Multiple Novel Therapeutic Advances, Fruition of Some Follow-on Strategies, Several Clinical Disappointments, and Intensification of Drug Development

Oncology drug development continues to provide bold clinical innovation, although some developers are choosing to make smaller incremental steps by developing agents within well-established drug classes. Alongside the explosion in the number of novel therapies approved this year, the continued trend for combination treatments, premium therapy prices, extended duration of treatment, improvements in efficacy, and growing incidence, the oncology sector will fuel pharmaceutical industry growth over the next decade.

2017 was a particularly busy and productive year. Not only here at Decision Resources Group (the oncology team launched two new data and insight solutions) but also within the oncology pharmaceutical and regulatory sectors.

The pace of clinical development, the number of revolutionary new treatments approved, and the sheer volume of clinical data has been overwhelming. While significant progress in innovation was demonstrated in 2017, we also witnessed approvals of several ‘me-too’ and same-in-class drugs in oncology.

Clinical development and clinical complexity is set to increase even further through next year! Driven by significant unmet need and based on the size of the commercial opportunity in oncology, the trial environment is more pronounced than ever. There were more than 34,000 cancer clinical trials logged with as of 31st December 2016; today there are in excess of 59,000 trials (using the search term “cancer” conducted 20th December 2017).  There has been an increase in the number of Phase III trials over the same time period from approximately 4,400 Phase III trials to more than 6,900 Phase III trials.  The number of trials being initiated is increasing rapidly as developers vie to demonstrate meaningful benefit in discrete patient segments with the intention of securing greater revenues and improving patient outcome.

We expect that the key trends that we are currently observing in oncology (specifically: the continued personalized medicine development, the high degree of clinical and technological innovation, the optimization of current treatment approaches through increased combinations and evaluation of optimal sequential treatments, the focus on immunotherapy development, and the need to demonstrate value to stakeholders) will continue through 2018 and beyond.

Here is a list of the top 5 trends that we think made 2017 a year to remember for oncology:

  1. The large number of original NDA/BLA FDA approvals
  2. Major clinical breakthroughs with first-in-class revolutionary treatment approvals
  3. Multiple same-in-class and follow-on drug approvals
  4. Significant advances in clinical efficacy demonstrated in clinical trials
  5. Notable set-backs, including clinical disappointments within the immune checkpoint inhibitor class

1. The large number of original NDA/BLA FDA approvals in oncology during 2017

  • With 13 new NDA/BLA original approvals in 2017 a plus two autologous cellular therapies approved by the FDA, 2017 is a landmark year based on the number of new therapeutic approvals. As a comparison, the FDA approved only four original NDA/BLAs for oncology in 2016 (Venclexta [venetoclax], Tecentriq [atezolizumab], Lartruvo (olaratumab), and Rubraca [rucaparib]).
  • The anti-neoplastic original therapeutic approvals for oncology in 2017a are summarized in the following table.

Note: only anti-neoplastic original NDA/BLA and cell therapies are listed. Supplemental approvals of drugs in additional indications and settings (e.g., Opdivo for hepatocellular carcinoma), new dosage forms (e.g., Jevtana for prostate cancer), new formulations (e.g., Rituxan Hycela), new combinations for previously approved therapies (e.g., Vyxeos for AML), and Biosimilars (e.g., biosimilar bevacizumab, Mvasi) are not included in this list

  • Interestingly, there has been a surge in FDA approvals of original new drugs for the treatment of hematology-oncology indications; eight of the 2017 approvals are indicated for these patient populations (specifically, AML, ALL, follicular lymphoma, DLBCL, or mantle cell lymphoma). There is high unmet need for new efficacious therapies to treat these indications; and the drugs approved in 2017 will contribute to partially reducing the level of unmet need, especially in difficult-to-treat patients.
  • The genetic heterogeneity of oncology means that the therapy area naturally lends itself to personalized treatment approaches. Indeed, oncology epitomizes precision medicine development; 2017 continues the theme because seven of the original NDA/BLAs this year are approved specifically for biomarker-defined patient subpopulations (i.e., Kisqali [HR], Rydapt [FLT3], Alunbrig [ALK], Nerlynx [HER2], Idhifa [IDH2], Mylotarg [CD33], and Verzenio [HR]).

