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Overview of ESMO Congress 2021

For a complete summary and additional details use the link ESMO Congress 2021 | OncologyPRO.

A few highlights are provided below:

  • IMpower010 study showed a disease-free survival benefit with atezolizumab versus best supportive care after adjuvant chemotherapy in patients with resected stage II–IIIA NSCLC, with pronounced benefit in the subgroup whose tumours expressed PD-L1 on 1% or more of tumour cells, and no new safety signals. Atezolizumab after adjuvant chemotherapy offers a promising treatment option for patients with resected early-stage NSCLC.
  • Highlights on combination of pembrolizumab plus chemotherapy in mTNBC: The KEYNOTE-355 study: Overall survival (OS)results study presented at the ESMO Congress 2021 support immune checkpoint inhibitors (ICIs) plus chemotherapy as the first-line treatment of choice for patients with PD-L1-positive (CPS ≥10) metastatic triple-negative breast cancer. The final results report a longer median OS with first-line pembrolizumab plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively) at a median follow-up of 44.1 months (LBA16). The pembrolizumab combination reduced the risk of death by 27% (hazard ratio 0.73; 95% confidence interval 0.55–0.95; p=0.0093) but no benefit was reported for pembrolizumab plus chemotherapy over chemotherapy by applying a cutoff of CPS ≥1.
(source: Figure. Overall survival with pembrolizumab plus chemotherapy in patients with PD-L1-positive (CPS ≥10) metastatic triple-negative breast cancer (Abstract LBA16, ESMO 2021)
  • DESTINY-BREAST03: The open-label, randomized, phase III DESTINY-BREAST03 study compared trastuzumab deruxtecan (T-DXd) with trastuzumab emtansine (T-DM1), in patients previously treated with trastuzumab and a taxane. In results presented today, T-DXd significantly improved PFS – the primary endpoint – compared with T-DM1 (hazard ratio [HR] 0.28; p=7.8 × 10-22), with median PFS not yet reached and 6.8 months, respectively. Differences in estimated 12-month overall survival (OS) rates (94.1% with T-DXd versus 85.9% with T-DM1) did not cross the pre-specified boundary for significance (HR 0.56, 95% confidence interval [CI], 0.36–0.86) (LBA1). Preliminary data from a second phase III trial – the SYD985.002/TULIP trial – that compared [vic-]trastuzumab duocarmazine with physician’s choice of chemotherapy in patients who had received at least two prior lines of treatment, or previous treatment with T-DM1 will be presented tomorrow (LBA15). Median PFS by blinded central review – the primary endpoint – was 7.0 months for [vic-]trastuzumab duocarmazine and 4.9 months for chemotherapy (HR 0.64, 95% CI, 0.49–0.84; p=0.002).
(source: Figure. Progression-free survival with T-Dxd versus T-DM1 in HER2-positive metastatic breast cancer (DESTINY-BREAST03 study) (Abstract LBA1, ESMO 2021)
  • Encouraging data also from a 2nd T-DXd study. The DESTINY-Lung01 study assessed the efficacy and safety of HER2 antibody-drug conjugate trastuzumab deruxtecan in patients with metastatic non-small cell lung cancer (NSCLC) with HER2 mutations. Trastuzumab deruxtecan demonstrated robust and durable activity in this population, with a manageable safety profile. HER2 mutations occur in approximately 3% of NSCLC. However, currently there are no approved HER2-targeted agents for the management of patients with NSCLC; thus, this setting represents a high unmet medical need. Patients included in the DESTINY-Lung01 study had HER2-mutated metastatic NSCLC refractory to standard treatment; all patients were treated with trastuzumab deruxtecan. Centrally confirmed ORR was 54.9% (95% confidence interval [CI] 44.2-65.4) with 1 complete response (1.1%) and 49 partial responses (53.8%). Disease control rate was 92.3% (95% CI 84.8-96.9). Median DoR was 9.3 months (95% CI 5.7-14.7). Median PFS was 8.2 months (95% CI 6.0-11.9). Median OS was 17.8 months (95% CI 13.8-22.1).


