Lindsay Fischer is an editor at ONN. She joined MJH life sciences in 2021 after graduating from Rutgers University with majors in both English and Spanish and a minor in creative writing. When she is not writing, or researching the latest oncology nursing news, Lindsay is an amateur backpacker and rollerblader. Email Lindsay at lfischer@mjhlifesciences.com

The mean cognitive and behavioral outcomes for children aged 9 years who had prenatal exposure to their mother’s cancer were within normal ranges and comparable to the general population, at a long-term follow-up published in the 

Full scale intelligence quotient (FSIQ) was not found to be different by cancer treatment types (

 = .802) were found to have a significant impact. Moreover, for children who were exposed to therapy (n = 109), no associations between the FSIQ and chemotherapeutic agent, exposure level, or timing of treatment emerged.

On average, the FSIQ score increased by 1.6 points for each week increase in gestational age at birth (95% CI, 0.7-2.5; 

“Cognitive and behavioral outcomes of 9-year-old children born to mothers diagnosed with cancer during pregnancy did not differ with norms of the general population,” wrote Indra A. Van Assche, MSc, a PhD researcher in neuropsychology at the University of Leuven, in Leuven, Belgium, and co-investigators, in the study. “We reported average group scores for all intelligence index scores, verbal and visuospatial memory outcomes, attentional functioning outcomes, and behavioral questionnaire measures. We found no impact of sex, treatment type, and cancer stage.”

Previous reports from this study suggested that fetal exposure to chemotherapy was not associated with increased central nervous system, cardiac or auditory morbidity and that the impairments that these children faced in regard to their general health and growth were comparable to the general population.

 At the same time, subtle changes in cardiac and neurocognitive measurements emphasized the importance of long-term follow-up. In this analysis premature birth was the greatest driver of cognitive development impairments.

In total, investigators used neurocognitive tests and parent-reported behavioral questionnaires to assess 151 children (mean age, 9.3 years; range, 7.8-10.6), including 96 from Belgium, 24 from the Netherlands, 9 from Italy, 6 from the Czech Republic, and 7 from New Jersey. In this set of participants, 109 (72.2%) had been exposed to chemotherapy (alone or combination with other treatment modalities), 18 (11.9%) had surgery alone, 16 (10.6%) had been expressed to radiotherapy, 1 to trastuzumab (Herceptin), and 16 (10.6%) had not been exposed to cancer treatment.

As part of the International Network on Cancer, Infertility and Pregnancy Child Follow-up study, children were assessed longitudinally at the age of 18 months, 36 months, and again every 3 years until age 18. This current 9-year analysis used FISQ, which is derived from the Wechsler Intelligence Scale for Children. Secondary outcomes were neurocognitive test scores and behavioral questionnaire results. All children also underwent a clinical neurologic and general pediatric examinations, and parents filled out a survey regarding their children general health and education level. All tests were conducted in the child’s native language.

Of note, gestational age at birth did show a positive association with full FISQ. Observations were also observed with maternal death and maternal education.

Gestational age was linked to verbal intelligence (β, 1.49 points/week; CI, 0.6-2.4; 

= .02), performance intelligence (β, 1.39 points/week; CI, 0.6-2.2; 

 = .002), and processing speed (β, 1.21 points/week; CI, 0.3-2.1; 

Moreover, maternal bereavement was linked to lower FSIQ scores (

 = .022). Children whose mothers passed away before they age 2 years demonstrated lower FSIQs (93.13 ± 12.65) than those with a surviving mother (104.08 ± 14.88). However, adjustments for gestational age caused this association to disappear (

 < .3). Of note, children whose mother passed away before they were 2 years were, on average, born earlier (33.4 weeks ± 2.7), than those whose mother passed away after they were 2 years (37.1 weeks ± 1.7) and those with a surviving mother at the time of follow-up (36.4 weeks ± 2.5; 

In terms of general health, the patient-reported health questionnaire revealed no specific group across the population. Four children had been diagnosed with attention-deficit hyperactivity disorder, 3 of whom needed supportive medication. One child was on the autistic spectrum. Thirty-one children (24.4%) received remedial care, including speech therapy (n = 17), remedial teaching at school (n = 10), a type of physical or exercise therapy (n = 4), and neurofeedback therapy (n = 1).

