[00:14] Speaker: Welcome to Project Oncology on ReachMD. I'm Dr.

[00:17] Speaker: Charles Turk, and joining me today to discuss first-line IO therapies for patients

[00:22] Speaker: with HER2-negative gastric or gastroesophageal junction cancer, otherwise known as

[00:26] Speaker: gastric or GEJ cancer, is Dr. June Gong.

[00:29] Speaker: He's an associate professor and a GI medical oncologist at Cedars-Sinai Cancer

[00:33] Speaker: Center in Los Angeles. Dr. Gong, thanks for being here today.

[00:37] Speaker: Thank you for having me here.

[00:38] Speaker: So, Dr. Gong, let's jump right in. What unmet needs are we currently facing when it

[00:43] Speaker: comes to first-line treatment of gastric or GEJ cancer?

[00:47] Speaker: Well, gastric cancer is the fifth most common cancer worldwide and the fifth

[00:51] Speaker: leading cause of cancer death. It's an aggressive cancer, and patients are often

[00:55] Speaker: diagnosed at advanced stages of disease.

[00:57] Speaker: For patients who are diagnosed with metastatic disease, the five-year overall

[01:01] Speaker: survival rate is roughly 7%. This underscores the urgent need for additional

[01:06] Speaker: treatment options for these patients.

[01:08] Speaker: Now, with that context in mind, I'd like to focus on patients who are HER2

[01:12] Speaker: negative, a group that comprises roughly 80% of those with gastric cancer.

[01:17] Speaker: Would you discuss the current immunotherapy treatments available for patients with

[01:20] Speaker: unresectable or metastatic HER2-negative gastric or GEJ cancer?

[01:25] Speaker: Fortunately, there's been quite a bit of advancement in gastric cancer treatment,

[01:29] Speaker: which gives patients more options.

[01:31] Speaker: Today, we will focus on immunotherapy treatment for patients with unresectable or

[01:35] Speaker: metastatic disease. For patients with unresectable or metastatic disease who are

[01:40] Speaker: PD-L1 positive, defined by PD-L1 greater than or equal to one, the standard of care

[01:46] Speaker: is anti-PD-1 plus chemotherapy. Chemotherapy, the regimen, typically consists of a

[01:51] Speaker: platinum plus a fluoropyrimidine, which is reflected in the NCCN guideline.

[01:56] Speaker: Now, you mentioned that there are some emerging treatment options.

[01:59] Speaker: Would you tell us about the most recently approved immunotherapy for patients with

[02:03] Speaker: unresectable or metastatic gastric or GEJ cancer?

[02:07] Speaker: I'd be happy to. The latest FDA approval for these patients is tislelizumab in

[02:11] Speaker: combination with platinum and fluoropyrimidine-based chemotherapy.

[02:15] Speaker: Tislelizumab is a humanized anti-PD-1 monoclonal antibody engineered to minimize

[02:21] Speaker: Fc gamma receptor binding on macrophages, thereby reducing antibody-dependent

[02:26] Speaker: phagocytosis of T-cells. It exhibits several preclinical differentiating

[02:31] Speaker: characteristics compared to other PD-1 inhibitors.

[02:34] Speaker: It has a high binding affinity to PD-1, which has a larger coverage of the

[02:38] Speaker: PD-1/PD-L1 binding pocket than nivolumab and pembrolizumab.

[02:43] Speaker: Preclinical data show tislelizumab completely blocked the binding of PD-1 to PD-L1,

[02:48] Speaker: while nivolumab and pembrolizumab show partial inhibition of this binding.

[02:53] Speaker: The high binding affinity leads to slower disassociation from PD-1 receptor.

[02:58] Speaker: This potentially allows more time for T-cells to proliferate and tumor kill, and

[03:02] Speaker: compared to nivolumab and pembrolizumab, the disassociation rate for tislelizumab

[03:07] Speaker: was 30 to 80-fold slower, respectively.

[03:11] Speaker: Thanks for walking us through those features, Dr. Gong.

[03:13] Speaker: And shifting gears now, would you tell us about the trial design that resulted in

[03:17] Speaker: FDA approval of tislelizumab for first-line treatment of gastric or GEJ cancer?

