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Dr. Marshall Video Transcript

(0:00) [Intro music and LONSURF logo appears on screen with the text: "Navigating 3L treatment options for patients living with mCRC"]

(0:04) [On-screen text: INDICATIONS AND IMPORTANT SAFETY INFORMATION] INDICATIONS: LONSURF is indicated as a single agent or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS:

Severe Myelosuppression: In the 1114 patients who received LONSURF as a single agent, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (38%), anemia (17%), thrombocytopenia (4%) and febrile neutropenia (3%). Three patients (0.3%) died due to neutropenic infection/sepsis; four other patients (0.5%) died due to septic shock. A total of 14% of patients received granulocyte-colony stimulating factors. In the 246 patients who received LONSURF in combination with bevacizumab, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (52%), anemia (5%), thrombocytopenia (4%) and febrile neutropenia (0.4%).

Please see additional Important Safety Information throughout this video and full Prescribing Information at LONSURF.com/PI.

(0:26) [Dr. John L. Marshall appears on screen]

[On-screen text: The opinions expressed in this video are based on Dr. Marshall's clinical experience.] Dr. John L. Marshall: My name is Dr. John Marshall. I'm a medical oncologist in Washington, DC, and I've been in practice focusing on GI cancers for over 30 years.

(0:36) [On-screen text: How would you describe the third-line treatment landscape for metastatic colorectal cancer?]

Dr. John L. Marshall: Our evolution in the treatment of patients with metastatic colorectal cancer has brought us to a better place where we now have multiple treatment options for patients in the third-line setting.

We have, first, LONSURF—trifluridine, tipiracil—and then we have LONSURF + bev, bevacizumab, which has demonstrated outcomes over LONSURF alone. We also have fruquintinib, and we have regorafenib, and of course, we have clinical trials and other options.

(2:11) [On-screen text: How do you choose a 3L treatment for patients with mCRC?]

Dr. John L. Marshall: Let's take a pause and look at that third-line patient. That patient has had 2 types of traditional chemotherapy with the appropriate biologic and is motivated to consider third-line options.

So how does one pick among them? My primary motivator is based on the single-agent data from LONSURF alone. Then subsequent data of the SUNLIGHT clinical trial, with the addition of bevacizumab. LONSURF + bev is a very key player and one that I regularly choose for my patients in this third-line setting.

[On-screen text: 3L mCRC treatment options

• Trifluridine and tipiracil (LONSURF)
• Trifluridine and tipiracil (LONSURF) + bevacizumab
• Fruquintinib
• Regorafenib
• Clinical trials
• Best supportive care]

(2:52) [On-screen text: How would you describe the SUNLIGHT trial?]

Dr. John L. Marshall: The SUNLIGHT trial is a very cleanly designed study.

Almost 500 patients evenly randomized 1-to-1 to the combination of LONSURF—traditional dosing, 35 mg/m² Days 1 through 5 and Days 8 through 12 every 28 days—combined with bevacizumab—5 mg/kg IV Days 1 and 15—compared to LONSURF alone. The endpoints were the traditional high-level endpoints, primary endpoint: overall survival, secondary endpoint: progression-free survival, disease control rate, time to worsening to ECOG PS ≥2, and of course, safety.

There was a clear improvement in overall survival with the combination. LONSURF + bevacizumab, 10.8 months vs 7.5 months for the single-agent LONSURF.

The important secondary endpoints, progression-free survival—the one I typically keep top of mind for patients—5.6 months for the combination, 2.4 months for LONSURF alone.

And then one that I also feel is highly important is disease control rate. If you look at the combination, 77% for LONSURF + bev and 47% for LONSURF alone.

So for all of these 3 key metrics, the combination proved superior to the single agent.

Many of us had already been incorporating the combination even before the SUNLIGHT study came forward. Mainly because we were observing clinical benefit. I have many patients who are on the treatment for many months, and I've had some patients who have been on the combination treatment for a year or more. So my experience mirrors the results of the SUNLIGHT clinical trial.

