[00:15] Speaker: Welcome to Project Oncology on RegMD. I'm Dr.

[00:18] Speaker: Charles Turk, and joining me today to discuss the latest first-line immunotherapy

[00:22] Speaker: treatment in esophageal squamous cell carcinoma, also known as ESCC, is Dr.

[00:27] Speaker: Jaffer Adjani. He's a GI medical oncologist working at the University of Texas MD

[00:31] Speaker: Anderson Cancer Center in Houston. Dr. Adjani, welcome to the program.

[00:35] Speaker: Yeah, thank you so much for having me.

[00:38] Speaker: So to start, Dr. Adjani, would you walk us through the unmet needs that patients

[00:42] Speaker: with esophageal cancer face?

[00:44] Speaker: Absolutely. Esophageal cancer is the 10th most common cancer worldwide,

[00:50] Speaker: and sixth most prevalent cause of death due to cancer.

[00:54] Speaker: More than two-thirds of patients with esophageal cancer are diagnosed with advanced

[01:00] Speaker: or metastatic disease, and five-year survival rate is 5% for patients with

[01:06] Speaker: metastatic disease. So it's clear that we need additional treatment

[01:12] Speaker: options for these patients.

[01:15] Speaker: With that context in mind, what are the current immunotherapy treatment options?

[01:20] Speaker: Well, first, it's important to note that there are two histologic types of

[01:24] Speaker: esophageal cancer.

[01:27] Speaker: One is called esophageal squamous cell carcinoma, or ESCC,

[01:33] Speaker: and the other one is adenocarcinoma, also called EAC.

[01:40] Speaker: ESCC comprises roughly 90% of esophageal cancers.

[01:47] Speaker: Currently, for unresectable, locally advanced, or metastatic ESCC, a

[01:53] Speaker: PD-1 inhibitor in combination with chemotherapy is the standard of care for

[01:58] Speaker: patients with tumor PD-L1 greater than or equal to one.

[02:04] Speaker: For patients with tumor PD-L1 less than one, the standard of care would be

[02:10] Speaker: chemotherapy alone. This aligns with the FDA approvals and the

[02:15] Speaker: NCCN guidelines.

[02:18] Speaker: And have there been any new FDA approvals in immunotherapy treatment for patients

[02:22] Speaker: with unresectable, locally advanced, or metastatic ESCC recently?

[02:27] Speaker: Yes. Tislelizumab plus platinum-based chemotherapy is the latest

[02:32] Speaker: FDA approval for these patients. Tislelizumab is an anti-PD-1 antibody

[02:39] Speaker: with three preclinical features that distinguish it from other PD-1 inhibitors

[02:45] Speaker: being used in ESCC. The first feature is the large coverage of the

[02:51] Speaker: PD-1 receptor compared to nivolumab or pembrolizumab.

[02:56] Speaker: In fact, preclinical data show that tislelizumab completely blocks PD-1

[03:02] Speaker: receptor, preventing PD-L1 or PD-L2 binding,

[03:07] Speaker: compared to nivolumab or pembrolizumab that show partial inhibition of the

[03:13] Speaker: PD-1 receptor. Second, the high binding affinity leads to slower

[03:18] Speaker: dissociation from the PD-1 receptor.

[03:22] Speaker: This potentially allows more time for T-cell to proliferate and

[03:28] Speaker: cause tumor cell killing. Compared to nivolumab and pembrolizumab,

[03:34] Speaker: the dissociation rate for tislelizumab was 30 to 80-fold slower,

[03:40] Speaker: respectively. Finally, the FC portion of tislelizumab has been modified

[03:46] Speaker: so that it has minimum binding to macrophages.

[03:49] Speaker: This modification limits active T-cell depletion in the tumor microenvironment

[03:55] Speaker: and may avoid resistance to PD-1 inhibition.

[04:00] Speaker: Thanks for explaining those features, Dr. Adjani.