[03:22] Speaker: Absolutely, Dr. Turk. The study was called RATIONAL 305, and it was a randomized,

[03:27] Speaker: double-blind, global Phase 3 clinical trial.

[03:30] Speaker: Patients with histologically confirmed, locally advanced, unresectable, or

[03:34] Speaker: metastatic gastric or gastroesophageal junction adenocarcinoma were recruited.

[03:39] Speaker: They were required to be HER2 negative, have an ECOG performance status of zero to

[03:43] Speaker: one, and have at least one measurable or non-measurable lesion.

[03:47] Speaker: They also cannot have had previous treatment with anti-PD-1/PD-L1 therapies or

[03:51] Speaker: other checkpoint inhibitors and had to have received no prior systemic therapy for

[03:56] Speaker: advanced or metastatic disease. The study was stratified by region, PD-L1

[04:00] Speaker: expression, with 5% as the cutoff, peritoneal metastasis status, and investigator's

[04:06] Speaker: choice of chemotherapy, including capecitabine and oxaliplatin or 5-fluorouracil

[04:11] Speaker: and cisplatin. The experimental arm was tislelizumab 200 milligrams IV every three

[04:16] Speaker: weeks plus chemotherapy versus the control arm, which was placebo plus

[04:20] Speaker: chemotherapy. Treatment continued until unacceptable toxicity or disease

[04:25] Speaker: progression. 997 patients were enrolled in this study with a one-to-one

[04:30] Speaker: randomization. The primary endpoint was overall survival for patients with PD-L1

[04:35] Speaker: greater than or equal to 5% and in the intent-to-treat population.

[04:39] Speaker: The key secondary endpoints included additional efficacy outcomes such as PFS and

[04:44] Speaker: ORR, as well as safety.

[04:46] Speaker: And with that in mind, how did tislelizumab perform in RATIONAL 305?

[04:50] Speaker: Great question, Dr. Turk. For the purposes of today's discussion, I'm going to

[04:54] Speaker: focus on the results that were published for the patients with PD-L1 greater than

[04:58] Speaker: or equal to 1%, which aligns with the FDA approval for this indication.

[05:03] Speaker: But before I dive into the results, I'd like to briefly go over the demographic

[05:07] Speaker: characteristics in the groups receiving tislelizumab plus chemotherapy and those

[05:11] Speaker: receiving placebo plus chemotherapy, which were quite consistent.

[05:15] Speaker: The median age group was 61 years old, with roughly 70% of patients being male.

[05:20] Speaker: About two-thirds of the patients had an ECOG performance status of one, almost

[05:25] Speaker: every patient had metastatic disease upon study entry, and most patients had

[05:29] Speaker: gastric cancer at the primary location of the tumor.

[05:32] Speaker: In terms of distant metastases, roughly 40% of patients had liver metastases, and

[05:38] Speaker: about 44% of patients had peritoneal metastases.

[05:42] Speaker: About 90% of patients had MSI stable or mismatch-repair-proficient disease.

[05:48] Speaker: 20% of patients had received previous adjuvant or neoadjuvant treatment, and most

[05:52] Speaker: patients received CAPOX as the chemotherapy of choice.

[05:56] Speaker: As for drug exposure, the median duration of treatment was 5.9 months for the

[06:00] Speaker: tislelizumab arm and 5.7 months for the placebo arm.

[06:05] Speaker: Now, in terms of efficacy, tislelizumab plus chemotherapy resulted in a clinically

[06:10] Speaker: meaningful improvement in overall survival as compared to placebo plus

[06:13] Speaker: chemotherapy. The median overall survival was 15.0 months versus 12.8

[06:19] Speaker: months, with a hazard ratio of 0.78.

[06:23] Speaker: It was a 2.2-month difference in OS benefit improvement with tislelizumab plus

[06:27] Speaker: chemotherapy combination. At the three-year long-term follow-up, OS improvement was

[06:33] Speaker: maintained with tislelizumab plus chemotherapy, and the tail end of the curves

[06:36] Speaker: remained separated. Lastly, the estimated three-year OS rates were 21% versus

[06:42] Speaker: 13%, respectively.