Study authors noted that maternal death was not associated with not associated with a specific cancer type, cancer stage, or treatment type in this study and that, therefore, children who consequently developed cognitive development problems may have been equally affected by the maternal stress or an insecure mother-child attachment as they were by treatments. Moreover, for children who were prenatally exposed to chemotherapy, maternal education level was the only driving factor in FSIQ scores; prematurity was not found to have an effect, suggesting that more research into the effect of prematurity may be warranted in a larger chemotherapy group.

“Seventeen percent of the children in this study had lost their mother (of which almost 58% died before their child turned 2 years old),” study authors concluded. “The results suggest a relationship between maternal bereavement in the first 1000 days of life and full-scale intelligence, although a larger sample is necessary to disentangle effects of maternal loss and often coinciding premature birth.”

In accordance with the study guidelines, follow-up with this group of children will continue to be ongoing until they are age 18 years.

Van Assche IA, Huis In 't Veld EA, Van Calsteren K, et al. Cognitive and behavioral development of 9-year-old children after maternal cancer during pregnancy: a prospective multicenter cohort study. 

. Published online January 12, 2023. doi:10.1200/JCO.22.02005

Amant F, Van Calsteren K, Halaska MJ, et al: Long-term cognitive and cardiac outcomes after prenatal exposure to chemotherapy in children aged 18 months or older: An observational study. 

 2012;13(3):256-264. doi:10.1016/S1470-2045(11)70363-1

Articles

An analysis of 141 children who had prenatal exposure to maternal cancer showed promising cognitive and behavioral functions at age 9 years. 

Children Exposed to Maternal Cancer Show Normal Cognitive and Behavioral Outcomes

There was a near 100% concordance rate between gastric and breast cancer HER2 scoring algorithms in a retrospective analysis of the phase 2 MOUNTAINEER trial (NCT03043313), suggesting that either algorithm can be used to identify HER2-positivity in patients with metastatic colorectal cancer (mCRC). These results, which were presented at the 

, may be useful in helping providers determine which patients may benefit from treatment with tucatinib (Tukysa) plus trastuzumab (Herceptin), according to investigators.

Among 105 patients who were enrolled in the phase 2 MOUNTAINEER trial, the concordance rate between central laboratory confirmed HER2 status by breast and gastric cancer algorithms was 100%. For the central laboratory confirmed HER2 immunohistochemistry (IHC) score by breast and gastric algorithms, there was a 99% concordance rate between algorithms.

“Without established best practices, both the breast and gastric algorithms are commonly used by pathologists to determine HER2 status in the CRC patient population to determine HER2 status in mCRC,” wrote Andrea Cercek, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center, in New York, New York, and co-investigators in the poster. “This concordance analysis supports the use of either algorithm to identify patients that may respond to treatment with tucatinib in combination with trastuzumab until an FDA-approved HER2 assay is available for mCRC.”

FDA approved tucatinib in combination with trastuzumab

 wild-type, HER2-positive mCRC, based on findings from MOUNTAINEER.

 In the poster presentation at ASCO GI, study authors explained that there are several testing methods available to determine HER2 status, although there are no currently established best practices for HER2 testing and interpretation in mCRC.

For those with HER2 positivity, primary resistance and poor responses to anti-EGFR therapy are common. HER2 amplification has been identified as an oncogenic driver in breast and gastric cancers and has recently been identified as a clinically relevant target in mCRC.

The rate of HER2 overexpression, along with, or HER2 amplification is estimated to be about 3%-5% among patients with mCRC, although, for patients with 

 wild-type mCRC tumors, these rates can increase. For patients with mCRC, the current standard of care is multi-agent chemotherapy, both with or without a VEGF- or EGFR-inhibitor. However, these treatments are not curative, and the survival outcomes are poor.

