Angelica  Welch

Real-world dosing data for regorafenib (Stivarga) in patients with metastatic colorectal cancer (mCRC) was presented at the 2018 ESMO Congress from the prospective, observational CORRELATE study. According to Juan Manuel O&rsquo;Connor, MD, incorporating real-world data has become increasingly important in daily use of anticancer agents.

A dose of regorafenib at 160 mg daily for a 3-week-on/1-week-off schedule is currently indicated for the treatment of refractory patients with mCRC. The real-world data from CORRELATE reported on regorafenib in patients across 13 countries in Europe, Latin America, and Asia. The principal aim of this study was to assess safety.

Findings showed that 57% of the 1037 patients evaluated started treatment at 160 mg, 30% of patients began at 120 mg, and 13% began at &le;80 mg. Investigators noted that dose reductions were most frequent in the 160-mg group, and treatment modifications were due mostly to treatment-emergent adverse events (TEAEs; 66%).

Grade &ge;3 TEAEs occurred in 62% of patients, 36% of which were attributed to regorafenib. The most common of the grade &ge;3 TEAEs related to regorafenib were fatigue (9%), hand-foot skin reaction (7%), and hypertension (6%). Although grade 5 TEAEs were observed in 17% of patients, only 1% were deemed to be regorafenib related.

The safety profile of regorafenib has led to studies evaluating dose escalation as a way to limit TEAEs. Most recently, the NCCN revised its guidelines regarding regorafenib, based on findings from the ReDOS study.

In ReDOS, investigators evaluated a dose-escalation strategy of regorafenib beginning at 80 mg and ending at 160 mg for previously treated patients with mCRC. Positive overall survival (OS) and progression-free survival (PFS) data led to the recommendation of a starting dose of 80 mg/daily on days 1 to 7, escalating to 120 mg/daily on days 8 to 14, and concluding with 160 mg/daily on days 15 to 21. From there, subsequent cycles should use 160 mg of regorafenib on days 1 to 21 every 28 days, according to the NCCN.

, O'Connor, head, Department Gastrointestinal Oncology, Department of Clinical Oncology, Institute Alexander Fleming, Buenos Aires, discussed the final results of the CORRELATE regorafenib study in patients with mCRC, emphasizing the importance of real-world data.

Could you please share the final results from CORRELATE?

The approval dose of regorafenib for the treatment of patients with mCRC is 160 mg. There are some differences between the real-world setting and the patients included in the randomized clinical trial. The aim of our study was to look at the data from the real-world setting of refractory mCRC in more detail.

The final results of our study described a starting dose in patients based on the decisions of the treating physicians. Of the patients enrolled on the study, 57% of those who started at the recommended dose of 160 mg, 30% at 120 mg, and 13% at 80 mg. That is very important information.

What are your thoughts on regorafenib in a dose-escalation regimen?

There were very important data from the ReDOS trial based on the escalation and re-escalation. In our study, around 20% of our patients required an escalated dose. We plan to analyze this subgroup based on the new data coming from the ReDOS trial.

The primary objective of our study was to characterize the use of regorafenib in a real-world setting based on safety and efficacy, mainly in terms of progression-free and overall survival. Based on the observational study, safety is a very important issue to keep in mind.

Can you speak to the tolerability of regorafenib?

One of the problems with the use of regorafenib is the starting dose. Therefore, in the real-world observational study, the data were not equal in terms of safety. There are many doctors that used a starting dose that was different than the recommended dose. It is important to keep the ReDOS data in mind with this study. These are important data because we have more data from the treating physician perspective, as they feel more confident in the dosing when treating patients with refractory mCRC.

What would be your take-home message about CORRELATE?

Our take-home message from this observational study was that, despite the flexible doses of regorafenib, there was no impact in the effectiveness in terms of the median OS and median PFS. It was 7.7 months in terms of median OS, which was a little bit more than the 2 previous trialsCORRECT and CONCUR. The median PFS was 2.9 months.

In the future, it is important to consider data from the real-world setting. There is likely a big difference between the patients included in the randomized clinical trial compared with the real world. We will get more information from routine clinical practice, mainly in terms of safety.