Flamingo Therapeutics Expands Alliance with Ionis Pharmaceuticals to Develop RNA-targeted Therapies for Oncology

Flamingo Therapeutics, Inc., a biotechnology company pioneering RNA-targeting therapies in oncology, entered into an agreement with Ionis Pharmaceuticals to develop RNA-targeted therapies to treat various forms of cancer. This alliance is an expansion of an existing collaboration with Ionis on the FLAME™ discovery engine, following Flamingo’s Series A financing in 2020.

Flamingo Therapeutics was founded by VIB, Ghent University, KU Leuven, the University of Michigan, Kurma Partners and PMV, based on pioneering work led by Professor Jean-Christophe Marine (VIB-KU Leuven), Professor Pieter Mestdagh (Ghent University) and Professor Arul Chinnaiyan (University of Michigan). These scientific teams broke new ground on non-coding RNA genes in cancer and were among the first to show a role for lncRNAs as disease drivers in oncology. To support and expand its pipeline, Flamingo has a proprietary discovery engine, FLAME™ (Flamingo LncRNA Antisense Mining Engine), that addresses lncRNAs, a large and untapped class of disease-causing targets within the “dark matter” of the human genome. Under the terms of the agreement, Ionis is eligible to receive milestone payments and royalties on future product sales of the STAT3, AR, IRF4 and MALAT1 programs. Flamingo retains full rights to its FLAME platform and all lncRNA programs outside of MALAT1.


In September the CHMP made the following recommendatiosn on new medicines:

  • Brukinsa (zanubrutinib,BeiGene Ireland Ltd) as monotherapy is indicated for the treatment of adult patients with Waldenström’s macroglobulinaemia (WM) who have received at least one prior therapy, or in first line treatment for patients unsuitable for chemo-immunotherapy. Zanubrutinib is a Bruton’s tyrosine kinase (BTK) inhibitor  which blocks the activity of BTK inactivating the pathways necessary for B-cell proliferation, trafficking, chemotaxis, and adhesion.
  • Conditional marketing authorization was granted for the medicinal product Gavreto (pralsetinib, Roche Registration GmbH) intended for the treatment of patients with rearranged during transfection (RET)-fusion positive non-small cell lung cancer (NSCLC). Pralsetinib is a RET receptor tyrosine kinase inhibitor targeting oncogenic RET fusion proteins (KIF5B-RET and CCDC6-RET). Certain point mutations in RET or chromosomal rearrangements involving in-frame fusions of RET with various partners can result in constitutively activated chimeric RET fusion proteins that can act as oncogenic drivers by promoting cell proliferation of tumor cell lines. The benefits of Gavreto are its objective response rate and response duration in patients with RET-fusion positive NSCLC as observed in a pivotal phase I/II, open-label, multi-cohort, single-arm study.
  • Marketing authorization for the medicinal product Qinlock1 (ripretinib, Deciphera Pharmaceuticals B.V.) intended for the treatment of advanced gastrointestinal stromal tumour (GIST) in patients who have received prior treatment with three or more kinase inhibitors. Qinlock is designed to selectively block the oncogenic KIT and PDGFRA kinases by blocking their active conformation. The benefits of Qinlock are its ability to prolong the time until disease progression in patients with GIST.
  • Extension of indications for the following medicines:
    • Firmagon (degarelix, Ferring Pharmaceuticals A/S) is a gonadotrophin releasing hormone (GnRH) antagonist indicated:
      • for treatment of high-risk localized and locally advanced hormone-dependent prostate cancer in combination with radiotherapy.
      • as neo-adjuvant treatment prior to radiotherapy in patients with high-risk localized or locally advanced hormone-dependent prostate cancer.
      • for treatment of adult male patients with advanced hormone-dependent prostate cancer.
    • Keytruda (pembrolizumab, Merck Sharp & Dohme B.V.) in combination with chemotherapy, is indicated for the treatment of locally recurrent unresectable or metastatic triple negative breast cancer in adults whose tumors express PD-L1 with a CPS ≥ 10 and who have not received prior chemotherapy for metastatic disease.
    • Opdivo (nivolumab, Bristol-Myers Squibb Pharma EEIG) in combination with fluoropyrimidine- and platinum-based combination chemotherapy indicated for the first‑line treatment of adult patients with HER2‑negative advanced or metastatic gastric, gastro‑esophageal junction or esophageal adenocarcinoma whose tumors express PD-L1 with a combined positive score (CPS) ≥ 5.


