple negative breast cancer failed to show a benefit when added to chemo.
- Additionally, treatment with Lynparza improved the time to second progression or death compared to chemo,suggesting patients who relapsed after Lynparza experienced a less aggressive return of their cancers.
Astrazeneca is studying olaparib with many combinations, including a study in TNBC with PD-L1 inhibitor durvalumab and CTLA-4 inhibitor tremelimumab.
The latest checkpoint inhibitor to be approved is AstraZeneca’s Imfinzi (durvalumab), a monoclonal antibody directed against PD-L1, which is expressed on cancer cells.
Immune checkpoint-directed therapy is producing unprecedented clinical results in many patients. So much so, that the FDA recently reversed its longstanding policy or approving cancer drugs based on site of origin, to the presence of a biomarker (microsatellite instability (MSI-H) or mismatch-deficient repair (dMDR) as the indication for therapy with pembrolizumab (Ketruda), and PD-1 blocker. Cancers expressing MSI-H or dMDR mutate at a rapid rate, presenting novel epitopes to the immune system, which is readily mobilized against them so that tumor infiltrating T-cells are reliably present. Blocking the PD-1/PD-L1 pathway in this context allows for prolongation of the immune response and better clinical results. Continue reading