[06:44] Speaker: So, Dr. Gong, let's continue our discussion of RATIONAL 305.

[06:48] Speaker: What did the study find regarding pre-specified patient subgroups?

[06:52] Speaker: In the predefined subgroup analyses for overall survival, a consistent improvement

[06:56] Speaker: in OS was observed across key subgroups, favoring the tislelizumab plus

[07:00] Speaker: chemotherapy combination. The subgroup worth highlighting are the primary tumor

[07:04] Speaker: location, either stomach or gastroesophageal junction, patients with or without

[07:09] Speaker: liver metastases, and patients with or without peritoneal metastases. Dr.

[07:14] Speaker: Turk, you may recall one of the stratification factors in this study was the

[07:17] Speaker: presence or absence of peritoneal metastases, which is unique for studies in

[07:21] Speaker: first-line gastric GEJ cancer. We know that patients with peritoneal metastases

[07:26] Speaker: have a poor prognosis, so it's good to see it being incorporated as a

[07:29] Speaker: stratification factor to ensure balance of patients in each arm.

[07:33] Speaker: The subgroup analysis examining the patients with peritoneal mets showed a hazard

[07:37] Speaker: ratio of 0.81, indicating patients with peritoneal metastases had 19%

[07:43] Speaker: reduction in the risk of death when they received tislelizumab plus chemotherapy

[07:47] Speaker: combination as compared with placebo plus chemotherapy.

[07:51] Speaker: I see. And when it comes to safety, what did the study find on the tislelizumab

[07:56] Speaker: plus chemotherapy combination?

[07:58] Speaker: The safety profile of tislelizumab in this study was found to be generally

[08:02] Speaker: manageable. Treatment-related adverse events were reported in 97% versus 96% of

[08:07] Speaker: patients in both the tislelizumab plus chemotherapy arm and the placebo plus

[08:12] Speaker: chemotherapy arm. 54% versus 50% of patients experienced Grade 3 or higher

[08:17] Speaker: treatment-related adverse events, respectively, and 23% versus 15% experienced

[08:23] Speaker: serious treatment-related adverse events, respectively.

[08:26] Speaker: A total of 31% of patients in the tislelizumab plus chemotherapy arm experienced

[08:31] Speaker: immune-related adverse events, with most of them being Grade 1 and 2.

[08:36] Speaker: For treatment-related adverse events that led to treatment discontinuation, there

[08:40] Speaker: were 16% in the tislelizumab plus chemotherapy arm and 8% in the placebo plus

[08:45] Speaker: chemotherapy arm. Six patients in the tislelizumab plus chemotherapy arm had

[08:50] Speaker: treatment-related adverse events that led to death, including four patients with

[08:55] Speaker: unspecified death, one due to colitis, and one due to sepsis.

[08:59] Speaker: In the placebo plus chemotherapy arm, it was two patients.

[09:03] Speaker: Overall, the most common treatment-related adverse events in both treatment arms

[09:07] Speaker: were consistent with the known safety profile of these therapies.

[09:11] Speaker: The most common Grade 3 or Grade 4 treatment-related adverse event were decreased

[09:15] Speaker: neutrophil count, decreased platelet count, neutropenia, and anemia.

[09:20] Speaker: Finally, the incidence was comparable between the two arms.

[09:23] Speaker: Thank you for this insightful interview of the RATIONAL 305 data, Dr. Gong.

[09:28] Speaker: Before we come to the end of our program, what are the main takeaways you want the

[09:31] Speaker: audience to remember from today's discussion?

[09:34] Speaker: Well, Dr. Turk, there are several key points that I want to call attention to.

[09:38] Speaker: Firstly, tislelizumab is a humanized anti-PD-1 monoclonal antibody, and it exhibits

[09:43] Speaker: several preclinical differentiating characteristics compared to other PD-1

[09:47] Speaker: inhibitors. Tislelizumab has a high binding affinity, slower disassociation rate,

[09:52] Speaker: and silent FC region. Next, in the global RATIONAL 305 study, tislelizumab plus

[09:58] Speaker: chemotherapy demonstrated a median overall survival of 15.0 months, an improvement

[10:03] Speaker: of 2.2 months in OS versus placebo plus chemotherapy for patients with PD-L1

[10:09] Speaker: greater than or equal to 1%, with a hazard ratio of 0.78.

