Explosion in GI Cancer Drugs 'Confusing for Clinicians'

Liam Davenport

June 27, 2018

BARCELONA, Spain — The huge number of new cancer drugs that have been approved in the past few years, including those for gastrointestinal tumors, has made it "difficult to make a choice of which treatment to use," said Jean-Yves Douillard, MD, PhD, chief medical officer at the European Society of Medical Oncology (ESMO).

Referring to the increase in the number of available therapies as an "explosion," he suggested that assessment tools can help clinicians choose between the myriad drugs and combinations available by ranking their degree of benefit.

Systematically examining clinical benefit with assessment tools can provide guidance as to which regimens to use in which patients, although it does not help with "the thorny question of the rising costs of treatments," he said.

How to select patients for individual drugs is often not clear, and the issue is not helped by the current design of many trials, commented Jorge Camarero, PhD, from the European Medicines Agency (EMA) and the Spanish Medicines Agency in Madrid.

Stephen Lemery, MD, MHS, US Food and Drug Administration (FDA), Silver Spring, Maryland, agreed. He called for greater oversight of trial designs by regulatory agencies and told the audience that they have the power to decide which trials are undertaken.

The three experts were speaking here at the World Congress on Gastrointestinal Cancer 2018. They noted the huge increase in approvals for new cancer drugs in recent years.

But the issue is wider than that, Douillard noted. "If you look not only at the drug approvals but also at the extent of indication, you see that, in 2017, 59 new indications were approved, and as of May 2018, 26 were," he said. "So it's not only the new drugs that are approved, it is the extension of indication that should also be considered."

Many Drugs, but Few Outliers

Regarding the benefits that the new drugs have provided, Douillard said that for 86 drugs that were approved during the past 11 years, "the median gain for all those drugs in overall survival is only 2.5 months, meaning that most of these drugs do not really contribute an improvement."

Some of the drugs are "outliers" and offer large gains in survival, "but they are not that numerous," he commented.

Recent decades have also seen a huge increase in the cost of cancer drugs, which Douillard said calls into question their sustainability.

From 1975 to 1979, the median monthly cost for new cancer drugs was just $129, but this had risen to more than $10,059 per month in the period 2010-2014.

"This raises major points, because cancer incidence is increasing, we treat more and more patients with better outcomes, since mortality is decreasing, but this has a cost, and most countries will no longer be able to face this cost," he said.

He explained that a number of different tools have been developed in recent years to help clinicians understand the relative benefit of different drugs and to prioritize between them.

These include the US National Comprehensive Cancer Network Evidence Blocks, the appraisals carried out by the UK's National Institute for Health and Care Excellence, the American Society of Clinical Oncology's (ASCO's) Value Framework, and the latest version of the ESMO–Magnitude of Clinical Benefit Scale (MCBS).

The first three take into account the cost of a treatment along with its clinical impact. The ESMO-MCBS focuses on overall survival, rather than progression-free survival; quality of life; the toxicity of treatment; and the prognosis associated with the condition.

These differences have led to some degree of discord between the results of the ASCO and ESMO assessments in the cases of noncurative diseases, Douillard commented.

Nevertheless, Douillard pointed out that, regardless of which of the scales is used, there is no significant difference in the monthly price of cancer drugs between the highest and lowest rated on both the ASCO and ESMO scales.

To help clinicians better choose between the most recently approved drugs and combinations for gastrointestinal tumors, Douillard presented a list of all recent colorectal cancer drugs, ranked by their ESMO-MCBS score.

No drug or drug combination achieved the highest score for clinical benefit of 5 for noncurative treatment, but five combinations achieved a score of 4 (see the table below).

Table. Therapies for CRC With Noncurative Intent With an ESMO-MCBS Score of 4

Medicines Colorectal Cancer Setting
FOLFOX4 + panitumumab 1st-line metastatic (post hoc KRAS, NRAS, BRAF wild type); RAS mutations
Panitumumab + mFOLFOX8 1st-line metastatic (KRAS wild type)
FOLFIRI + cetuximab 1st-line metastatic stratified for KRAS wild type (post hoc KRAS, MRAS wild type); RAS wild type
Cetuximab Refractory metastatic KRAS wild type
2nd-line nivolumab + ipilimumab Microsatellite instability high
FOLFOX, folinic acid, fluorouracil, oxaliplatin; FOLFIRI, folinic acid, fluorouracil, irinotecan


Douillard noted that the following five drug combinations achieved the lowest score of 1 on the ESMO-MCBS:

  • FOLFIRI plus ramucirumab in second-line metastatic colorectal cancer after bevacizumab

  • Oxaliplatin and fluoropyrimidine

  • Regorafinib in third-line metastatic disease

  • FOLFIRI plus afibercept as second line after oxaliplatin

  • Second-line chemotherapy plus bevacizumab following progression with bevacizumab alone

For pancreatic cancer, only FOLFIRINOX was given a score of 5 for first-line advanced or metastatic disease in patients who have a good performance status. Gemcitabine plus erlotinib was given the lowest score.