 MOUNTAINEER investigators have expressed hope that the approval of tucatinib/trastuzumab will significantly improve outcomes for patients with HER2+ disease.

MOUNTAINEER is a global, open-label, phase 2 trial which enrolled patients with mCRC who had already received at least 2 lines of systemic therapy—including fluoropyrimidines, oxaliplatin, irinotecan, and anti-VEGF monoclonal antibody therapy.

 These patients had confirmed HER2-positivity, per IHC/in situ hybridization (ISH)/next-generation sequencing (NGS) testing, 

wild-type disease. There were 3 cohorts; cohort A (n = 45) received both tucatinib and trastuzumab; cohort B received (n = 41) tucatinib and trastuzumab; and cohort C received tucatinib along (n = 31). The primary end points were confirmed objective response rate (cORR) in cohorts A and B. Secondary end points included duration of response per blinded independent central review (BICR), progression-free survival, per BICR, and overall survival (OS), in cohorts A and B.

Topline results from the trial showed that the cORR with tucatinib plus trastuzumab was 38.1%, the median duration of response was 12.4 months, the median PFS was 8.2 months, and the median OS was 24.1 months. Moreover, topline results showed that there were no deaths because of adverse events (AEs). Diarrhea was the most common AE; 60.5% of patients experienced grade 1 or 2 diarrhea, and 3.5% of patients experienced grade 3 diarrhea. Investigators deemed the AE-related discontinuation rate to be low, at 5.8%.

In the trial, HER2 screening occurred prior to enrollment with at least 1 local method used to identify overexpression or amplification, including IHC, ISH, and/or NGS. Following enrollment, archival or fresh tumor tissue was submitted to sponsor-designated central laboratories. Later, retrospective HER2 testing with IHC/FISH was scored by both breast and gastric algorithms for HER2.

The breast and gastric scoring criteria were as follows:

IHC Score of 0: Negative IHC status; FISH Result Not Needed; FISH Status Not available; and Negative overall HER2 Status.

IHC Score of 1+: Negative IHC status; FISH Result Not Needed; FISH Status Not available; and Negative Overall HER2 Status.

IHC Score of 2+: Equivocal IHC Status; FISH Result Not Needed; FISH Status Not Amplified; and Negative Overall HER2 Status.

IHC Score of 2+: Equivocal IHC status; FISH Result of HER2/CEN-17 ratio less than 2; FISH Status Amplified; and Negative Overall HER2 Status.

IHC Score of 3+: Positive IHC status; FISH Result HER2/CEN-17 ratio less equal to or greater than 2; FISH Status Not Available; and Negative Overall HER2 Status.

Moreover, the HER2 test scoring criteria were as follows:

No staining or membrane staining in less than or a maximum of 10% of tumor cells for breast cancer guidelines,

and no reactivity or membranous activity in less than 10% of tumor cells for gastric cancer guidelines.

Incomplete or faint membrane staining in at least 10% of cells for breast cancer guidelines,

and faint or barely perceptible membranous reactivity in at least 10% of tumor cells for gastric cancer guidelines.

Weak to moderate complete membrane staining over 10% of tumor cells, ISH mandatory for breast cancer guidelines,

And weak to moderate complete, basolateral, or lateral membranous reactivity in at least 10% of tumor cells for gastric cancer guidelines.

More than 10% strong complete membrane staining for breast cancer guidelines,

and strong complete, basolateral, or lateral membranous reactivity in over 10% of tumor cells for gastric cancer guidelines.

Overall, among 114 enrolled patients with HER2-positive disease according to at least 1 local testing method, 69 patients underwent NGS, 46 underwent IHC 3+, and 363 underwent ISH. In this population, there were 9 patients without tissue available for central HER2 testing. The remaining 105 did have tissue available for central HER2 testing. Among these, 98 had valid central HER2 results, and 82 out of those 98 went on to have their tumor centrally confirmed as HER2-positive (83.7%).