[10:13] Speaker: Notably, in a subgroup analysis for patients with peritoneal metastases,

[10:18] Speaker: tislelizumab plus chemotherapy also showed favorable overall survival compared to

[10:22] Speaker: placebo plus chemotherapy. This was the only first-line GC study that used

[10:27] Speaker: peritoneal metastases as a stratification factor for randomization.

[10:31] Speaker: The safety profile was also generally manageable, and there were no new safety

[10:35] Speaker: signals detected. The toxicity of chemotherapy did not appear to worsen with the

[10:40] Speaker: addition of tislelizumab. Finally, based on these results, tislelizumab plus

[10:45] Speaker: chemotherapy is approved for first-line treatment of unresectable or metastatic

[10:49] Speaker: gastric GG cancer with tumors that express PD-L1 greater than or equal to one, and

[10:54] Speaker: is also listed as a preferred treatment option in the NCCN guideline.

[10:58] Speaker: The dosing of tislelizumab in RATIONAL 305 was 200 milligrams IV every three weeks.

[11:03] Speaker: Tislelizumab is approved for every two weeks, every three weeks, every four weeks,

[11:06] Speaker: and every six weeks by the FDA. These different dosing schedules may help offer

[11:10] Speaker: additional treatment flexibility and convenience.

[11:13] Speaker: That's a great way to round out our discussion. And I want to thank my guest, Dr.

[11:16] Speaker: Jun Gong, for helping us better understand an additional first-line treatment

[11:20] Speaker: option for patients with HER2-negative gastric or gastroesophageal junction cancer.

[11:26] Speaker: Dr. Gong, it was great speaking with you today.

[11:28] Speaker: Thank you, Dr. Turk for having me. And it was great talking about this new standard

[11:31] Speaker: option in these patients.

[11:33] Speaker: For Reg-MD, I'm Dr. Charles Turk. Before we close, let's take a moment to review

[11:37] Speaker: some important safety information.

[11:41] Speaker: Indications. TEVIMBRA is a programmed death-receptor 1 (PD-1) blocking

[11:46] Speaker: antibody indicated for the treatment of adults with gastric, gastroesophageal

[11:52] Speaker: junction, or esophageal adenocarcinoma in combination with zenidomab

[11:58] Speaker: HRI and fluoropyrimidine and platinum-containing chemotherapy for first-line

[12:03] Speaker: treatment of HER2-positive, IHC 3+, or IHC 2+,

[12:10] Speaker: ISH-positive, unresectable, locally advanced, or metastatic gastric,

[12:15] Speaker: gastroesophageal junction, or esophageal adenocarcinoma.

[12:21] Speaker: Esophageal cancer. In combination with platinum-containing chemotherapy for

[12:26] Speaker: first-line treatment of unresectable or metastatic esophageal squamous cell

[12:30] Speaker: carcinoma

[12:33] Speaker: expressing PD-L1 greater than or equal to 1, or as a single agent

[12:39] Speaker: for unresectable or metastatic ESCC after prior systemic chemotherapy

[12:45] Speaker: that did not include a PD-L1 inhibitor. Gastric cancer.

[12:50] Speaker: In combination with fluoropyrimidine and platinum-containing chemotherapy for

[12:54] Speaker: first-line treatment of unresectable or metastatic HER2-negative gastric or

[13:00] Speaker: gastroesophageal junction adenocarcinoma whose tumors expressed PD-L1 greater than

[13:06] Speaker: or equal to 1.

[13:09] Speaker: Important safety information. Warnings and precautions.

[13:14] Speaker: Immune-mediated adverse reactions, IMARs.

[13:18] Speaker: TEVIMBRA can cause immune-mediated adverse reactions, which may be severe or fatal

[13:24] Speaker: and can occur in any organ system or tissue.