In September, the FDA granted approval for:

  • Brukinsa (zanubrutinib BeiGene) for adult patients with Waldenström’s macroglobulinemia (WM). Zanubrutinib was investigated in ASPEN (NCT03053440), a randomized, active control, open-label trial, comparing zanubrutinib and ibrutinib in patients with MYD88 L265P mutation (MYD88MUT) WM. Patients in Cohort 1 (n=201) were randomized 1:1 to receive zanubrutinib 160 mg twice daily or ibrutinib 420 mg once daily until disease progression or unacceptable toxicity. Cohort 2 enrolled patients with MYD88 wildtype (MYD88WT) or MYD88 mutation unknown WM (n=26 and 2, respectively) and received zanubrutinib 160 mg twice daily.
  • Accelerated approval to Brukinsa (zanubrutinib, BeiGene) for adult patients with relapsed or refractory marginal zone lymphoma (MZL) who have received at least one anti-CD20-based regimen. Approval is based on two open-label, multicenter, single-arm trials: BGB-3111-214 (NCT03846427), which evaluated 66 patients with MZL who received at least one prior anti-CD20-based therapy, and BGB-3111-AU-003 (NCT02343120), which included 20 patients with previously treated MZL. Zanubrutinib was administered orally at 160 mg twice daily or 320 mg once daily.
  • Accelerated approval to Exkivity (mobocertinib, Takeda Pharmaceuticals, Inc.) for adult patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) exon 20 insertion mutations, as detected by an FDA-approved test, whose disease has progressed on or after platinum-based chemotherapy. Approval was based on Study 101, an international, non-randomized, open-label, multicohort clinical trial (NCT02716116) which included patients with locally advanced or metastatic NSCLC with EGFR exon 20 insertion mutations. Efficacy was evaluated in 114 patients whose disease had progressed on or after platinum-based chemotherapy. Patients received mobocertinib 160 mg orally daily until disease progression or intolerable toxicity. The main efficacy outcome measures were overall response rate (ORR) according to RECIST 1.1 as evaluated by blinded independent central review (BICR) and response duration. The ORR was 28% (95% CI: 20%, 37%) with a median response duration of 17.5 months (95% CI: 7.4, 20.3).
  • The FDA also approved the Oncomine Dx Target Test (Life Technologies Corporation) as a companion diagnostic device to select patients with the above mutations for mobocertinib treatment.
  • Cabometyx (cabozantinib, Exelixis, Inc.) for adult and pediatric patients 12 years of age and older with locally advanced or metastatic differentiated thyroid cancer (DTC) that has progressed following prior VEGFR-targeted therapy and who are ineligible or refractory to radioactive iodine. Efficacy was evaluated in COSMIC-311, a randomized (2:1), double-blind, placebo-controlled, multicenter clinical trial (NCT03690388) in patients with locally advanced or metastatic DTC that had progressed following prior VEGFR-targeted therapy and were ineligible or refractory to radioactive iodine. Patients were randomized to receive either cabozantinib 60 mg orally once daily or placebo with best supportive care until disease progression or intolerable toxicity. The primary efficacy outcome measures were progression-free survival (PFS) in the intent-to-treat population and overall response rate (ORR) in the first 100 randomized patients, assessed by a blinded independent radiology review committee per RECIST 1.1. CABOMETYX significantly reduced the risk of disease progression or death versus placebo (p<0.0001). The median PFS was 11.0 months (95% CI: 7.4, 13.8) in the cabozantinib arm compared to 1.9 months (95% CI 1.9, 3.7) for those receiving placebo. The ORR was 18% (95% CI: 10%, 29%) and 0% (95% CI 0%, 11%) in the cabozantinib and placebo arms, respectively.
  • Accelerated approval to Tivdak (tisotumab vedotin-tftv, Seagen Inc.), a tissue factor-directed antibody and microtubule inhibitor conjugate, for adult patients with recurrent or metastatic cervical cancer with disease progression on or after chemotherapy. Approval was based on innovaTV 204, an open-label, multicenter, single-arm clinical trial (NCT03438396). Efficacy was evaluated in 101 patients with recurrent or metastatic cervical cancer who had received no more than two prior systemic regimens in the recurrent or metastatic setting, including at least one prior platinum-based chemotherapy regimen. Sixty-nine percent of patients had received bevacizumab as part of prior systemic therapy. Patients received tisotumab vedotin-tftv 2 mg/kg every 3 weeks until disease progression or unacceptable toxicity. The main efficacy outcome measures were confirmed objective response rate (ORR) as assessed by an independent review committee (IRC) using RECIST v1.1 and duration of response (DOR). The ORR was 24% (95% CI: 15.9%, 33.3%) with a median response duration of 8.3 months (95% CI: 4.2, not reached).
  • Jakafi (uxolitinib, Incyte Corp.) for chronic graft-versus-host disease (cGVHD) after failure of one or two lines of systemic therapy in adult and pediatric patients 12 years and older. Efficacy was evaluated in REACH-3 (NCT03112603), a randomized, open-label, multicenter clinical trial of ruxolitinib compared to best available therapy (BAT) for corticosteroid-refractory cGVHD after allogeneic stem cell transplantation. The trial randomized 329 patients (1:1) to receive either ruxolitinib 10 mg twice daily or BAT. The major efficacy outcome used to support approval was overall response rate (ORR) (2014 NIH Response Criteria) through cycle 7 day 1. The ORR was 70% (95% CI 63%, 77%) for the ruxolitinib arm and 57% (95% CI 49%, 65%) for the BAT arm with a difference in response rate of 13% (95% CI 3%, 23%). The median durations of response, calculated from first response to progression, death, or new systemic therapies for chronic GVHD, were 4.2 months (95% CI 3.2, 6.7) and 2.1 months (95% CI 1.6, 3.2) for the ruxolitinib and BAT arms, respectively. The median times from first response to death or new systemic therapies for cGVHD were 25 months (95% CI 16.8, NE)  and 5.6 months (95% CI 4.1, 7.8) for the ruxolitinib and BAT arms, respectively.