O'Connor JM, Ducreux M, Petersen LN, et al. Real-world dosing of regorafenib (REG) in metastatic colorectal cancer (mCRC): final results from the prospective, observational CORRELATE study.

2018;29 (suppl_8): viii150-viii204. 10.1093/annonc/mdy281

Bekaii-Saab TS, Ou FS, Anderson DM, et al. Regorafenib dose optimization study (ReDOS): Randomized phase II trial to evaluate dosing strategies for regorafenib in refractory metastatic colorectal cancer (mCRC)an ACCRU Network study.

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Real-world dosing data for regorafenib in patients with metastatic colorectal cancer was presented at the 2018 ESMO Congress from the prospective, observational CORRELATE study.

Expert Discusses Real-World Data for Regorafenib in mCRC

There are several biosimilars for trastuzumab (Herceptin) coming down the pipeline, but so far the only FDA-approved biosimilar for this biologic in the United States is MYL-1401O (Ogivri; trastuzumab-dkst), according to Francisco J. Esteva, MD, PhD.

One potential trastuzumab biosimilar, CT-P6, is currently being investigated for safety and efficacy. Investigators aim to determine whether it is equivalent to reference trastuzumab in patients with early-stage breast cancer already being treated with neoadjuvant chemotherapy (NCT02162667).

published findings demonstrating that CT-P6 used as treatment for patients with HER2-positive breast cancer demonstrated equivalent efficacy to reference trastuzumab. The adverse events observed in both arms were also similar with this biosimilar.

The randomized, double-blind, active-controlled, phase III trial led to the February 2018 European Union approval of CT-P6, marketed as Herzuma.

The biosimilar is approved for the treatment of patients with early breast cancer, metastatic breast cancer, or metastatic gastric cancer whose tumors have either HER2 overexpression or

gene amplification. This type of extrapolation beyond the indication studied in pivotal studies is expected from regulatory agencies in the future.

Celltrion, the manufacturer of CT-P6, resubmitted an abbreviated biologics license application for the biosimilar to the FDA in June 2018. In January, the company received a complete response letter from the FDA to their application regarding their manufacturing facility in Incheon, South Korea.

Of 546 patients enrolled on the pivotal phase III trial, 271 were randomized to CT-P6, while 278 received reference trastuzumab. The rates of pathologic complete response (pCR) were similar between the treatment arms. In the CT-P6 arm, the pCR was 46.8%, which is comparable with the pCR of 50.4% for reference trastuzumab.

&ldquo;It is important to show that biosimilars for originator biologics can be as effective and safe as the reference product,&rdquo; said Esteva, global principal investigator for the pivotal registration trial. &ldquo;I believe that with CT-P6, we have been able to show that.&rdquo;

Esteva, director of breast medical oncology at NYU Langone&rsquo;s Perlmutter Cancer Center, discussed the current data surrounding CT-P6 demonstrating its potential as a biosimilar for trastuzumab in the United States.

Could you provide some background information on this phase III equivalence trial of CT-P6?

We conducted a randomized, phase III, multicenter trial to compare the reference trastuzumab with the biosimilar candidate CT-P6. We decided to study it in patients with early-stage breast cancer in the neoadjuvant setting with standard chemotherapy with the primary endpoint of pCR as opposed to overall survival (OS) or disease-free survival (DFS), which takes much longer.

When we planned this trial with the sponsor, the FDA had provided some guidance regarding patient population and endpoints, but there were no biosimilars approved at that time. The guiding principle was that the agency would look at the totality of the evidence.

Several trastuzumab biosimilars were studied in the metastatic setting and some in early-stage breast cancer. However, it was not completely clear what the FDA would consider a valid endpoint for approval. We thought pCR was an appropriate endpoint in HER2-positive breast cancer, since pertuzumab (Perjeta) had been approved in the neoadjuvant setting by the FDA based on pCR. Therefore, we chose early stagemostly stage II and III&mdash;breast cancer in the neoadjuvant setting with an endpoint of pCR. We showed that the pCR was within the statistical boundaries for the prespecified similarity between reference trastuzumab and the trastuzumab biosimilar CT-P6.