[04:02] Speaker: And now shifting gears a bit, would you walk us through the design of the trial

[04:06] Speaker: that led to the FDA approval of tislelizumab first-line in ESCC?

[04:11] Speaker: Of course. The global study was called RATIONALE-306.

[04:16] Speaker: It enrolled patients with unresectable, locally advanced, or metastatic ESCC

[04:22] Speaker: who were not treated previously with systemic therapy for advanced disease.

[04:27] Speaker: Patient needed to have an ECOG performance status of zero to one with measurable or

[04:32] Speaker: evaluable disease at the time of enrollment.

[04:35] Speaker: The study was stratified by geographic region,

[04:39] Speaker: use of prior definitive therapy or chemotherapy.

[04:43] Speaker: The experimental arm was tislelizumab 200 milligram IV every three weeks, plus

[04:49] Speaker: chemotherapy, and the control arm was placebo plus chemotherapy.

[04:54] Speaker: Treatment continued until unacceptable toxicity or disease progression.

[04:59] Speaker: It's important to note that the chemotherapy options were physician's choice of

[05:05] Speaker: platinum plus fluoropyrimidine or platinum plus paclitaxel.

[05:10] Speaker: Although FOLFOX is the most commonly used chemotherapy in the US, platinum plus

[05:15] Speaker: paclitaxel can offer an alternative to patients who are unable to tolerate

[05:21] Speaker: capecitabine, which is given orally, or when there's no access to infusion pump.

[05:27] Speaker: It was one-to-one randomization in this study with roughly 650

[05:33] Speaker: patients enrolled. The primary endpoint was overall survival, also called OS, in

[05:39] Speaker: the intent-to-treat population.

[05:41] Speaker: The key secondary endpoints included additional efficacy endpoints and

[05:47] Speaker: safety.

[05:49] Speaker: So, Dr. Adjani, now that we've discussed the design of RATIONALE-306, let's move on

[05:54] Speaker: to the results. What were some of the key findings?

[05:57] Speaker: Great question. For context, I will be focusing on patients with tumor

[06:03] Speaker: PD-L1 greater than or equal to 1%, and that is

[06:08] Speaker: aligned with the ODAC recommendation and the FDA approval.

[06:14] Speaker: The patient demographics showed that the median age was about 65 years,

[06:20] Speaker: and more than 85% of patients were men, and roughly 80% of patients

[06:26] Speaker: were either former or current smokers.

[06:31] Speaker: 75% of patients enrolled in this study were from Asia, which is likely due to high

[06:37] Speaker: incidence of ESCC in that region. Most of the patients had metastatic

[06:42] Speaker: disease at the time of study enrollment.

[06:46] Speaker: The primary analysis showed that tislelizumab plus chemotherapy resulted in a

[06:52] Speaker: clinically meaningful improvement in OS compared to placebo plus chemotherapy.

[06:58] Speaker: The median OS was 16.8 months for tislelizumab

[07:04] Speaker: plus chemotherapy, compared to 9.6 months for placebo and chemotherapy,

[07:10] Speaker: resulting in a hazard ratio of 0.64.

[07:14] Speaker: There was a 7.2-month difference in overall survival favoring tislelizumab

[07:19] Speaker: plus chemotherapy. The survival improvement was maintained at three-year follow-up,

[07:25] Speaker: and the tail end of the curves continued to separate with long-term follow-up.

[07:32] Speaker: And building off that, what did the analyses of the pre-specified subgroups show?

[07:37] Speaker: So when we look at the pre-specified subgroup analysis for OS, a clinically

[07:43] Speaker: meaningful improvement was observed across key subgroups favoring tislelizumab

[07:49] Speaker: plus chemotherapy. These included chemotherapy regimens, just platinum

[07:55] Speaker: plus fluoropyrimidine or platinum plus paclitaxel, patients with metastatic

[08:01] Speaker: disease, patients with locally advanced unresectable ESCC.