[13:28] Speaker: Early identification and management of IMARs are essential to ensure safe use of

[13:34] Speaker: PD-1/PD-L1 blocking antibodies.

[13:37] Speaker: IMARs may occur at any time during or after treatment.

[13:41] Speaker: Monitor for signs and symptoms of IMARs.

[13:45] Speaker: Evaluate liver enzymes, creatinine, and thyroid function at baseline and

[13:50] Speaker: periodically during treatment. For suspected IMARs, initiate appropriate workup to

[13:56] Speaker: exclude alternative etiologies.

[13:59] Speaker: Withhold or permanently discontinue TEVIMBRA based on severity and administer

[14:04] Speaker: systemic corticosteroids or other immunosuppressants as clinically indicated.

[14:10] Speaker: The IMARs listed were observed in clinical studies of TEVIMBRA, n equals

[14:15] Speaker: 2,390, and may not include all possible severe and fatal

[14:21] Speaker: IMARs.

[14:23] Speaker: Pneumonitis. TEVIMBRA can cause immune-mediated pneumonitis, which can be fatal.

[14:29] Speaker: Immune-mediated pneumonitis occurred in 4.7% of patients, including Grade 3 to

[14:35] Speaker: 4 reactions in 1.7% and fatal events in

[14:40] Speaker: 0.1%. Colitis. TEVIMBRA can cause immune-mediated colitis,

[14:46] Speaker: which can be fatal. Immune-mediated colitis occurred in 0.8% of patients,

[14:52] Speaker: including Grade 3 reactions in 0.3%. Hepatitis.

[14:58] Speaker: TEVIMBRA can cause immune-mediated hepatitis, which can be fatal.

[15:03] Speaker: Immune-mediated hepatitis occurred in 1.3% of patients, including Grade 3 to 4

[15:09] Speaker: reactions in 0.9%.

[15:13] Speaker: Endocrinopathies. TEVIMBRA can cause immune-mediated endocrinopathies, including

[15:19] Speaker: adrenal insufficiency, hypophysitis, hypopituitarism, thyroid

[15:24] Speaker: disorders, and Type 1 diabetes mellitus.

[15:28] Speaker: Reported rates included adrenal insufficiency, 0.5%, Grade 3 to 4,

[15:35] Speaker: 0.24%. Hypophysitis/hypopituitarism,

[15:40] Speaker: 0.3%, all Grade 2. Thyroiditis, 1.0%,

[15:46] Speaker: Grade 2, 0.5%. Hyperthyroidism, 4.9%,

[15:53] Speaker: Grade 3, 0.04%. Hypothyroidism,

[15:58] Speaker: 12.5%, Grade 3 to 4, 0.08%. And

[16:04] Speaker: diabetes mellitus, 0.7%, Grade 3 to 4,

[16:09] Speaker: 0.4%.

[16:12] Speaker: Nephritis with renal dysfunction.

[16:14] Speaker: TEVIMBRA can cause immune-mediated nephritis with renal dysfunction, which can be

[16:19] Speaker: fatal. Immune-mediated nephritis with renal dysfunction occurred in 0.2% of

[16:24] Speaker: patients, including Grade 3 reactions in 0.04%.

[16:31] Speaker: Dermatologic adverse reactions.

[16:33] Speaker: TEVIMBRA can cause immune-mediated rash or dermatitis, including severe cutaneous

[16:39] Speaker: adverse reactions. Immune-mediated dermatologic adverse reactions occurred in 13%

[16:45] Speaker: of patients, including Grade 3 to 4 reactions in 1.2%.

[16:51] Speaker: Stevens-Johnson syndrome occurred in 0.04% of patients.

[16:56] Speaker: Other immune-mediated adverse reactions.

[16:59] Speaker: Other clinically significant immune-mediated adverse reactions occurred in less

[17:03] Speaker: than 1% of patients and may involve cardiac, vascular, neurologic,

[17:10] Speaker: ocular, gastrointestinal, musculoskeletal/connective tissue, endocrine,

[17:16] Speaker: hematologic, immune systems, including solid organ transplant rejection, and

[17:23] Speaker: myocarditis, myositis, myasthenia gravis, or myasthenia-like overlap

[17:28] Speaker: syndrome. Severe or fatal cases have been reported for some of these

[17:33] Speaker: reactions. Infusion-related reactions.