2. 2017 was a year of major clinical breakthroughs with first-in-class revolutionary treatments being approved

  • We expect 2017 will be remembered for the first approvals of autologous chimeric antigen receptor (CAR) T-cells. Novartis’ Kymriah was the first approved CAR T-cell treatment for the treatment of ALL patients who have failed at least two other treatments. Approximately one and a half months later, Gilead’s Yescarta (the second CAR T-cell product to gain FDA approval) was indicated for DLBCL patients who have failed at least two other treatments.  These products are autologous (whereby patient’s own T-cells are collected, genetically altered, and re-infused; the intention is to reprogram the patient’s T-cells to recognize specific cells for destruction). These products offer impressive efficacy for select late-line hematology-oncology patients and represent a paradigm-shifting novel approach to cancer treatment, however many hurdles remain for broader routine use of this technology (see here).
  • The approval of Novartis’ Rydapt for the treatment of AML is significant because it was the first therapy to be approved for AML in approximately 25 years, and the very first FLT3 inhibitor to enter the oncology market.  Furthermore, the approval of Rydapt defines a new patient sub-population through FLT3 testing (Invivoscribe Technologies also received approval of LeukoStrat companion diagnostic for FLT3 mutations in AML patients)
  • Other innovative first-in-class drugs approved in 2017 include:
  1. Celgene and Agios Pharmaceuticals’ Idhifa (enasidenib) which was approved for AML and is the first isocitrate dehydrogenase-2 inhibitor in oncology.
  2. Pfizer’s Besponsa (inotuzumab ozogamicin) which was approved for ALL is the first conjugated CD22 antibody to gain approval.
  3. One could argue that Pfizer’s Mylotarg (gemtuzumab ozogamicin) approved for AML is also the first CD33 antibody (despite it being approved initially 10 years ago and subsequently removed from the market before re-approval in 2017).

3. Despite the high degree of innovation, 2017 also witnessed multiple same-in-class and follow-on drug approvals

  • Two CDK4/6 drugs (Novartis’ Kisqali [ribociclib] and Eli Lilly’s Verzenio [abemaciclib]) were approved for the treatment of breast cancer in 2017. These drugs follow in the wake of Pfizer’s first-in-class Ibrance (palbociclib) which was approved in 2015.  Ibrance launch has been particularly successful from a commercial perspective, and revenues are forecasted to be in excess of $2.5B in the U.S. for full year 2017. While we don’t expect Kisqali and Verzenio to demonstrate significantly better efficacy than Ibrance, the earlier generic entry of Ibrance will mean Kisqali and Verzenio sales will be the class leaders in breast cancer by 2026. Interestingly, in May 2017 Novartis also gained approval of the Kisqali Femara co-pack for breast cancer – a clever first-of-its-kind combination strategy. The innovative packaging of Kisqali and Femara will give patients the convenience of obtaining a full 28-day cycle of the two agents in one package, one prescription, and one copay.
  • Tesaro gained approval of their PARP inhibitor, Zejula (niraparib) for the treatment of ovarian cancer in March this year; however, Zejula follows in the footsteps of AstraZeneca’s Lynparza for the treatment of ovarian cancer (approved in 2014) and Clovis Oncology’s Rubraca (approved in 2016). Unlike Lynparza and Rubraca, Zejula is approved irrespective of BRCA status and therefore does not require biomarker testing, enabling it to be prescribed to a larger number of patients.
  • Ariad Pharmaceuticals’ Alunbrig (brigatinib) gained approval in 2017; however, Alunbrig is the fourth ALK inhibitor to enter the NSCLC market. Pfizer was first-to-market in the class with Xalkori (approved in 2011) followed by Novartis’ Zykadia (ceritinib) in 2014 and Roche’s Alecensa (alectinib) in 2015. Although securing first-to-market approval is normally a competitive advantage, later entrants can occasionally out-compete earlier ones if they are adequately differentiated (in clinical profile or price, for example). ALK inhibitors is one such class where this is evident. Third-to-market Alecensa is expected to be the class leader in share and sales by some margin (based on the 2017 ASCO data which demonstrated superiority over Xalkori); this means Alunbrig which was approved this year will face significant competition unless it can demonstrate superiority to Alecensa.
  • Although 2017 saw significantly increased penetration of immune checkpoint inhibitors across oncology indications, the two new approvals in 2017 do not represent first-in class approvals.
  1. Merck KGaA/Pfizer’s Bavencio (avelumab) was approved in March for Merkel cell carcinoma (and in May for urothelial carcinoma). At its first approval, Bavencio was the second PD-L1 inhibitor in oncology (behind Roche’s Tecentriq [atezolizumab]), and the fourth approved checkpoint inhibitor for urothelial carcinoma (although Bavencio is the first and only checkpoint inhibitor approved for Merkel cell carcinoma].
  2. AstraZeneca’s Imfinzi (durvalumab) was approved in May for the treatment of urothelial carcinoma and is the third PD-L1 inhibitor in oncology (behind Tecentriq and Bavencio), the third checkpoint inhibitor to be approved for urothelial cancer (behind Tecentriq and Opdivo, although Bavencio and Keytruda were approved for this indication within three weeks following Imfinzi), and the sixth immune checkpoint inhibitor approved for oncology.
  • Biosimilars are intended to be highly similar to a reference product, and therefore are clearly same-in-class competitors to previously launched products. The advantage of biosimilars is derived purely on price and market access benefits. Two biosimilar monoclonal antibody biosimilars were FDA approved in 2017: Mvasi (Amgen’s bevacizumab biosimilar approved in September) and Ogivri (Mylan’s trastuzumab biosimilar approved in December). On 20th Samsung Bioepis revealed that the FDA had accepted their application for biosimilar trastuzumab. Based on the significant sales of Roche/Genentech’s Avastin and Herceptin, these brands represent highly attractive targets for biosimilar developers (although Mvasi and Ogivri will not launch until 2019 in the U.S. owing to patient protection of the brands).