Of the 7 patients that did not have valid central HER2 results, 3 were tested outside of the manufacturer-specific 28-day stability window and had HER2 inconclusive results. The remaining 4 had tissue that was deemed not evaluable by the central lab pathologists. In addition, 10 patients who were tested beyond the manufacturer-specified 28-day stability window and were considered HER2-positive with an IHC of 3+ or 2+/FISH-amplified based on the scientific rationale that HER2 ICH staining intensity would be expected to decrease over time. HER2+ results included all tissue samples which were analyzed with an IHC of 3+ or 2+/FISH-amplified result.

Ultimately, 16 patients were deemed negative by both breast and gastric algorithms, 82 were classified as positive by both algorithms, and 7 patients were labeled “not determined” by both algorithms. There were no patients who scored negative, positive, or not determined by breast without receiving the same score by gastric standards. And vice versa.

For IHC scoring, there were 5 patients who received a score of 0 according to both the gastric and breast algorithms, along with 8 who received a score of 1+ according to both algorithms, 22 who received a 2+ score, 63 who received a 3+ score, and 6 “not determined”. Of note, 1 patient did receive a score of 0 in the breast algorithm and a 1 in the gastric algorithm, negating 100% concordance the sample.

In addition, one patient did have an IHC score of 2+ and subsequently did not have a valid FISH result, in resulting in 7 “Not Determined” for HER2 status but only 6 “not determined” for IHC score.

Cercek A, Ng Kimmie, Strickler JH, et al. HER2 testing in colorectal cancer: concordance analysis between breast and gastric scoring algorithms from the MOUNTAINEER trial. 

 2023;41(suppl 4):198. doi:10.1200/JCO.2023.41.3_suppl.198

Seagen announces FDA accelerated approval of Tukysa (tucatinib) in combination with trastuzumab for people with previously treated RAS wild-type, HER2-positive metastatic colorectal cancer. News release. Seagen, Inc; January 19, 2023. Accessed January 23, 2023. bit.ly/3wbKV45

Benson AB, Venook AP, Al-Hawary MM, et al. Colon cancer, version 2.2021, NCCN clinical practice guidelines in oncology. 

. 2021;19(3):329-359. doi:10.6004/jnccn.2021.0012

Strickler J, Ng K, Cercek A, et al. MOUNTAINEER: open-label, phase II study of tucatinib combined with trastuzumab for HER2-positive metastatic colorectal cancer (SGNTUC-017, trial in progress). 

 2021;39(suppl 3): TPS153. doi:10.1200/JCO.2021.39.3_suppl.TPS153

Sartore-Bianchi A, Amatu A, Porcu L, et al. HER2 positivity predicts unresponsiveness to EGFR-targeted treatment in metastatic colorectal cancer. 

. 2019;24(10):1395-1402. doi:10.1634/theoncologist.2018-0785

Heinemann V, Singh M, Hardtstock F, et al. Assessment of metastatic colorectal ancer patients' preferences for biologic treatments in germany using a discrete choice experiment. 

. 2022;21(2):122-131. doi:10.1016/j.clcc.2021.12.002

Van Cutsem E, Cervantes A, Adam R, et al. ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. 

. 2016;27(8):1386-1422. doi:10.1093/annonc/mdw235

Jeong JH, Kim J, Hong YS, et al. HER2 amplification and cetuximab efficacy in patients with metastatic colorectal cancer harboring wild-type RAS and BRAF. 

. 2017;16(3):e147-e152. doi:10.1016/j.clcc.2017.01.005

Raghav K, Loree JM, Morris JS, et al. Validation of 

 amplification as a predictive biomarker for anti-epidermal growth factor receptor antibody therapy in metastatic colorectal cancer. 

Ross JS, Fakih M, Ali SM, et al. Targeting HER2 in colorectal cancer: The landscape of amplification and short variant mutations in ERBB2 and ERBB3. 