Summarizing, Douillard said: "With this explosion of drugs, we have several options available in a similar clinical setting. Of course, accessibility is one issue in certain countries.

"Affordability will soon be an issue in many countries, and patient preference has to be considered," he added.

Consequently, he believes that the ESMO-MCBS "is a good tool to discuss with the patient and explain why this regimen has been chosen rather than that one."

Camarero believes, however, that the picture is a little more complex. Despite several breakthroughs in cancer management, there are uncertainties regarding how to use the latest drugs, as well as concerns regarding access.

In delivering precision medicine, which he defined as "providing the right treatments to the right patients at the right time," he said it is necessary to identify the proper target population for a therapy and that this requires biomarkers.

These biomarkers, he said, should be capable of objectively measuring a normal biological process, a pathologic process, or a response to treatment. He asked, "Are all available targeted therapies biomarker based?"

Taking as an example niraparib (Zejula, Tesaro) for the treatment of ovarian cancer, Camarero pointed out that the drug showed similar activity regardless of whether patients had a germline BRCA mutation or homologous recombination deficiency.

For anti–programmed death ligand 1 (PD-L1) immunotherapies, the intended target is expression of PD-L1 by tumors and other cells in the tumor microenvironment.

However, the level of PD-L1 expression required can be extremely low — it was ≥1% in one study of advanced nonsquamous non–small cell lung cancer in which there was improvement in overall survival with nivolumab (Opdivo, Bristol-Myers Squibb) vs docetaxel.

Some data suggest that it may not be necessary to determine the level of PD-L1 expression. In a study that compared nivolumab with everolimus (Afinitor, Novartis) in the treatment of patients with advanced renal cell carcinoma, median overall survival was similar among patients with PD-L1 expression <1% and those with PD-L1 expression ≥1%.

Camarero also reminded the audience that, although immunotherapies are broadly active, in at least 12 distinct forms of cancer, they only benefit 10% to 30% of patients.

"Is it time to select and treat patients regardless of histology?" he therefore wondered.

An additional issue is that currently available trial data do not make it clear whether combination therapies are better than monotherapies or how best to sequence treatments.

Furthermore, findings from many of the single-arm trials, which by definition are not randomized, are open to interpretation. This can lead to discrepancies between the FDA and the EMA as to whether to approve a drug for a particular indication.

One example is that of nivolumab for the treatment of advanced hepatocellular carcinoma. The FDA granted accelerated approval of nivolumab for use in patients who had been previously treated with sorafenib, but the drug was rejected by the EMA.

Camarero said that the EMA has developed a series of tools to offer scientific advice and protocol assistance so as to improve the quality and the likelihood of success of applications for marketing approval.

The quality of trials supporting applications for drug approval was also discussed by Lemery, who pointed out that the appropriate trial design and the choosing of appropriate endpoints for those trials depend on the context in which the trials are carried out.

Emphasizing that randomization "still has value" in trial designs, he called for more inclusive trials, in which patients more closely reflect the real world, and argued that companies and research organizations need to "learn from the past."

Lemery said that, particularly for large, "seamless" trials that aim to capture as much information as possible about a drug, there should be greater oversight by relevant experts or divisions in the FDA and the EMA regarding the size and quality of the safety databases.

Moreover, he believes that companies should have to justify the design and sample size used for their trials.

Lemery said that, particularly when moving into phase 3 studies, the results of earlier-phase trials should not be overinterpreted.

"It does apply mathematically that, the more times you test — and we see this over and over presented in academic meetings — you'll see a P value of less than 0.05," he said. It dose not follow that "just by chance, it's likely to occur if you test enough."

He said that if a drug is found not to be effective, companies should "move onto the next drug earlier." Conversely, "if there's unprecedented drug activity," then trials can be modified and expanded.

Lemery told the audience that, as clinicians and researchers, they "have the power regarding enrollment."

"It's hard for us to stop a trial just for an efficacy reason," he told the audience. "It's really up to the academic community to really think hard about whether you should pursue this trial if it doesn't appear that promising."

Concluding, he said: "In an area of unprecedented drug effects in targeted populations, we need to use the appropriate, context-specific regulatory approaches, encourage inclusive enrolment, consider new trial designs, but more thoughtfully so."

Emphasizing the need for the "thoughtful use of biomarkers," he added: "We need to learn from prior negative trials, and you, as the investigators, really can control what drugs are studied."

The investigators have disclosed no relevant financial relationships.

World Congress on Gastrointestinal Cancer 2018. Presented June 23, 2018.

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