4. Significant advances in clinical efficacy demonstrated in clinical trials in 2017

  • Some of the most exciting efficacy data achieved in decades have been achieved by CAR T-cells this year.  Although it’s too early to confidently be using the word “cure” for large groups of patients, complete remission rates appear excellent for some hard-to-treat hematology-oncology patient cohorts. Currently marketed CAR T-cell therapies—Kymriah and Yescarta—are autologous, CD19-targeting CAR T-cells which the FDA approved for patients who have exhausted other treatment options. However, both therapies are associated with severe, life-threatening, and potentially fatal side effects. Encouragingly, future development of CAR T-cells are evaluating better tolerated, more controlled, and logistically simpler (allogeneic) versions of this exciting class. Newer CAR T-cell therapies, for example Juno Therapeutics’ lisocabtagene maraleucel (a CD-19 targeted product) and Bluebird Bio/Celgene’s BCMA targeted strategy have demonstrated impressive efficacy in other clinical trials. We watch the class as a whole with great interest.
  • In breast cancer ASCO this year revealed some exciting clinical data including:
  1. The highly anticipated results of the APHINITY trial, which showed that when Perjeta is added to Herceptin and chemotherapy it demonstrates an improved invasive disease-free survival compared with Herceptin and chemotherapy alone.
  2. Data from the MONARCH-2 trial which showed that at an interim analysis, Verzenio improved the median progression-free survival of locally-advanced or metastatic HR-positive/HER2-negative patients compared with fulvestrant alone.
  3. Phase IIII data from the OlympiAD trial which showed that, at an interim analysis, previously-treated metastatic breast cancer patients with germline BRCA1/2 mutations receiving Lynparza achieved a progression-free survival of 7 months compared with 4.2 months for those receiving chemotherapy. Lynparza also reduced the chance of disease progression by 42%, thus becoming the first targeted agent to show a significant clinical benefit in the metastatic germline BRCA1/2-mutated population.
  • In NSCLC:
  1. AstraZeneca’s Tagrisso demonstrated progression-free survival benefits over standard of care therapy in first-line EGFR-positive disease in the Phase III FLAURA trial. These results support the label expansion of Tagrisso into the first-line EGFR-positive setting and will significantly expand the eligible patient population.
  2. In May 2017, Keytruda received the second first-line label expansion in combination with chemotherapy. After approving Keytruda for first-line, PD-L1-positive NSCLC, the FDA granted it a label expansion in the first-line setting in combination with pemetrexed and carboplatin. The combination is indicated for nonsquamous patients irrespective of PD-L1 status and it received accelerated approval based on statistically significant progression-free survival and overall response rate benefits compared with chemotherapy alone in the Phase II KEYNOTE-021 trial. This approval significantly expands the number of treatment opportunities for Keytruda by allowing its use in patients with low PD-L1 or PD-L1-negative tumors, a significantly larger patient population. Notably, Keytruda is the first immune checkpoint inhibitor to receive approval in combination with chemotherapy for any oncology indication.
  3. ASCO 2017 highlighted the impressive progression-free survival improvements for Alecensa compared with Xalkori in the pivotal Phase III ALEX trial in first-line ALK-translocation-positive patients. Alecensa received a label expansion into the first-line setting in November and we expect it to rapidly displace Xalkori for ALK-translocation-positive patients. Novartis received first-line approval Zykadia six months before Roche, but the use of chemotherapy as the comparator in the pivotal trial is likely to limit Zykadia’s uptake.
  • The combination of Tecentriq with Avastin significantly improved outcomes in two separate oncology indications:
  1. Progression-free survival was improved for the combination compared with Avastin and chemotherapy in the pivotal Phase III IMpower-150 trial for first-line advanced non-squamous NSCLC patients (without ALK or EGFR mutations). The 12-month progression-free survival rate doubled from 18% to 37%.
  2. The combination also significantly reduced the risk of disease progression or death compared with Sutent in first-line advanced or metastatic renal cell carcinoma patients for patients with at least 1% PD-L1 expression.