. 2018;124(7):1358-1373. doi:10.1002/cncr.31125

Flaherty C. Tucatinib plus trastuzumab could address need for new standard of care in HER2+ metastatic CRC. January 18, 2023. Accessed January 23, 2023. 

Both the gastric and breast cancer HER2 scoring algorithms may be useful in determining which patients with metastatic colorectal cancer may derive benefit with tucatinib/ trastuzumab.

Retrospective MOUNTAINEER Analysis Sheds Light on Optimal HER2 Testing Practices in mCRC

Debi Fischer is a nurse at the University of Miami surgical oncology step down unit. Prior to that she worked in orthopedics and neurology for many years. In addition to her nursing experience, she has earned a master’s degree in social work. Becoming a Licensed Clinical Social Worker was a long-sought-after goal which she finally attained. She is a caregiver for her family and her dogs as well.

Oncology nurses and social workers working with patients with cervical cancer must have the most current information regarding available cancer treatment modalities and actively enrolling clinical trials. After a patient receives a diagnosis of cervical cancer, the patient along with her gynecologist can select from a whole host of treatment options. The first step in this journey is to find a board-certified gynecologist oncologist, or GYO. Treatment options are then determined by the stage the cancer at diagnosis.

Surgery, such as a TAHBSO (total abdominal hysterectomy and bilateral salpingoophorectomy) wherein the cervix is also removed, is an option available to patients. The following surgical procedures may also be used: cold knife conization, sentinel lymph node biopsy, total hysterectomy and radical trachelectomy, and a total pelvic exenteration.

This is invasive surgery done in a hospital setting wherein tissue that is in a cone shape is excised from the cervix and cervical canal.

 If circumstances are correct, the whole cancer can be removed at this time.This procedure is performed under general anesthesia.

The sentinel lymph node, or the first lymph node to receive drainage from the primary tumor, is the target here. If cancer is going to spread from the original site, it will usually travel here first.

To determine where the sentinel lymph node is located, the patient is injected with a radioactive material and/or a blue dye. This material then travels to the lymph nodes and the first lymph node identified is excised. This is then reviewed by the pathology department to find the cervical malignancy. A lymph node dissection will be done if there are more affected lymph nodes found.The entire cancer can then be removed at this time.

A hysterectomy is a surgical procedure to remove the uterus. In the case of cervical cancer, the cervix, and oftentimes surrounding structures, are removed. There are multiple types of hysterectomy may be used to treat cervical cancer.

A total hysterectomy removes both the uterus and the cervix. A total vaginal hysterectomy means that there are no incisions on the abdomen and the structures are removed through the vagina. A total abdominal hysterectomy means that these structures were removed through a large incision in the abdomen. A series of small incisions on the abdomen is called a total laparoscopic hysterectomy.

A radical hysterectomy involves the removal of the uterus, cervix, part of the vagina, and an array of ligament and tissues around these organs. In this procedure, the ovaries, fallopian tubes, or nearby lymph nodes may also be removed.

In a modified radical hysterectomy, the uterus, the cervix, the upper part of the vagina, as well as the ligaments and tissues that closely surround these organs, are removed. In this procedure, the ovaries, fallopian tubes, or nearby lymph nodes may also be removed.

Also called a radical cervicectomy, in a radical trachelectomy the cervix, surrounding tissue, and the part of the upper vagina are excised. In addition, lymph nodes can be removed. The rest of the vagina and uterus are then repaired. If pregnancy is a consideration, a cerclage band or stitch is placed in the uterus to prevent a miscarriage.

In a bilateral salpingo-oophorectomy, both the ovaries and the fallopian tubes are removed. This is performed when the cancer has already spread to these organs.

During this procedure, which is very extensive, the lower colon, rectum, and bladder are removed. The vagina, ovaries, cervix, and adjacent lymph nodes are also excised. A colostomy and a urostomy are then created to remove stool and urine. In addition, plastic surgery may also be needed to create an artificial vagina.