[17:37] Speaker: TEVIMBRA can cause infusion-related reactions, which may be severe or

[17:42] Speaker: life-threatening. Infusion-related reactions occurred in 4.7% of patients.

[17:48] Speaker: Grade greater than or equal to 3, 0.2%.

[17:52] Speaker: Monitor patients during infusion. Slow the infusion for Grade 1 reactions.

[17:58] Speaker: Interrupt the infusion for Grade 2.

[18:00] Speaker: And permanently discontinue TEVIMBRA for Grade 3 or higher.

[18:05] Speaker: Complications of allogeneic hematopoietic stem cell transplantation, HSCT.

[18:11] Speaker: Fatal and serious complications, including graft versus host disease, have occurred

[18:16] Speaker: in patients who received allogeneic HSCT before or after treatment with

[18:22] Speaker: PD-1/PD-L1 blockade. Complications may occur despite intervening

[18:27] Speaker: therapy between treatment with PD-1, PD-L1 blockade, and allergenic HSCT.

[18:34] Speaker: Monitor patients closely and intervene promptly. Embryo-fetal toxicity.

[18:40] Speaker: TEVIMBRA can cause fetal harm and potential fetal death, as shown in animal

[18:45] Speaker: studies. Advise females of reproductive potential of the potential risk to a fetus.

[18:51] Speaker: Verify pregnancy status prior to initiation of TEVIMBRA.

[18:55] Speaker: Advise females of reproductive potential to use effective contraception during

[19:00] Speaker: treatment and for four months after the last dose.

[19:04] Speaker: Adverse reactions. The most common adverse reactions, greater than or equal to 20%,

[19:10] Speaker: including lab abnormalities, were gastric, gastroesophageal junction, or

[19:16] Speaker: esophageal adenocarcinoma, combination with xanatumaab-hrii and chemotherapy

[19:22] Speaker: first-line, diarrhea, nausea, anemia, decreased appetite,

[19:29] Speaker: vomiting, hypokalemia, fatigue, rash, decreased neutrophil

[19:34] Speaker: count, decreased platelet count, peripheral neuropathy, infusion-related

[19:40] Speaker: reaction, and increased AST. Esophageal cancer,

[19:46] Speaker: combination with chemotherapy first-line, decreased neutrophil count, decreased

[19:51] Speaker: sodium, increased glucose, anemia, fatigue, decreased appetite,

[19:58] Speaker: increased AST, decreased potassium, increased serum

[20:03] Speaker: creatinine, decreased calcium, increased ALT, diarrhea,

[20:09] Speaker: stomatitis, and vomiting. Esophageal cancer, monotherapy

[20:15] Speaker: second line, increased glucose, decreased hemoglobin, decreased lymphocytes,

[20:21] Speaker: decreased sodium, decreased albumin, increased alkaline phosphatase,

[20:26] Speaker: anemia, fatigue, increased AST, musculoskeletal pain,

[20:32] Speaker: decreased weight, increased ALT, and cough.

[20:38] Speaker: Gastric cancer, combination with chemotherapy first-line, nausea,

[20:43] Speaker: fatigue, decreased appetite, anemia, peripheral sensory neuropathy,

[20:49] Speaker: vomiting, decreased platelet count, decreased neutrophil count, increased

[20:55] Speaker: AST, diarrhea, abdominal pain, increased ALT,

[21:01] Speaker: decreased white blood cell count, decreased weight, and pyrexia.

[21:06] Speaker: Specific populations. Lactation.

[21:09] Speaker: Advise women not to breastfeed during treatment and for four months after the last

[21:14] Speaker: dose. To report suspected adverse reactions, contact be B-One Medicines at

[21:20] Speaker: 1-877-828-5596, or FDA

[21:26] Speaker: at 1-800-FDA-1088, or

[21:31] Speaker: www.fda.gov/medwatch. Please

[21:37] Speaker: see full prescribing information.