Do biosimilar monoclonal antibodies perform as well as the original medicine for cancer treatment?

Key messages

– For people with lung, colorectal (a cancer that develops in the colon or rectum), non-Hodgkin's lymphoma (type of blood cancer), or breast cancers, bevacizumab, rituximab, and trastuzumab biosimilars (products similar to a medicine made from living organisms) or original (called originator) medicines have similar effects on outcomes considered important by consumers.

– The length of time people are alive and cancer-free after the start of treatment was similar between biosimilar medicines and their originators, without a higher rate of harmful effects or deaths. We found only one small study that reported people's well-being receiving one of these medicines and there were no differences.

What is a biosimilar and an originator medicine?

There are several medicines used in cancer treatment that are made with materials from living organisms. This type of medicine is called a biological. Biologicals work in cancer by killing cancer cells. Biosimilars are medicines that are similar to the original biological medicine (called an originator). Although they have a slightly different structure, they target cancer cells in the same way. Originator medicines receive approval from a regulatory agency before biosimilars. Originator medicines may also be called a reference or innovator medicine. Different from generic (non-branded) medicines that are chemically derived molecules, originators and biosimilars are biological medicines and, for this reason, it is more difficult for the manufacturer to develop biosimilars with identical characteristics as the originators. Biosimilars are often cheaper to use than originators, and this could improve access to effective cancer treatment if they have comparable effects on survival and harms.

What did we want to find out?

We wanted to compare the benefits and harms of bevacizumab, rituximab, and trastuzumab biosimilars with their originators. Based on the opinion of five people with cancer, we classified the following outcomes as critical for making clinical decisions.

– The average length of time after the start of treatment in which a person is alive, and their cancer does not grow or spread.

– The average length of time from the start of treatment that people remain cancer-free.

– The average length of time people are alive after the start of treatment.

– The number of people whose cancer assessed in the breast tissue removed after the surgery disappears with the treatment.

– Unwanted or harmful severe effects.

– Well-being.

We classified the following outcomes as important for making clinical decisions.

– The number of people whose cancer shrinks or disappears after treatment.

– Death.

– The average length of time after the start of treatment until the cancer grows or spreads, or death.

What did we do?

We searched for studies that compared bevacizumab, rituximab, or trastuzumab biosimilar with each originator to treat people with lung, colorectal (a cancer that develops in the colon or rectum), non-Hodkin's lymphoma (type of blood cancer), and breast cancers.

We compared and summarised their results, and rated our confidence in the evidence, based on factors such as study methods and sizes.

What did we find?

We found 55 studies with 22,046 people with cancer. Of these, 10,639 people received bevacizumab and included people with lung cancer where the cancer had returned (advanced) or spread to other parts of the body (metastatic); 4412 received rituximab and included mainly people with non-Hodgkin's lymphoma; and 6995 people received trastuzumab to treat advanced or metastatic breast cancer. The average age of individuals ranged from 47 to 62 years. Studies took place around the world, including Asia, Europe, and North and South America. Pharmaceutical companies that manufactured the biosimilars funded all studies.

Main results and our confidence in the findings

Receiving biosimilars of bevacizumab, rituximab, or trastuzumab or originator medicines led to similar results. Overall, we are moderately confident that the biosimilar is as good as the respective originator medicine in treating cancer. To make sure the results were identical between biosimilars and originator medicines, we defined a very restricted range in which the results would be considered sufficiently similar. Most results fell outside this range, which is why we are moderately confident in the results.

What are the limitations of the evidence?

Most studies were well run, but in a few of the studies it was possible that people were aware of which treatment they were getting, and not all the studies provided data about everything that we were interested in.

How up to date is the evidence?

The evidence is up to date to 10 February 2024.

Authors' conclusions: 

Treatment with bevacizumab, rituximab, and trastuzumab biosimilars are likely similar to their originator drugs in terms of their impact on progression-free survival, duration of response, overall survival, serious adverse events, objective response, and mortality. Limited evidence showed similarity in pathological complete response for trastuzumab and quality of life for bevacizumab compared with originators, which was not assessed in the other comparisons. The overall certainty of evidence was moderate and imprecision was the main reason for downgrading our certainty in the findings.

Read the full abstract...
Background: 

Biosimilars are products containing an approved biological medicine. They are similar, but not identical, to an originator medicine. In cancer, biosimilars have been developed from the monoclonal antibodies, bevacizumab, rituximab, and trastuzumab. They have become available for the treatment of lung, colorectal, non-Hodkin's lymphoma, and breast cancers. As these biological products are not identical, synthesis of evidence of the clinical effects of biosimilars compared to their originators is needed to understand their comparative effectiveness and harms.

Objectives: 

To evaluate the benefits and harms of biosimilar monoclonal antibodies versus their originator drugs for adults with cancer.

Search strategy: 

We searched bibliographic (CENTRAL, MEDLINE, Embase, Web of Science) and clinical trials databases to February 2024.