[08:06] Speaker: At recent congress, the post hoc analysis of patients with locally advanced

[08:11] Speaker: unresectable ESCC demonstrated consistent OS

[08:16] Speaker: benefit for tislelizumab plus chemotherapy.

[08:19] Speaker: The primary analysis reported a stratified hazard ratio of 0.38,

[08:25] Speaker: translating into 52% reduction in risk of death for these patients.

[08:31] Speaker: The median overall survival was 25.6 months for tislelizumab plus

[08:36] Speaker: chemotherapy arm, compared to 11.5 months for placebo plus

[08:42] Speaker: chemotherapy arm.

[08:44] Speaker: Interesting. And what can you tell us about the safety profile of tislelizumab plus

[08:48] Speaker: chemotherapy?

[08:50] Speaker: So in terms of safety, we see that tislelizumab plus chemotherapy had

[08:55] Speaker: generally a manageable safety profile.

[08:58] Speaker: Nearly all patients experienced one or more treatment-related events.

[09:03] Speaker: A comparable proportion of patients in each arm experienced at least one Grade 3 or

[09:08] Speaker: higher treatment-related adverse event.

[09:11] Speaker: 67% of patients In tislelizumab plus chemotherapy and 64% of

[09:17] Speaker: patients in placebo plus chemotherapy.

[09:21] Speaker: The most common Grade 3-4 side effects were related to

[09:27] Speaker: decreased neutrophil count, 31% in tislelizumab arm, 33%

[09:33] Speaker: in the placebo arm. Decrease in white blood cell count, 11% in tislelizumab arm,

[09:39] Speaker: 16% in the placebo arm, and anemia 15% in tislelizumab arm,

[09:45] Speaker: and 13% in the placebo arm. Treatment emergent events leading to

[09:51] Speaker: death occurred in 5% of patients in both arms.

[09:56] Speaker: But in 9% of patients in tislelizumab plus chemotherapy arm and

[10:01] Speaker: 19% in the placebo and chemotherapy arm discontinued therapy due

[10:07] Speaker: to treatment-related adverse event, and 70% of patients in

[10:12] Speaker: tislelizumab arm and 63% in the placebo arm had treatment-related

[10:17] Speaker: events that led to dose modification.

[10:21] Speaker: So since tislelizumab is a PD-1 inhibitor, patients may experience immune-related

[10:27] Speaker: adverse event that you see with other anti-PD-1 inhibitors.

[10:32] Speaker: So the healthcare provider should monitor patients closely for this toxicity.

[10:39] Speaker: Thank you for that overview, Dr. Ajani.

[10:41] Speaker: And now before we wrap up our program, do you have any final thoughts you'd like

[10:44] Speaker: our audience to take away from this discussion?

[10:47] Speaker: Yes. I'd like to summarize that tislelizumab is a uniquely

[10:52] Speaker: designed PD-1 inhibitor with high binding affinity to PD-1

[10:57] Speaker: receptor. The modified FC portion of the antibody

[11:02] Speaker: minimizes binding to macrophages, preventing them from clearing T-cells

[11:08] Speaker: in the tumor microenvironment, a process believed to contribute to anti-PD-1

[11:13] Speaker: resistance. In the global RATIONALE-306 trial,

[11:19] Speaker: tislelizumab plus chemotherapy demonstrated a median OS of

[11:24] Speaker: 16.8 months, an improvement of 7.2

[11:29] Speaker: months in OS versus placebo plus chemotherapy for patients

[11:35] Speaker: with tumor PD-L1 greater than or equal to 1%.

[11:41] Speaker: A post hoc analysis of patients with locally advanced resectable ESCC

[11:46] Speaker: demonstrated consistent overall survival benefit for tislelizumab plus

[11:52] Speaker: chemotherapy arm, with a median overall survival of 25.6 months

[11:59] Speaker: and a 14.1-month improvement over the placebo plus chemotherapy arm.

[12:05] Speaker: Its safety profile was generally manageable with no new safety signals identified.

