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Oncology Highlights - September 2019

Stay informed on the latest news within oncology drug development. Subscribe to our newsletter to keep up to date with last month's science, industry and regulatory oncology highlights.

Enjoy reading! - The SMS-oncology team


Tumor mutational burden not associated with pembrolizumab efficacy in NSCLC

Together with PD-L1 expression, tumor mutational burden (TMB) is a useful biomarker spanning multiple cancer types. Two recent clinical trials, KEYNOTE-021 and -189, assessed the effect of TMB on the efficacy of pembrolizumab in patients with untreated, advanced non-small cell lung cancer (NSCLC). TMB was determined by whole-exome sequencing of the tumor and matched normal DNA. Its clinical utility on outcomes was assessed using pre-specified cut-points of 175 and 150 Mut/Mb. In 70 patients from the phase I/II KEYNOTE-021 trial who received chemotherapy (carboplatin/pemetrexed) alone or combined with pembrolizumab, TMB was not significantly associated with objective response rate (ORR), progression-free survival (PFS) or overall survival (OS). Similar results were reported for the evaluable patients (293/616; 48.3%) of the KEYNOTE-189 phase III trial following treatment with chemotherapy alone or in combination with pembrolizumab. These results were recently presented at the 2019 World Conference on Lung Cancer.

A new safe and potent anti-CD19 CAR T cell therapy:

Severe cytokine release syndrome (CRS) and neurotoxicity are among the most worrisome side effects observed with anti-CD19 chimeric antigen receptor (CAR) T cell therapies. The new anti-CD19 CAR T cells (derived from the CD19-BBz prototype bearing co-stimulatory 4-1BB and CD3ζ domains) developed by Ying et al produced lower levels of cytokines, expressed higher levels of anti-apoptotic molecules, and proliferated slower than the prototype, while retaining potent cytolytic activity. Results from a phase I trial in patients with B cell lymphoma reported complete remission in 6/11 (54.5%) patients treated with 2×108 - 4×108 CD19-BBz(86) CAR T cells, and no significant increases in serum cytokines, neurological toxicity or CRS (>Grade 1) in patients treated at all doses. The CAR T cells subsequently differentiated into memory cells in vivo. In conclusion, therapy with these new CAR T cells produces a potent and durable anti-lymphoma response without causing severe CRS or neurotoxicity. Results were published in Nature Medicine.  




A few highlights of industry & academy:

  • Immatics and Celgene enter strategic collaboration in which Celgene secures exclusive options to 3 Immatics T-cell receptor engineered T-cell therapy (TCR-T) targets. Immatics will receive a $75M upfront payment and may be eligible for future milestones and royalties up to $505M per licensed product. Immatics retains options to co-develop or co-fund certain licensed products.
  • Lupin and Boehringer Ingelheim enter into a licensing, development, and commercialization agreement for Lupin’s MEK inhibitor LNP3794 as a potential targeted therapy for patients with difficult-to-treat cancers. The aim is to combine this with Boehringer Ingelheim’s KRAS inhibitor. Lupin receives a $20 million upfront payment with potential milestones and royalties of >$700 million.
  • University of Pennsylvania enters exclusive R&D alliance with Novartis following their concluded 7-year R&D alliance that started in 2012. The first successful alliance of this caliber between academia and industry led to approval of the CAR T cell therapy Kymriah (tisagenlecleucel) for treatment of ALL. Penn and Novartis now enter into a landmark agreement focused on 4 clinical trials evaluating different CAR T cell therapies, alone or combined with pembrolizumab, in multiple myeloma, glioblastoma, and hematologic malignancies.


The Committee for Medical Products for Human Use (CHMP) adopted a positive opinion for:

New medicines:

  • Xospata (gilteritinib, Astellas Pharma), for treatment of adult patients who have relapsed or refractory AML with a FLT3 mutation, as the first and only oral FLT3-targeting therapy for this population.

Extension of indications:

  • Bavencio (avelumab, Merck Europe BV), in combination with axitinib, for first-line treatment of advanced renal cell carcinoma in adults, following its initial approval as monotherapy for metastatic Merkel cell carcinoma (MCC)
  • Taxotere (docetaxel, Aventis Pharma SA) and Docetaxel Zentiva (docetaxel, Zentiva), in combination with androgen-deprivation therapy, with or without prednisone/ prednisolone, for treatment of patients with metastatic hormone-sensitive prostate cancer.