(4:48) [On-screen text: How do you determine the right dose of LONSURF + bevacizumab for patients?]

Dr. John L. Marshall: So what I do is I go to the LONSURF website, and on there is a dose calculator.

All I need to remember is the BSA of the patient or height and weight, and it will do the rest for me.

It'll print a calendar for you, and it'll also calculate dose modifications if that's what you need.

(5:13) [On-screen text: How have your patients generally tolerated LONSURF + bevacizumab, and how do you address its side effects?]

Dr. John L. Marshall: In my experience in my patients, the side effects that we are observing very much mirror those of the publication from the SUNLIGHT study. The common side effects that I go in and talk to a patient about are going to be myelosuppression—we know that these drugs can do that—fatigue, and nausea towards the end of a treatment week.

There are, of course, other less common side effects that we need to watch out for that one sees from this combination.

(5:48) [On-screen text: In short, why would you recommend LONSURF + bevacizumab in 3L mCRC?]

Dr. John L. Marshall: In third-line metastatic colorectal cancer, the SUNLIGHT clinical trial shows us that the combination of LONSURF + bevacizumab was superior to LONSURF alone; in overall survival, progression-free survival, and disease control rate. So when I am sitting across the exam room from a patient, I go back to the SUNLIGHT data and remember that this improvement was significant and important for the patient in front of me.

And so this is my motivation for the combination of LONSURF + bev to be my favorite choice for most patients in the third-line setting.

By thoughtfully using a proven therapy like LONSURF + bevacizumab at the right time, we give our patients the best opportunity to extend their overall survival.

(6:44) [Outro music and LONSURF logo appears with link to LONSURFHCP.com]

Dr. Fakih Video Transcript

[00:00 - 01:27] Important Safety Information

(On-screen text) LONSURF^® (trifluridine and tipiracil) tablets logo.

Importance of timely intervention in patients with refractory mCRC

Indications and Important Safety Information

INDICATIONS
LONSURF is indicated as a single agent or in combination with bevacizumab for the treatment of adult patients with metastatic colorectal cancer previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and if RAS wild-type, an anti-EGFR therapy.

IMPORTANT SAFETY INFORMATION
WARNINGS AND PRECAUTIONS
Severe Myelosuppression: In the 1114 patients who received LONSURF as a single agent, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (38%), anemia (17%), thrombocytopenia (4%) and febrile neutropenia (3%). Three patients (0.3%) died due to neutropenic infection/sepsis; four other patients (0.5%) died due to septic shock.

A total of 14% of patients received granulocyte-colony stimulating factors. In the 246 patients who received LONSURF in combination with bevacizumab, LONSURF caused severe or life-threatening myelosuppression (Grade 3-4) consisting of neutropenia (52%), anemia (5%), thrombocytopenia (4%) and febrile neutropenia (0.4%).

Please see additional Important Safety Information throughout this video and full Prescribing Information at LONSURF.com/PI.

[01:27 - 01:37] Speaker Introduction

My name is Marwan G. Fakih. I'm a medical oncologist, and I focus on gastrointestinal cancers, specifically colorectal cancer. I practice at City of Hope in Duarte, California.

[01:38 - 02:37] Why is it important for patients with metastatic colorectal cancer to make a timely transition to third-line treatment?

Over and over again, studies show that patients who benefit from systemic therapy benefit the most if they have an ECOG performance status of 0 to 1. In our patients who are receiving second-line therapy, we perform imaging studies on an every-2-months basis.

The main reason for that is that you want to know if the treatment is working, and you want to stop a treatment that is not effective any longer as soon as possible.

Now this provides us with the opportunity to start on a third-line therapy immediately at the time of progression when the patient is still maintaining a good performance status. If we wait until a patient not only has exhausted therapy but has gone through continuation of treatment beyond progression on a second-line treatment and wait until that patient has deteriorated, we may not derive the same benefit.

[02:37 - 03:11] What is your approach to 3L mCRC treatment?