[12:10] Speaker: The most common treatment-related adverse event for all grades and Grade 3-4

[12:17] Speaker: in both groups were consistent with the adverse event profile for this type of

[12:22] Speaker: treatment. In addition, tislelizumab offers flexible treatment option

[12:27] Speaker: that can be combined with platinum plus fluoropyrimidine or platinum plus

[12:32] Speaker: paclitaxel. The treatment data led to the approval of tislelizumab

[12:38] Speaker: plus platinum-containing chemotherapy for first-line treatment of unresectable or

[12:44] Speaker: metastatic ESCC with tumors that express PD-L1 greater than

[12:50] Speaker: or equal to one. It's important to note that the FDA also

[12:55] Speaker: approved tislelizumab for different dosing schedules.

[13:00] Speaker: They include every two, every three, every four, or every six weeks,

[13:07] Speaker: offering extra flexibility and convenience to prescribers and patients.

[13:13] Speaker: Tislelizumab plus chemotherapy is listed as the preferred treatment option in the

[13:18] Speaker: NCCN guideline, providing an additional immunotherapy option for patients

[13:25] Speaker: with untreated metastatic ESCC.

[13:28] Speaker: It's a great summary as we come to the end of today's program.

[13:31] Speaker: And I want to thank my guest, Dr. Jafar Ajani, for sharing his insight into

[13:35] Speaker: treating esophageal squamous cell carcinoma first line with a PD-1 inhibitor. Dr.

[13:40] Speaker: Ajani, it was great speaking with you today.

[13:42] Speaker: Yeah. It was great to participate in this program. Thank you.

[13:46] Speaker: For ReachMD, I'm Dr. Charles Turk.

[13:48] Speaker: Please stay tuned to hear some important safety information.

[13:51] Speaker: Indications. TEVIMBRA is a programmed death receptor 1 [PD-1] blocking

[13:57] Speaker: antibody indicated for the treatment of adults with gastric, gastroesophageal

[14:02] Speaker: junction, or esophageal adenocarcinoma in combination with zanubrutinib

[14:08] Speaker: HRII and fluoropyrimidine and platinum-containing chemotherapy for first-line

[14:13] Speaker: treatment of HER2-positive, IHC 3+ or IHC 2+,

[14:20] Speaker: ISH-positive, unresectable, locally advanced, or metastatic gastric,

[14:26] Speaker: gastroesophageal junction, or esophageal adenocarcinoma.

[14:31] Speaker: Esophageal cancer. In combination with platinum-containing chemotherapy for

[14:36] Speaker: first-line treatment of unresectable or metastatic esophageal squamous cell

[14:41] Speaker: carcinoma, ESCC expressing PD-L1 greater than or equal to

[14:47] Speaker: one or as a single agent for unresectable or metastatic

[14:51] Speaker: ESCC after prior systemic chemotherapy that did not include a PD-L1

[14:57] Speaker: inhibitor. Gastric cancer. In combination with fluoropyrimidine and

[15:03] Speaker: platinum-containing chemotherapy for first-line treatment of unresectable or

[15:07] Speaker: metastatic HER2-negative gastric or gastroesophageal junction

[15:12] Speaker: adenocarcinoma whose tumors expressed PD-L1 greater than or equal to one.

[15:19] Speaker: Important safety information. Warnings and precautions.

[15:24] Speaker: Immune-mediated adverse reactions, IMARs.

[15:28] Speaker: TEVIMBRA can cause immune-mediated adverse reactions, which may be severe or fatal

[15:34] Speaker: and can occur in any organ system or tissue.

[15:39] Speaker: Early identification and management of IMARs are essential to ensure safe use of

[15:44] Speaker: PD-1, PD-L1 blocking antibodies.

[15:48] Speaker: IMARs may occur at any time during or after treatment.

[15:52] Speaker: Monitor for signs and symptoms of IMARs.