New generics:

  • Arsenic trioxide Accord (arsenic triozide, Accord Healthcare) for acute promyelocytic leukaemia, a generic of Trisenox which has been authorized in EU since 2002
  • Bortezomib Fresenius Kabi (bortezomib, Fresenius Kabi Deutschland) for multiple myeloma and mantle cell lymphoma, a generic of the approved Velcade in 2004
  • Ivozall (clofarabine, ORPHELIA Pharma) for acute lymphoblastic leukaemia in paediatric patients, a generic of Evoltra that got approval in 2006.


The FDA granted approval for:

  • Darzalex (daratumumab, Janssen) for adult patients with multiple myeloma in combination with bortezomib, thalidomide, and dexamethasone in newly diagnosed patients who are eligible for autologous stem cell transplant (ASCT)
  • Lenvima (lenvatinib, Eisai) combined with pembrolizumab for advanced endometrial carcinoma that is not microsatellite instability high (MSI-H) or mismatch repair deficient (dMMR) and who have disease progression following prior systemic therapy but are not candidates for curative surgery or radiation. This is the first ever approval granted in the Project Orbis framework, which targets international collaboration between regulatory agencies (in this case: FDA (US), the Australian Therapeutic Goods Administration, and Health Canada).
  • Erleada (apalutamide, Janssen Biotech, Inc), for patients with metastatic castration-sensitive prostate cancer. The approval was based on the ongoing TITAN phase 3 trial, in which improvements in both major efficacy outcomes of OS and radiographic progression-free survival (rPFS) were demonstrated.
  • Cologuard (Exact Sciences), a stool DNA test that offers a sensitive, noninvasive, at-home option for eligible average-risk individuals aged 45-49 to screen for colorectal cancer. This decision expands on Cologuard’s previous indication for ages ≥50 years and comes at a critical time when the incidence of colorectal cancer is rising in adults <50 years of age.

In addition to approvals, FDA granted breakthrough therapy/device designation to several products to progress their development. These include:

  • Capmatinib (Novartis), as first-line treatment of patients with MET-mutated advanced non-small cell lung cancer (NSCLC). The designation was based on the GEOMETRY mono-1 trial, whose results reported an overall response rate of 68% for treatment-naive and 41% for previously treated patients who underwent capmatinib therapy.
  • The Liver Cancer detection test of Laboratory for Advanced Medicine, a liquid biopsy blood test designed to detect the presence of hepatocellular carcinoma with >95% specificity and sensitivity as early as Stage I by analyzing cell-free DNA methylation patterns. This test is of crucial relevance, considering the 15-fold increase in 5-year survival rates when the cancer is detected at early vs late stages.
  • The LifeKit® Prevent Test of Prescient Metabiomics, a non-invasive diagnostic test designed to detect pre-cancerous polyps, as well as early-stage carcinomas, and potentially aiding carcinogenesis interception and colorectal cancer prevention. This is the first designation for non-invasive tests for this purpose, as all other non-invasive tests on the market primarily detect full-blown cancer.
  • Tepotinib (Merck KGaA), for patients with metastatic NSCLC harboring MET exon 14 skipping alterations who progressed following platinum-based therapy. The designation was based on the ongoing VISION phase 2 trial, whose interim results reported an objective response rate of 50.0% for L-box gene (LBx)-identified patients. With an overall median duration of response >1 year and a favorable safety profile, tepotinib offers an improvement over available therapy in select patient subsets.


FDA finalizes guidance on placebos and blinding for cancer trials:

The FDA recently finalized guidance on placebos and blinding for cancer trials following the initial draft of August 2018. Recommendations include that placebos may only be used in select circumstances due to ethical concerns that would arise when alternative therapies are available. As such, a placebo-controlled study design may be useful or preferred only in: maintenance therapy, add-on trial designs, trials of adjuvant therapies (for which standard of care is surveillance), and for indications where no treatment is available. For placebo-controlled studies, the guidance provides clear considerations in which sponsors should provide a rationale for the trial design, and a clear description of the patient (un-)blinding plan. Main updates regarding blinding include that not only the patient, but also the investigator, should be unblinded upon disease recurrence or progression. They should also be unblinded in the case of an adverse event (AE) suspected to be related to the IMP when it would require treatment with “one/more drug products with substantial toxicity or invasive procedures.” Otherwise, a justification for the decision and acknowledgment of the risks should be captured in the informed consent documents. In addition, a note is now added that it does not address statistical considerations when unblinding data.