In the management of my patients with metastatic colorectal cancer who are ready to proceed with a third-line therapy, I often choose LONSURF and bevacizumab. And the reason for choosing LONSURF and bevacizumab is really based on Level 1 evidence from a large Phase 3 randomized clinical trial that showed that LONSURF and bevacizumab is superior to a monotherapy active comparator, namely LONSURF.

[03:11 - 05:01] How would you describe the SUNLIGHT trial and its key efficacy outcomes?

The SUNLIGHT trial is a Phase 3 randomized clinical trial that enrolled patients with metastatic colorectal cancer who had progressed on no more than 2 prior lines of therapies that included oxaliplatin, a fluoropyrimidine, irinotecan, an anti-EGFR therapy, if indicated, as well as bevacizumab. Patients were randomized to receive LONSURF + bevacizumab or LONSURF monotherapy in a 1-to-1 fashion.
The SUNLIGHT clinical trial met its primary endpoint of overall survival...

With an overall survival of 10.8 months in the LONSURF + bevacizumab arm vs 7.5 months in the LONSURF monotherapy arm.

The SUNLIGHT trial also showed an improvement in progression-free survival. The median progression-free survival with LONSURF and bevacizumab was 5.6 months vs 2.4 months for LONSURF monotherapy. This translated in a 56% prolongation in progression-free survival.

LONSURF and bevacizumab resulted in a 77% disease control rate. This again compared favorably to LONSURF monotherapy where the disease control rate was 47%.

In addition to the improvement in disease control rate, LONSURF and bevacizumab resulted in a prolongation to the time to deterioration in ECOG performance status. The time to deterioration to an ECOG performance status of 2 and above was a median of 9.3 months for LONSURF + bevacizumab vs 6.3 months for LONSURF monotherapy. This translated in a 46% improvement in the time to deterioration in favor of LONSURF and bevacizumab.

[05:01 - 05:53] How have your patients generally tolerated LONSURF + bevacizumab, and how do you address its side effects?

The most common side effects that I see in my patients include fatigue, mild nausea, and occasionally mild diarrhea. The majority of these side effects are Grade 1 or sometimes Grade 2 in nature. In addition, I monitor them closely with laboratory testing. It is important to note that neutropenia can be seen quite often in patients receiving LONSURF + bevacizumab, but this is typically an asymptomatic adverse event, but it still needs to be addressed either with the use of growth factors or possibly with dose modifications.

I would defer you to LONSURFHCP.com website for further directions related to dose delays and dose modifications.

[05:53 - 07:08] In short, why would you recommend LONSURF + bevacizumab in 3L mCRC?

The SUNLIGHT clinical trial provides Level 1 evidence that LONSURF + bevacizumab improves overall survival, progression-free survival, and time to deterioration in ECOG performance status when compared to an active treatment, namely LONSURF monotherapy. These data are not only statistically significant, but they are also clinically meaningful for our patients. Effective third-line therapy is important as an option for our patients. Patients receiving second-line therapy should be evaluated repeatedly, at least on an every 2- to 3-months basis, in my opinion, to assess for benefit from ongoing therapy at the time of disease progression in the second-line therapy.

We need to consider and initiate third-line therapy sooner rather than later so that we do not miss the window for intervention, especially when the patient has a good performance status and benefits the most from a third-line treatment.

See 3L mCRC in a different light—explore the SUNLIGHT data at LONSURFhcp.com.

[07:08 - 11:18] IMPORTANT SAFETY INFORMATION (Continued) and Closing

Severe Myelosuppression: One patient (0.4%) died due to abdominal sepsis and two other patients (0.8%) died due to septic shock. A total of 29% of patients received granulocyte-colony stimulating factors. Obtain complete blood counts prior to and on Day 15 of each cycle of LONSURF and more frequently as clinically indicated. Withhold LONSURF for severe myelosuppression and resume at the next lower dosage.

Embryo-Fetal Toxicity: LONSURF can cause fetal harm when administered to a pregnant woman. Advise pregnant women of the potential risk to the fetus. Advise females of reproductive potential to use effective contraception during treatment and for at least 6 months after the final dose.