Selection criteria: 

We included head-to-head randomised controlled trials conducted in adults with cancer treated with biosimilar or originator monoclonal antibodies.

Data collection and analysis: 

We followed standard Cochrane methodology. Primary outcomes were progression-free survival, duration of response, overall survival, breast cancer's pathological complete response, serious adverse events, and health-related quality of life. If survival estimates were adjusted or provided as rates, we did not combine them. We used Cochrane's RoB 1 tool to assess the risk of bias and GRADE to evaluate the certainty of evidence of critical and important outcomes according to the relevance determined by consumers.

Main results: 

We included 55 studies with 22,046 adults (23 of bevacizumab, 10,639 participants with colorectal or lung cancer; 17 of rituximab, 4412 participants with non-Hodgkin's lymphoma; and 15 of trastuzumab, 6995 participants with breast cancer). Studies were conducted in all continents, most were multicentre, and all were funded by the drug manufacturer. Participants' ages ranged from 47 (mean) to 62 (median) years and the proportion of women from 18% to 100%. Fifteen studies were conducted as non-inferiority and 40 as equivalence. The overall risk of bias was low; main biases were in the incomplete outcome data and selective reporting domains.

Bevacizumab biosimilar versus bevacizumab originator in lung or colorectal cancer

Progression-free survival is likely similar between bevacizumab biosimilar and the originator (per 1000: 380 in both groups at 12 months, hazard ratio (HR) 1.00, 95% confidence interval (CI) 0.91 to 1.09; 5 studies, 2660 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancer subgroups.

Bevacizumab biosimilar is likely similar to the originator in duration of response (per 1000: 219 participants who achieved response progressed with biosimilar versus 210 with originator at 12 months; HR 1.05, 95% CI 0.81 to 1.37; 1 study, 762 participants; moderate-certainty evidence) and overall survival (per 1000: 592 with biosimilar versus 610 with originator at 12 months; HR 1.06, 95% CI 0.94 to 1.19; 5 studies, 2783 participants; moderate-certainty evidence). There were no differences in cancer type subgroups.

Bevacizumab biosimilar is likely similar to the originator in serious adverse events (per 1000: 303 with biosimilar versus 309 with originator; risk ratio (RR) 0.98, 95% CI 0.93 to 1.03; 23 studies, 10,619 participants; moderate-certainty evidence).

Bevacizumab biosimilar may be similar to originator in health-related quality of life as scores were comparable in the one study that assessed this outcome in metastatic colorectal cancer (low-certainty evidence). This critical outcome was not assessed in other biosimilars comparisons.

Bevacizumab biosimilar is likely similar to originator in objective response (per 1000: 481 with biosimilar versus 501 with originator; RR 0.96, 95% CI 0.93 to 1.00; 23 studies, 10,054 participants; moderate-certainty evidence) and mortality (per 1000: 287 with biosimilar versus 279 with originator; RR 1.03, 95% CI 0.97 to 1.09; 19 studies, 9231 participants; moderate-certainty evidence). There were no differences in lung or colorectal cancers.

Rituximab biosimilar versus rituximab originator in non-Hodgkin's lymphoma

Rituximab biosimilar is likely similar to originator in progression-free survival (7 studies, 2456 participants), duration of response (2 studies, 522 participants), and overall survival (7 studies, 2353 participants; data not pooled as survival estimates were adjusted for different factors or reported as rates) (all moderate-certainty evidence).

Rituximab biosimilar is likely similar to originator in the risk of serious adverse events (per 1000: 210 with biosimilar versus 204 with originator; RR 1.03, 95% CI 0.94 to 1.14; 15 studies, 4197 participants; moderate-certainty evidence) and objective response (per 1000: 807 with biosimilar versus 799 with originator; RR 1.01, 95% CI 0.98 to 1.04; 16 studies, 3922 participants; moderate-certainty evidence). No study reported quality of life.

Rituximab biosimilar is similar to originator in mortality (per 1000: 52 with biosimilar versus 53 with originator; RR 0.97, 95% CI 0.70 to 1.35; 8 studies, 2557 participants; high-certainty evidence).

Trastuzumab biosimilar versus trastuzumab originator in breast cancer

Trastuzumab biosimilar is likely similar to originator in progression-free survival (4 studies, 2221 participants), duration of response (3 studies, 1488 participants), and overall survival (6 studies, 2221 participants), which were not pooled due to adjustment for different factors or provided as rates. No study reported quality of life.

Trastuzumab biosimilar may be similar to originator in pathological complete response (per 1000: 459 with biosimilar versus 433 with originator; RR 1.06, 95% CI 0.95 to 1.17; 7 studies, 3403 participants; low-certainty evidence), is likely similar in serious adverse events (per 1000: 129 in both groups; RR 1.00, 95% CI 0.85 to 1.17; 13 studies, 6183 participants; moderate-certainty evidence), and slightly increases objective response (per 1000: 801 with biosimilar versus 777 with originator; RR 1.03, 95% CI 1.01 to 1.05; 13 studies, 5509 participants; moderate-certainty evidence).