FDA draft guidance documents of interest:

Benefit-Risk Assessment for New Drug and Biological Products

The intent of this guidance is to clarify for drug sponsors and other stakeholders how considerations about a drug’s benefits, risks, and risk management options factor into certain premarket and postmarket regulatory decisions that the Food and Drug Administration (FDA or Agency) makes about new drug applications (NDAs) submitted under section 505(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) as well as biologics license applications (BLAs) submitted under section 351(a) of the Public Health Service Act (PHS Act). 

Investigator Responsibilities – Safety Reporting for Investigational Drugs and Devices

This guidance is intended to help clinical investigators comply with the following safety reporting requirements:

  • Investigational new drug application (IND) studies under § 312.64(b) (21 CFR 312.64(b)
  • Investigational device exemption (IDE) studies under § 812.150 (21 CFR 812.150)

S12 Nonclinical Biodistribution Considerations for Gene Therapy Products

The objective of this guideline is to provide harmonized recommendations for the conduct of nonclinical biodistribution (BD) studies in the development of gene therapy (GT) products. This document provides recommendations for the overall design of nonclinical BD assessments. Considerations for interpretation and application of the BD data to support a nonclinical development program and the design of clinical trials are also provided. The recommendations in this guideline endeavor to facilitate the development of GT products while avoiding unnecessary use of animals, in accordance with the 3Rs (reduce/refine/replace) principles.

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