[15:55] Speaker: Evaluate liver enzymes, creatinine, and thyroid function at baseline and

[16:01] Speaker: periodically during treatment. For suspected IMARs, initiate appropriate workup to

[16:07] Speaker: exclude alternative etiologies.

[16:10] Speaker: Withhold or permanently discontinue TEVIMBRA based on severity and administer

[16:15] Speaker: systemic corticosteroids or other immunosuppressants as clinically

[16:19] Speaker: indicated. The IMARs listed were observed in clinical studies of TEVIMBRA, N

[16:25] Speaker: equals 2,390, and may not include all possible severe and

[16:31] Speaker: fatal IMARs.

[16:33] Speaker: Pneumonitis. TEVIMBRA can cause immune-mediated pneumonitis, which can be fatal.

[16:39] Speaker: Immune-mediated pneumonitis occurred in 4.7% of patients, including Grade 3 to

[16:45] Speaker: four reactions in 1.7% and fatal events in

[16:50] Speaker: 0.1%. Colitis. TEVIMBRA can cause immune-mediated colitis,

[16:56] Speaker: which can be fatal. Immune-mediated colitis occurred in 0.8% of patients,

[17:03] Speaker: including Grade 3 reactions in 0.3%. Hepatitis.

[17:08] Speaker: TEVIMBRA can cause immune-mediated hepatitis, which can be fatal.

[17:13] Speaker: Immune-mediated hepatitis occurred in 1.3% of patients, including Grade 3 to four

[17:19] Speaker: reactions in 0.9%. Endocrinopathies.

[17:25] Speaker: TEVIMBRA can cause immune-mediated endocrinopathies, including adrenal

[17:29] Speaker: insufficiency, hypophysitis, hypopituitarism, thyroid disorders,

[17:36] Speaker: and type 1 diabetes mellitus. Reported rates included adrenal insufficiency,

[17:42] Speaker: 0.5%, Grade 3 to 4, 0.24%.

[17:47] Speaker: Hypophysitis/hypopituitarism, 0.3%, all Grade 2.

[17:53] Speaker: Thyroiditis, 1.0%, Grade 2, 0.5%.

[18:00] Speaker: Hyperthyroidism, 4.9%, Grade 3, 0.04%.

[18:06] Speaker: Hypothyroidism, 12.5%, Grade 3 to 4,

[18:12] Speaker: 0.08%. And diabetes mellitus, 0.7%,

[18:18] Speaker: Grade 3 to 4, 0.4%.

[18:22] Speaker: Nephritis with renal dysfunction.

[18:24] Speaker: TEVIMBRA can cause immune-mediated nephritis with renal dysfunction, which can be

[18:29] Speaker: fatal. Immune-mediated nephritis with renal dysfunction occurred in 0.2% of

[18:35] Speaker: patients, including Grade 3 reactions in 0.04%.

[18:41] Speaker: Dermatologic adverse reactions.

[18:44] Speaker: TEVIMBRA can cause immune-mediated rash or dermatitis, including severe cutaneous

[18:49] Speaker: adverse reactions. Immune-mediated dermatologic adverse reactions occurred in 13%

[18:55] Speaker: of patients, including Grade 3 to 4 reactions in 1.2%.

[19:01] Speaker: Stevens-Johnson syndrome occurred in 0.04% of patients.

[19:06] Speaker: Other immune-mediated adverse reactions.

[19:09] Speaker: Other clinically significant immune-mediated adverse reactions occurred in less

[19:14] Speaker: than 1% of patients and may involve cardiac, vascular, neurologic,

[19:20] Speaker: ocular, gastrointestinal, musculoskeletal, connective tissue, endocrine,

[19:26] Speaker: hematologic, immune systems, including solid organ transplant rejection,

[19:32] Speaker: and myocarditis, myositis, myasthenia gravis, or

[19:37] Speaker: myasthenia-like overlap syndrome.

[19:40] Speaker: Severe or fatal cases have been reported for some of these reactions.

