Oncology Highlights - November 2018
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Enjoy reading! - The SMS-oncology team
Patients with BRCA1/2 mutation driven cancers develop de novo and acquired resistance to PARP inhibitors (PARPis) and cisplatin. In a recent study published in Nature, researchers show the resistance can be obtained through inactivation of DYNLL1 protein which resets the DNA repair mechanism in BRCA1 resistant cells only. BRCA1/2 mutant cancer resistance has been previously explained through drug avoidance by pumping drugs out, re-mutation of BRCA to re-gain its functions that sets back the repair. This novel pathway through DYNLL1 demonstrates that cancer cells with same genetic mutation respond with distinctive molecular functions to ensure their survival. Cancer patients carrying BRCA1 and BRCA2 mutations are currently grouped together in many genome studies and when considering treatment options, increased understanding of variable molecular mechanisms will help finding the right subsequent treatment when resistance develop.
A recent review published in Nature Reviews Cancer discusses the uninhabited potential of engineered tumor targeting bacteria as the ideal vehicles to deliver cancer treatments due to their tumor selectivity and vast gene courier capacity. Unlike radiotherapy and chemotherapy, bacteria can filtrate and thrive in hypoxic and necrotic tumor microenvironment (TME) thus resulting in less cytotoxicity to normal tissue and more specificity. Different bacteria species are described in this review to employ unique intrinsic mechanisms to eliminate cancer in animal studies: intracellular bacteria like Salmonella sp. can lead to bursting of the invaded tumor cells. Listeria spp. can infect immunosuppressive myeloid-derived suppressor cells (MDSCs) to induce natural killer (NK) cell response. Clostridium spp. can trigger elevated cytokines and chemokines that induces immune response. Attenuated, nonpathogenic bacteria can deliver payloads in the form of RNA, DNA and cytotoxic agents in oxygen deprived TMEs. With advances in engineering bacteria, mini-robots will serve to overcome resistance against targeted therapy and immunotherapy.
Cancer risk is increased with up to 49% in those with higher body fat due to obesity. A new insight is gained in the understanding of the link between obesity and cancer: in the presence of excess fat, the immune surveillance system fails due to an obesity-fueled lipid accumulation in natural killer (NK) cells, preventing their cellular metabolism and trafficking. The study published in Nature Immunology, shows that NK cells in an ‘obese environment’ display increased lipid accumulation, which has a negative effect on their cellular bioenergetics. Such metabolic paralysis leads to loss of anti-tumor activity. However, the researchers also discovered that it was possible to reverse the metabolic paralysis by either inhibiting PPARα/δ or by blocking lipid transport, suggesting that metabolic reprogramming of NK cells could restore their anti-tumor activity.
Professor Cornelis Melief is selected for 2018 ESMO immuno-oncology award in recognition for his work in studying the interactions of the immune system with cancer. Professor Melief dedicated his career to understanding how the cytotoxic lymphocytes interact with cancer and for developing new therapeutic cancer vaccine strategies. His work on virally induced cancer in mice led to the implementation of synthetic long peptide (SLP) vaccines in clinical trials in cancer patients. Melief and his team were able to show the clinical effectiveness of these vaccines in pre-malignant lesions caused by HPV type 16. They also demonstrated that SLP vaccination and standard chemotherapy strengthened cervical cancer patients’ immune response and prolonged their survival. Prof. Melief is the Chief Scientific Officer of a Dutch immunotherapeutics biotech named ISA Pharmaceuticals and Professor Emeritus in tumor immunology at the Leiden University Medical Center.
IO market news: Genentech’s $100M generous offer to Immunocore, SQZ and Roche deal for antigen-presenting cells, Moderna breaks IPO record, LSP raises a record €750M
Genentech, a Roche group member, will pay UK-based Immunocore €87.3M to co-develop TCR expert’s IMC-C103C, a molecule targeting MAGE-A4 (Melanoma-Associated Antigen A4) tumors. This is an expansion to their existing partnership, which began in 2013, and will permit the first-in-human clinical trial of IMC-C103C in combination with atezolizumab (Tecentriq) as well as monotherapy. Cell therapy company SQZ announced the expansion of its collaboration with Roche with $1.37B plus deal. SQZ APCs posses native immune functions that leads target-specific killer (CD8) T cell responses in vivo. Boston Cambridge based Moderna Therapeutics filed an IPO worth $500M, making it the largest American biotech IPO so far. mRNA medicine maker experimental treatments has not yet reached far in the FDA pipeline, however succeeded in raising capitals including a $500M series G in February to continue to increase research funding. Constituting a record fundraise in European life sciences, LSP raised more than €750M for three different funds: LSP6, LSP HEF2 and LSP Public. Since its inception in 1998 LSP funded 120 companies including argenix, Kiadis, eTheRNA, Artios and Oncode institute.