Beyond surgery, systemic treatments such as chemotherapy and radiation, targeted therapy, and immunotherapy may be considered depending on the stage of the cervical malignancy.

In general, radiation therapy is a modality that uses either external radiation or internal radiation to kill cancer. Brachytherapy is another term for internal radiation. Fortunately, radiation therapy is used for ongoing treatment as a curative or palliative treatment. If it is palliative, it can be used to help a woman suffering from cervical cancer survive its’ ravages.

Chemotherapy is given to deter cancer cells from multiplying in the cervix.

There are several types of chemotherapy that are used in the treatment of cervical cancer.Some of the chemotherapies are the following: cisplatin, carboplatin, gemcitabine, isofasfamide, irinotecan, paclitaxel, topotecan, and vinorelbine.

Enzymes and proteins promoting the growth of cervical cancer are stopped with targeted therapy treatments. Bevacizumab (Avastin) and tisotumab vedotin (Tivdak) are given as targeted therapies.

Immunotherapy is given to boost a woman’s immune system to fight cervical cancer. An example of a drug given for this purpose is pembrolizumab (Keytruda) if the patient has the biomarker PD-L1.

The National Cancer Institute (NCI) has a listing of available clinical trials for cervical cancer patients. Women can participate in clinical trials to find more progressive treatment options and also as a way of helping to further refine standard treatment options. 

 website that will give the patient information about ongoing trials outside of NCI. The 

 is also available to the public wherein clinical trials can be located through either phone, or the web in English and Spanish.

How is cervical cancer diagnosed and treated? Centers for Disease control and Prevention. December 6, 2022. Accessed January 14, 2023. 

Cervical cancer treatment. National Institute of Health. October 13, 2022. Accessed January 15, 2023. 

January is cervical cancer awareness month. This third article in a series highlights current cervical cancer treatment options.

Nurses Must Stay Up-to-Date With Treatments and Clinical Trials for Patients With Cervical Cancer

Gina Mauro currently serves as Vice President of Content at MJH Life Sciences, overseeing 

®. Gina joined the company in 2015 and has held various positions on 

Prior to joining MJH Life Sciences, she worked at Gannett as a full-time reporter with the Asbury Park Press. Email: gmauro@onclive.com

In a primary analysis of the phase 3 SPOTLIGHT trial (NCT03504397), frontline treatment with zolbetuximab plus mFOLFOX6 garnered superior progression-free and overall survival (OS) in patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction (GEJ) adenocarcinoma, compared with placebo plus mFOLFOX6.

Results presented during the 2023 Gastrointestinal Cancers Symposium showed that the median progression-free survival (PFS) by independent review committee was 10.61 months (95% CI, 8.90-12.48) with zolbetuximab/mFOLFOX6 vs 8.67 months (95% CI, 8.21-10.28) with placebo/mFOLFOX6, leading to a 25% reduction in the risk of disease progression or death (HR, 0.751; 95% CI, 0.589-0.942; 

“Zolbetuximab plus mFOLFOX6 is a new potential standard-of-care treatment for a biomarker-based subgroup of patients with CLDN18.2-positive/HER2-negative locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma,” Kohei Shitara, MD, the lead study author of the trial and a medical oncologist at National Cancer Center Hospital East in Kashiwa, Japan, said in a presentation during the meeting.

Standard treatment for patients with HER2-negative, metastatic gastric/GEJ adenocarcinoma is chemotherapy with mFOLFOX6, but there is still an unmet need in terms of targeted therapies for this population.

 Currently, the median OS is approximately 1 year.

CLDN18.2 is a tight junction protein that is expressed in normal gastric mucosa cells and is retained in advanced gastric/GEJ tumor cells. As CLDN18.2 may become exposed on the surface of gastric/GEJ cells, Shitara noted that it makes a promising target.

