Oncology Drug Discovery – 5 Years of Translational Success

Oncology Drug Discovery – 5 Years of Translational Success

Oncology Drug Discovery

Delivering Translational Excellence &

Fulfilling the Promise of Individualized Care

March 31, 2021

Wes Chapman

Figure 1

 Translation: “the process of turning observations in the laboratory, clinic, and community into interventions that improve the health of individuals and populations – from diagnostics and therapeutics to medical procedures and behavioral interventions.”

NIH National Center for Advancing Translational Sciences (NCATS)


Cancer is a disease of genetic origin, and it mirrors and amplifies through mutation the diversity of the people that it impacts. This is the fourth year of following drug oncology approvals, and the first time that I have had sufficient data to put together 5-year review. This analysis is focused on: 1) what are the drug approvals, 2) how can they best be categorized for broad understanding, and 3) the translation success of these drugs – do they actually “move the needle” for cancer patients. To do so, they must be safe and efficacious – and to be viable they must be economically impactful for the companies that produce them. This year the principal criteria that we included in this review includes:

  • Drug Type I break this down into immune therapy, targeted biological, biosimilar, chemotherapy. For convenience we include CART-T drugs into immune therapy, while recognizing that it has a different method of action, toxicity etc. than the normal checkpoint inhibitor. We also note combination trials, which seem to be growing rapidly in use.
  • Approval Type I target accelerated approval (created by the FDA in 1992) with this criterion and include oncology specific analogs including Real Time Oncology Review (RTOR). These approval methods were created to use surrogate clinical endpoints to hasten the introduction of potentially impactful medications.
  • Special Designation The special designation criterion captures FDA methods to facilitate drug review including fast track (1997), breakthrough (2012), priority (2012) and orphan drug (1983).
  • Indication The indicated use for which the drug is approved. These have historically focused on the organ of origin of the cancer but are increasingly used for genetic targets independent of cancer origin.
  • Trial Description This is a summary of the trial leading to the approval, including summary, number of patients and phase of trial – typically I, II or III. This year for the first time, I have included an analysis of cancer trials available in the US for cancer patients.
  • Noteworthy Effectiveness We created 10 criteria to denote noteworthy effectiveness – drugs which are effective to a degree to impact the life of cancer patients positively. These are subjective criteria developed with physicians over several years based on their view of patient impact rather than statistical relevance. While I recognize that both ASCO and ESMO are developing much more thorough and professionally researched methods, this is an effective shorthand, which we feel is directionally valid.
  • Administration This year our updated our data includes the method of administration for these drugs based on oral, infused or injected. We felt that this was relevant given the growth in orals as a rapidly growing part of total approvals.
  • Translation Success This year we have included a list of the top ten oncology drugs, measured by sales. This is one critical measure of translational success which we will be expanding in the future updates. This year we have also included selected references to literature which has analyzed the total addressable market for new immune therapies.
  • Sources The fundamental source of drug approvals is the list of hematology and oncology drug approvals updated daily by the FDA (here). The underlying data and bibliography for this blog are available upon request.

Oncology Drug Approvals

The growth of drug approvals forms the potential for translational success along multiple drug pathways. The last decade has seen the rate of drug approvals grow from a historical rate of around 5 per year (1990-2002) to an average of over 52 for the last 5 years. The approvals over the 5-year period have grown at a compounded rate of 29.9%, reaching 57 approvals in 2020.

Fortunately, the pace of drug discovery and approval increasingly offers a broad array of new drugs, targeted at specific genetic mutations and cell growth processes. Perhaps more importantly, the new drugs – targeted biologicals and immune therapies – are frequently less toxic and more efficacious than earlier chemotherapy. In other cases, the new drugs are combined with older therapies in combination trials, making both drugs more effective. Actual approvals for the 5-year period covered in this paper are 217 total approvals. Of these, 60 were novel compounds, 152 were previously approved drugs (new indications approved), 1 was for a supportive oncology drug, and 4 were for biosimilars – offering the potential for lower prices (see discussion of Neulasta and Herceptin below).

Oncology Drug Approvals

(Year Ending 12/31)

Figure 2

Figure 3

Drug approvals totaled 57 in 2020, growing 46% from 2019. Of note is the rebound in novel drug approvals, which increased 50% to 18 compounds. New approvals are the best measure of future expansions of new indications. In 2020 we saw the approval of only one new immune therapy, but 8 additional indications approved for existing compounds. As we will discuss more fully below, immune therapies – particularly the checkpoint inhibitors have accounted for a disproportionate share of total approvals in the last 5 years, expanding immune therapy treatment options to approximately 40% of all cancer patients. New drug entrants in this category are potentially important to future translational success.