5. While major advances are evident, there have been some notable set-backs during 2017, including clinical disappointments within the immune checkpoint inhibitor class

  • Despite some earlier encouraging Phase II data, in April 2017 BMS revealed that Opdivo failed to significantly improve overall survival compared with Avastin (the standard of care) in the Phase III CheckMate-143 study which was evaluating second-line glioblastoma multiforme patients. Other trials evaluating Opdivo in glioblastoma multiforme continue.
  • In May 2017, data from the pivotal Phase III IMvigor-211 trial revealed that Tecentriq failed to significantly improve overall survival compared with chemotherapy for advanced or metastatic urothelial carcinoma patients with disease progression during or after platinum-based chemotherapy. The trial was intended to support continued approval (accelerated approval was granted in May 2016).
  • In July 2017, AstraZeneca announced that Imfinzi plus tremelimumab failed to meet its primary endpoint of progression-free survival for first-line PD-L1 positive NSCLC patients (in the Phase III MYSTIC trial). Although this is a significant blow to the development of the combination in the first-line setting, some interviewed physicians emphasize that the overall survival endpoint could still be reached.
  • In July 2017, Keytruda failed to meet primary endpoint of overall survival compared with current standards of care for previously treated recurrent or metastatic squamous cell carcinoma of the head and neck patients (in the Phase III KEYNOTE-040 trial). While Keytruda did not reach its primary end point, it was superior to investigator’s choice in terms of toxicity, an important consideration in treatment decisions for these poor-prognosis patients. Furthermore, subsequent treatment with an immunotherapy in the standard-of-care arm may have confounded overall survival analysis. There was also a trends towards an overall survival benefit in patients with PD-L1 combined positive score ≥ 1%, especially those with combined positive score ≥ 50%.
  • Developers of immune checkpoint inhibitors hit a stumbling block in multiple myeloma in 2017. As a result of a number of unexpected deaths in the combination experimental arms of Keytruda’s KEYNOTE trials, clinical holds have been placed on several studies of Keytruda and Opdivo (including all late-phase studies). The FDA considers the potential risks of adding PD-1 inhibitors to already established multiple myeloma treatments to outweigh the potential benefits. The future of PD-1/PD-L1 targeting agents (particularly in combination with other therapies) for multiple myeloma remains uncertain until further light is shed on the safety of such regimens.
  • Late in November, data from the pivotal Phase III JAVELIN trial revealed that Bavencio failed to demonstrates significant improvement in overall survival compared with chemotherapy for third-line unresectable, recurrent, or metastatic gastric cancer patients. Currently. Keytruda is the only immune checkpoint to be FDA approved for gastric cancer (approval was granted in September 2017).
  • In December 2017, Keytruda failed to significantly improve overall survival compared with paclitaxel for PD-L1 positive second-line gastric and gastroesophageal junction cancer patients (in the Phase III KEYNOTE-061 trial). The co-primary endpoint of progression-free survival was also not significantly improved. Nevertheless, the Phase III KEYNOTE-062 trial is ongoing and evaluating Keytruda in the first-line setting among PD-L1 positive patients.

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Contributors: Andrew Merron: Ph.D., Executive Director, Oncology and Biosimilars, Biopharma Insights
Published on: 29 December, 2017