The primary endpoint of the study was pCR at the time of definitive surgery. We are now assessing the DFS and the OS rates, which are secondary endpoints on the study. We hope the totality of the data generated by this trial will be sufficient to get it approved by the FDA.

Can you touch on the development and&nbsp;testing of a biosimilar?

When we started this project, no biosimilars were approved by the FDA [for the treatment of cancer]. Now, there are several monoclonal antibody biosimilars approved, and there will be more in the next few years. The standard drug development for originator antibodies such as [trastuzumab] involves phase I, II, and III trials. But, for biosimilars, that is not required by the FDA. Once similarity is demonstrated, the agency will likely allow extrapolation to other indications related to the reference drug.

For CT-P6, the sponsor completed a phase I trial

and the pivotal randomized phase III trial described above. The phase I study showed the safety and pharmacokinetics of the CT-P6 biosimilar compared with reference trastuzumab. What is different about this phase I trial compared with traditional phase I trials is that this was a randomized trial. Phase I trials are not usually randomized, as they involve a small number of patients. In this trial, we had to randomize participants to be able to compare the pharmacokinetics of the biosimilar with the originator product. The other difference is that this was done in patients without cancer. These patients were given 1 dose, and then we looked at the pharmacokinetics of both monoclonal antibodies.

Prior to launching any clinical trials, manufacturers must produce extensive preclinical data to demonstrate that their molecule is the same as the reference drug through amino acid sequencing, purity, functional studies and other in vitro and in vivo experiments. This is very different to the drug development of generic drugs, for which the preclinical development is much less stringent. Biologics are protein-based therapies made in living cells, which is much more complex than chemical entities.

Manufacturing a monoclonal antibody similar to trastuzumab, bevacizumab (Avastin), or rituximab (Rituxan), is extremely difficult and requires sophisticated technology. First, they have to show that it is the same molecule in vitro and in vivo. Then in patients, sponsors must show that the pharmacokinetics and efficacy are the same in randomized trials.

Although all this guidance and experience is leading to the first wave of biosimilars, in the future we may not need to complete large randomized trials like the one we recently completed for CT-P6.

Although there is already a trastuzumab biosimilar approved, it isn't available for use in the clinic yet. When do you think these agents will start being used?

My understanding is that biotechnology companies may not be able to market trastuzumab biosimilars until the original patents expire in the United States, even if the drug is FDA approved. Patents are different in each country.

What are your thoughts on bringing biosimilars into the treatment of cancer?

I was personally involved in the clinical development of CT-P6 and I believe the totality of the evidence supports its use for the appropriate indications. I hope this and other biosimilar monoclonal antibodies are incorporated into patient care, and help reduce the cost of healthcare in the long run. Although trastuzumab biosimilars are not an improvement over what is already available in terms of safety and efficacy, having more options should bring down the costs of older medications so that we can spend more resources developing new drugs.

Stebbing J, Baranau Y, Baryas V, et al. CT-P6 compared with reference trastuzumab for HER2-positive breast cancer: a randomised, double-blind, active-controlled, phase 3 equivalence trial.

2017;18(7):917-928. doi: 10.1016/S1470-2045(17)30434-5.

Celltrion Receives EU Approval for Trastuzumab Biosimilar. Published February 14, 2018. https://www.celltrion.com/en/pr/reportDetail.do?seq=476. Accessed August 21, 2018.

Esteva FJ, Stebbing J, Wood-Horrall RN, et al. A randomised trial comparing the pharmacokinetics and safety of the biosimilar CT-P6 with reference trastuzumab.

2018;81(3):505-514. doi: 10.1007/s00280-017-3510-7.

Francisco J. Esteva, MD, PhD,&nbsp;discusses the current data surrounding CT-P6 demonstrating its potential as a biosimilar for trastuzumab in the United States.

Angelica Welch | Authors

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Expert Discusses Real-World Data for Regorafenib in mCRC

Trastuzumab Biosimilar Candidate Shows Promise in Early-Stage Breast Cancer