Oncology Drug Approvals

(Year Ending 12/31)

Figure 4

We have grouped drug types for recent approvals into four broad categories. For the 5-year period these total combination drug trials (63) (including multiple drugs tested in a combination or actual drug conjugates), targeted biological therapies (104), immune therapies (44), bio-similars (4) and chemotherapy (2).

Drug Type

(Year Ending 12/31)

Figure 5

Targeted biologicals are designed to address a limited and specific mutation caused abnormality in the cancer, tend to have smaller addressable markets than either chemotherapy or immune therapies, but account for the largest number of approvals in the period. Combination trials are becoming increasingly important as manufacturers look to expand approvals through improved efficacy or reduced toxicity.

Figure 6

3d structure of Midostaurin, a multi-target protein kinase inhibitor being investigated for the treatment of acute myeloid leukemia,

myelodysplastic syndrome and advanced systemic mastocytosis

Multiple approvals for individual drugs are an increasingly important source of drug approvals. During the 5-year period, 28 drugs accounted for 110 of the total 217 approvals. The six immune therapies based on checkpoint inhibition (Opdivo, Yervoy, Keytruda, Bavencio, Tecentriq and Imfinzi) noted in the period accounted for 56 approvals in the period (51%). Of these, Keytruda accounted for 21, reflecting the breadth of applications for this compound.

(5 Year Period 2016-2020)

Figure 7


Not surprisingly, some of these new drugs – Merck’s Keytruda in particular – are having notable success in the marketplace, but at a difficult price point for payers and patients. Keytruda is projected to hit over $14 billion in sales in 2020, up 100% since 2018. This expansion in clinical applicability has expanded the total addressable market for immune therapies to 44% of total cancer patients in 2018, with an estimated 13% expected to have a therapeutic response (find the paper here). We assume that the expansion of approvals since the data used in this paper (2018) have further expanded the applicability of these drugs.


Figure 8

It should be noted that both Neulasta and Herceptin are showing sales declines in 2019 (and presumably into the future) due to competition from biosimilars. (Truxima as a biosimilar for rituximab in 2019 and Ogivri for Herceptin in 2017).

Oncology Drug Approvals

(Year Ending 12/31)

Figure 9

(Year Ending 12/31)

Figure 10

The increasing number and efficacy of the new targeted therapies and immunotherapies has contributed to changes in the regulatory approval process by the FDA and is leading to a sea change in how clinical trials are conducted in oncology.

The FDA recognized the critical need for patients to have access to effective therapies at the earliest possible opportunity and created several mechanisms for patients to get access to drugs sooner than the traditional approval process allowed. The tools available to get more rapid patient access include:

  • Accelerated approval: created in 1992, regulations that allow drugs for serious conditions that filled an unmet medical need to be approved based on a surrogate endpoint.
  • Fast track: created in 1997, a process designed to facilitate the development, and expedite the review of drugs to treat serious conditions and fill an unmet medical need.
  • Priority review: created in 2007, designation means FDA’s goal is to act on an application within 6 months.
  • Breakthrough therapy: created in 2012, a process designed to expedite the development and review of drugs which may demonstrate substantial improvement over available therapy.
  • The Real Time Oncology Review pilot (RTOR) begun in 2019 to facilitate much earlier review of trial data for high potential drugs in straightforward studies using easily interpreted endpoints.

Finally, as oncology drug development has increasingly focused on specific genetic disorders, more of these drugs are focused on a small number of patients. Accordingly, these drugs are also frequently accorded Orphan Drug Status by the FDA, which provides certain tax credits for their clinical development and other commercial advantages.

The FDA has adopted a practical and balanced view regarding the design and implementation of clinical trials to be responsive to:

  • Patient needs for new, safe, and efficacious therapies,
  • The need for open and vigorous debate over evolving trial design and scientific criteria,
  • The need for safety and efficacy of those therapies validated by ongoing rigorous scientific analysis, and
  • A scientific approach to the development and validation of surrogate endpoints in clinical trials.

Our analysis indicated that new drugs approvals are increasingly being granted accelerated approval status and special designation. Additionally, we are seeing an increase in approvals based on Phase I and II trials, both in absolute numbers and as a proportion of total approvals.

Figure 11

Analysis of Approval Type and Special Designation

(Year Ending 12/31)

Figure 12

(Year Ending 12/31)

Figure 13

This year we examined the total pharmaceutical industry sponsored cancer trials enrolling or waiting to enroll adult patients in the US as noted in ClinicalTrails.gov. The availability of early phase trials is critically important to cancer patients seeking alternative therapies. In 2020 there were 18 novel compounds approved, of which 14 were approved in early phase (1&2) trials. The objective of the analysis is to examine: 1) the growth in total cancer trials available for patients, and 2) the relative availability of early phase trials compared to phase III and IV trials. Total cancer trials fitting our criteria totaled 2,914 as of December 31, 2020 an increase of 12% over the prior year. Early phase trials grew at a comparable rate and constituted 2,583 trials, 88.6% of total trials – a clear indication of the number of new compounds and applications pending trials.