USE IN SPECIFIC POPULATIONS

Lactation: It is not known whether LONSURF or its metabolites are present in human milk. There are no data to assess the effects of LONSURF or its metabolites on the breastfed child or the effects on milk production. Because of the potential for serious adverse reactions in breastfed children, advise women not to breastfeed during treatment with LONSURF and for 1 day following the final dose.

Male Contraception: Because of the potential for genotoxicity, advise males with female partners of reproductive potential to use condoms during treatment with LONSURF and for at least 3 months after the final dose.

Geriatric Use: Patients 65 years of age or older who received LONSURF as a single agent had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (46% vs 32%), Grade 3 anemia (20% vs 14%), and Grade 3 or 4 thrombocytopenia (6% vs 3%). Patients 65 years of age or older who received LONSURF in combination with bevacizumab had a higher incidence of the following hematologic laboratory abnormalities compared to patients younger than 65 years: Grade 3 or 4 neutropenia (60% vs 46%) and Grade 3 or 4 thrombocytopenia (5% vs 4%).

Renal Impairment: No adjustment to the starting dosage of LONSURF is recommended in patients with mild or moderate renal impairment (CLcr of 30 to 89 mL/min). Reduce the starting dose of LONSURF for patients with severe renal impairment (CLcr of 15 to 29 mL/min) to a recommended dosage of 20 mg/m2.

Hepatic Impairment: Do not initiate LONSURF in patients with baseline moderate or severe (total bilirubin > 1.5 times ULN and any AST) hepatic impairment. Patients with severe hepatic impairment (total bilirubin > 3 times ULN and any AST) were not studied. No adjustment to the starting dosage of LONSURF is recommended for patients with mild hepatic impairment.

ADVERSE REACTIONS

Serious adverse reactions occurred in 25% of patients. The most frequent serious adverse reactions (≥2%) were intestinal obstruction (2.8%), and COVID-19 (2%). Fatal adverse reactions occurred in 1.2% of patients who received LONSURF in combination with bevacizumab, including rectal fistula (0.4%), bowel perforation (0.4%) and atrial fibrillation (0.4%).

The most common adverse reactions or laboratory abnormalities (≥10% in incidence) in patients treated with single agent LONSURF at a rate that exceeds the rate in patients receiving placebo in mCRC: anemia (77% vs 33%), neutropenia (67% vs 0.8%), asthenia/fatigue (52% vs 35%), nausea (48% vs 24%), thrombocytopenia (42% vs 8%), decreased appetite (39% vs 29%), diarrhea (32% vs 12%), vomiting (28% vs 14%), abdominal pain (21% vs 19%), and pyrexia (19% vs 14%). In metastatic gastric cancer or gastroesophageal junction (GEJ): neutropenia (66% vs 4%), anemia (63% vs 38%), nausea (37% vs 32%), thrombocytopenia (34% vs 9%), decreased appetite (34% vs 31%), vomiting (25% vs 20%), infections (23% vs 16%) and diarrhea (23% vs 14%).

Pulmonary emboli occurred more frequently in LONSURF-treated patients compared to placebo: in mCRC (2% vs 0%) and in metastatic gastric cancer and GEJ (3% vs 2%).

Interstitial lung disease (0.2%), including fatalities, has been reported in clinical studies and clinical practice settings in Asia.

The most common adverse reactions or laboratory abnormalities (≥20% in incidence) in patients treated with LONSURF in combination with bevacizumab vs LONSURF alone were neutropenia (80% vs 68%), anemia (68% vs 73%), thrombocytopenia (54% vs 29%), fatigue (45% vs 37%), nausea (37% vs 27%), increased aspartate aminotransferase (34% vs 28%), increased alanine aminotransferase (33% vs 23%), increased alkaline phosphate (31% vs 36%), decreased sodium (25% vs 20%), diarrhea (21% vs 19%), abdominal pain (20% vs 18%), and decreased appetite (20% vs 15%).

Please see full Prescribing Information.