[19:45] Speaker: Infusion-related reactions. TEVIMBRA can cause infusion-related reactions, which

[19:51] Speaker: may be severe or life-threatening.

[19:53] Speaker: Infusion-related reactions occurred in 4.7% of patients.

[19:58] Speaker: Grade greater than or equal to 3, 0.2%.

[20:02] Speaker: Monitor patients during infusion.

[20:05] Speaker: Slow the infusion for Grade 1 reactions, interrupt the infusion for Grade 2, and

[20:11] Speaker: permanently discontinue TEVIMBRA for Grade 3 or higher.

[20:15] Speaker: Complications of allogeneic hematopoietic stem cell transplantation

[20:21] Speaker: . Fatal and serious complications, including graft versus host disease, have

[20:27] Speaker: occurred in patients who received allogeneic HSCT before or after treatment with

[20:32] Speaker: PD-1, PD-L1 blockade. Complications may occur despite intervening

[20:38] Speaker: therapy between treatment with PD-1, PD-L1 blockade and allogeneic HSCT.

[20:44] Speaker: Monitor patients closely and intervene promptly. Embryo-fetal toxicity.

[20:50] Speaker: TEVIMBRA can cause fetal harm and potential fetal death, as shown in animal

[20:55] Speaker: studies. Advise females of reproductive potential of the potential risk to a fetus.

[21:01] Speaker: Verify pregnancy status prior to initiation of TEVIMBRA.

[21:06] Speaker: Advise females of reproductive potential to use effective contraception during

[21:10] Speaker: treatment and for four months after the last dose. Adverse reactions.

[21:16] Speaker: The most common adverse reactions, greater than or equal to 20%, including lab

[21:22] Speaker: abnormalities were gastric, gastroesophageal junction, or esophageal

[21:27] Speaker: adenocarcinoma, combination with zamidotamab HRI and chemotherapy first line:

[21:34] Speaker: diarrhea, nausea, anemia, decreased appetite, vomiting,

[21:40] Speaker: hypokalemia, fatigue, rash, decreased neutrophil count,

[21:46] Speaker: decreased platelet count, peripheral neuropathy, infusion-related reaction,

[21:52] Speaker: and increased AST. Esophageal cancer, combination with chemotherapy

[21:58] Speaker: first line: decreased neutrophil count, decreased sodium, increased

[22:03] Speaker: glucose, anemia, fatigue, decreased appetite, increased

[22:09] Speaker: AST, decreased potassium, increased serum creatinine,

[22:14] Speaker: decreased calcium, increased ALT, diarrhea, stomatitis,

[22:20] Speaker: and vomiting. Esophageal cancer, monotherapy, second line:

[22:26] Speaker: increased glucose, decreased hemoglobin, decreased lymphocytes, decreased sodium,

[22:33] Speaker: decreased albumin, increased alkaline phosphatase, anemia, fatigue,

[22:39] Speaker: increased AST, musculoskeletal pain, decreased weight, increased

[22:45] Speaker: ALT, and cough.

[22:48] Speaker: Gastric cancer, combination with chemotherapy, first line: nausea,

[22:54] Speaker: fatigue, decreased appetite, anemia, peripheral sensory neuropathy,

[23:00] Speaker: vomiting, decreased platelet count, decreased neutrophil count, increased

[23:05] Speaker: AST, diarrhea, abdominal pain, increased ALT,

[23:11] Speaker: decreased white blood cell count, decreased weight, and pyrexia.

[23:16] Speaker: Specific populations. Lactation.

[23:20] Speaker: Advise women not to breastfeed during treatment and for four months after the last

[23:24] Speaker: dose. To report suspected adverse reactions, contact V1 Medicines at

[23:31] Speaker: 1-877-828-5596, or FDA at

[23:37] Speaker: 1-800-FDA-1088, or

[23:42] Speaker: www.fda.gov/medwatch. Please

[23:47] Speaker: see full prescribing information.