Figure 14


(Year Ending 12/31)

Figure 15

The noteworthy effectiveness metric is based on 10 common surrogate endpoints used for approval in oncology drug trials. These metrics have been developed in consultation with oncologists over the last 4 years and are designed to bridge the gap between what is statistically meaningful and what is practically relevant to patients. They are definitionally not scientific in their derivation, and are designed to be estimates of impact on patient impacts – which are always individual and change over time. ASCO began an extensive investigation into this issue beginning in 2012, and has been active ever since (here). The methods that they are considering are much more robust than the simple measures utilized herein, but we feel that our parameters are simple, comprehensible, developed with expert practicing physicians, and have been used consistently over the period of our analysis – and are accordingly presented this year. Over the period in question, drug approvals with noteworthy effectiveness have ranged from a low of 60% in 2018 to a high of 85% in 2016 and 2020.

(Year Ending 12/31)

Figure 16

This year we began looking at the method of administration of the drug (infusion, oral or injection), and re-examined the historical data to provide a complete picture. We were surprised to find that approvals of oral compounds have become the largest method for all drug approvals in 2019 and 2020. This is clearly a reflection in the growth of small molecule targeted biologicals and the nature of those compounds. We expect that additional clinical pathways in the future will include oral compounds and understand that this change is impacting the design and execution of clinical trials in the future.

(Year Ending 12/31)

Figure 17

(Year Ending 12/31)

Figure 18

It is a fact that almost all cancer trials are based on surrogate endpoints rather than overall survival rates for 5 years – the gold standard for medical oncology. As new drugs are approved, however, we would expect to see a decline in the rate of death due to cancer in the population – assuming that they are being widely and effectively used in the population.

The history for efficacious targeted therapy dates back to the 1970s. Targeted cancer therapy was initiated in the 1970’s with the introduction of tamoxifen, a drug that interferes with estrogen’s ability to stimulate cancer growth in ER-positive breast cancer. The approval of imatinib mesylate (Gleevec) in May of 2001 is noted as the first approval of a rationally designed, molecularly targeted therapy. Gleevec, a very successful therapy used on Philadelphia chromosome-positive CML and GIST cancers, was approved using AA and a single phase one trial of 83 patients, paired with three roughly simultaneous phase 2 trials totaling 1027 patients. The FDA approved ipilimumab (Yervoy) in March of 2011, the first checkpoint antibody (immunotherapy), for the treatment of melanoma. The approval was based on a phase 3 trial with 1783 participants.

Based on the most recent evidence (shown below) the rate of cancer death is declining in the US. While this can have many reasons including reduced smoking, improved screening, reduction of carcinogens in the environment etc., there can be little doubt that increased drug choice, availability and efficacy has made a major contribution as well.

Figure 19

The examination of oncology drug approval data for this year confirms the continuation of trends noted in prior years:

  1. The total pace of drug approvals continues to grow, with commensurate growth in novel compounds,
  2. Most new drugs are approved with some form of accelerated approval and/or special designation,
  3. Phase I and II trials continue to grow as the operative method for new drug approval, and constitute 88.5% of total oncology drug trials,
  4. Drugs with multiple approvals continue to constitute the majority of new approvals, and checkpoint inhibitors disproportionately dominate multiple approvals,
  5. Almost all new drug approvals are based on immune therapies, targeted biological, or combination trials, and
  6. New drug approvals continue to deliver noteworthy effectiveness to patients.

New criteria included this year indicate that:

  1. Oral administration is rapidly growing as the largest class of new approvals,
  2. Early phase trials dominate the total number of cancer trials, and
  3. Population statistics regarding cancer death rates in the population tend to confirm the success of these new therapies.

Based on these trends, it is clear that:

  1. The acceleration of drug approvals is dramatically expanding the potential formulary available in medical oncology. The drugs being approved are targeted at specific mutation targets and increase the need for good formulary control in value-based care programs,
  2. The large and increasing number of early stage trials offer patients many alternatives in their search for effective cancer care,
  3. Close monitoring of response to immune therapies is vital to determine efficacy,
  4. Systematic patient reviews such as tumor boards need to consider the alternatives presented by clinical trials, and
  5. The continued success of clinical trials in delivering effective treatments is good news for cancer patients.



Wes Chapman
Written by Wes Chapman

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