The Committee for Medicinal Products for Human Use (CHMP) recommended granting marketing authorization for:
- Erleada (apalutamide, Janssen-Cilag) for the treatment of non-metastatic castration resistant prostate cancer. The selective androgen receptor showed ability to delay metastases. Approval of this enzalutamide analog is based on the SPARTAN study which showed apalutamide decreased the risk of distant metastasis or death by 72% and improved median metastasis-free survival (MFS) by more than two years
The CHMP extended the therapeutic indication for:
- Kisqali (ribociclib, Novartis) in combination with an aromatase inhibitor or fulvestrant as initial endocrine based therapy or in women who received prior endocrine therapy. The CDK4/6 inhibitor showed the first-line evidence of superior and sustained efficacy vs. endocrine therapy alone.
- Blincyto (blinatumomab, Amgen) as monotherapy for the treatment of adults with Philadelphia chromosome negative (Ph-) and CD19+ B-precursor ALL in first or second complete remission with minimal residual disease (MRD) greater than or equal to 0.1%. The bi-specific T-cell engager is already approved for the treatment of Ph- relapsed or refractory B-cell precursor ALL in Europe as well as US.
- Opdivo (nivolumab, BMS) in combination with ipilimumab for the first-line treatment of adult patients with intermediate/poor-risk advanced renal cell carcinoma (RCC). FDA approved the combination also based on the same study (CheckMate-214) in April 2018.
The FDA granted approval for:
- Daurismo (glasdegib, Pfizer) in combination with low-dose cytarabine (LDAC), for newly-diagnosed AML in patients who are 75 years or older or who are not eligible for chemo. The drug is not alone in the market: Venclexta-chemo regimen is approved in the same way.
- Adcetris (brentuximab, Seattle Genetics) in combination with chemotherapy for previously untreated systemic anaplastic large cell lymphoma or other CD30-expressing peripheral T-cell lymphomas. Approval was based on ECHELON-2 study, and was granted in record time under a US Food and Drug Administration pilot program so-called Real-Time Oncology Review.
The FDA granted accelerated approval for:
- Venclexta (venetoclax, AbbVie) in combination with azacitidine or decitabine or low-dose cytarabine for the treatment of newly-diagnosed AMLin adults who are 75 years or older, or who are not eligible for chemo similar to Daurismo. For this Bcl-2 blocker, it is the first FDA nod outside of the CLL arena.
- Vitrakvi (larotrectinib, Loxo Oncology) for adult and pediatric patients with solid tumors that have a neurotrophic receptor tyrosine kinase (NTRK) gene fusion without a known acquired resistance mutation, that are either metastatic or who have no satisfactory alternative treatments.
- Keytruda (pembroluzimab, Merck) for patients with hepatocellular carcinoma (HCC) who have been previously treated with sorafenib. Approval is based on the phase II KEYNOTE-224 study, HCC is the most common type of liver cancer.
- Lobrena (lorlatinib, Pfizer) for patients with anaplastic lymphoma kinase (ALK) + metastatic non-small cell lung cancer (NSCLC) whose disease has progressed on crizotinib and at least one other ALK inhibitor for metastatic disease. Biomarker driven treatments for ALK+ NSCLC has been led by Pfizer and were approved for the first time in 2011.
One draft guideline from FDA is published:
Nonmetastatic, Castration Resistant Prostate Cancer: Considerations for Metastasis-Free Survival Endpoint in Clinical Trials:
This guidance provides recommendations to sponsors regarding the use of MFS as an endpoint in clinical trials for nonmetastatic castration-resistant prostate cancer (nmCRPC) development programs for drug or biological products. nmCRPC is defined by rising prostate-specific antigen (PSA) despite castrate levels of testosterone and no radiographic evidence of distant metastatic disease. Oncologic Drugs Advisory Committee (ODAC) acknowledged MFS as an endpoint with guidance of the following study design and analyses considerations: 1) MFS definition should be not include local progression events 2) Stratification by prior local therapy (e.g. surgery, radiation) or lack of prior therapy 3) Plan sensitivity analyses to assess the effect of patient discontinuation for reasons other than disease progression 4) Exclude patients who could benefit from radiation therapy to the prostate or pelvis 5) The trial entry criteria should include the definition of castration-resistant disease. Guidelines also includes the considerations for imaging modalities and analyses of MFS.