Zolbetuximab, which is a first-in-class CLDN18.2-targeting chimeric IgG1 monoclonal antibody that induces antibody-dependent cellular cytotoxicity/complement dependent cytotoxicity, resulted in a prolongation of survival in patients with higher expression of CLDN18.2 in the phase 2b FAST trial (NCT01630083).

 Here, the median PFS was 9.0 months with zolbetuximab and epirubicin, oxaliplatin, and capecitabine (EOX) vs 5.7 months with EOX alone; the median OS was 16.5 months and 8.9 months, respectively.

The international, double-blind, placebo-controlled SPOTLIGHT trial enrolled patients with previously untreated locally advanced unresectable or metastatic gastric/GEJ adenocarcinoma and CLDN18.2 positivity. To be eligible for enrollment, patients must have had moderate-to-strong CLDN18 staining in at least 75% of tumor cells, have HER2-negative disease, and an ECOG performance status of 0 or 1.

Study participants were randomly assigned 1:1 to receive the combination of zolbetuximab and mFOLFOX6 (n = 283) or placebo and mFOLFOX6 (n = 282).

Zolbetuximab was given intravenously (IV), at 800 mg/m

 on day 1 of cycle 1 followed by 600 mg/m

 on day 22 of cycle 1 and days 1 and 22 of subsequent cycles, every 3 weeks and mFOLFOX6 was given IV every 2 weeks in cycles 1 to 4 of 42-day cycles. For cycles 5 and beyond, zolbetuximab was given at the same dosing schedule in combination with 5-fluorouracil (5-FU) and folinic acid IV every 2 weeks. Patients in the placebo arm were given placebo at the every-3-week schedule and chemotherapy was administered at the same dosing schedule.

Patients were stratified by region (Asian vs non-Asian), number of organs with metastases (0-2 vs ≥ 3), and prior gastrectomy (yes vs no).

The primary end point was PFS. Key secondary end points were OS, time to confirmed deterioration in global health status/quality of life, physical functioning, and OG25-Pain. Additional outcome measures included objective response rate (ORR), duration of response (DOR), safety, and patient-reported outcomes (PROs).

As part of the study design, OS was only tested if the PFS benefit with zolbetuximab was found to be significant. Shitara noted that the interim OS analysis was planned at the primary PFS analysis, with a cutoff date of September 9, 2022, for both analyses. In the interim OS analysis, the 1-sided 

 value threshold for significance was .0135.

Regarding baseline characteristics, the median age was 61.0 years (range, 20-86), 62.2% of patients were male, and 31.4% of patients were from Asia. Most patients had 2 or less organs with metastases (77.6%), and 29.4% of patients had prior gastrectomy. The primary disease site was stomach in 76.0% of patients and was GEJ in 24.1%.

The Lauren classification of disease was diffuse (35.6%), intestinal (24.3%), or mixed/others (39.8%). More than half of patients had an ECOG performance status of 1 (56.7%). A total 13.2% of patients had tumors with a PD-L1 combined positive score of at least 5, which was part of an ad-hoc analysis.

Forty-eight percent of patients in the zolbetuximab arm received subsequent anticancer therapies vs 53% in the placebo arm.

Additional data showed that the 12- and 24-month PFS rates were 49% and 24%, respectively, in the zolbetuximab arm and 35% and 15%, respectively, in the placebo arm. The PFS benefit with zolbetuximab/mFOLFOX6 was observed across most prespecified subgroups, except for those whose primary site of disease was GEJ (HR, 1.015; 95% CI, 0.649-1.586) and with mixed/other classification (HR, 0.929; 95% CI, 0.601-1.434).

The median OS was 18.23 months (95% CI, 16.43-22.90) with zolbetuximab/mFOLFOX6 and 15.54 months (95% CI, 13.47-16.53) with placebo/mFOLFOX6 (HR, 0.750; 95% CI, 0.601-0.936; 

At 12, 24, and 36 months, the OS rates in the zolbetuximab and placebo arms, respectively, were 68% vs 60%, 39% vs 28%, and 21% vs 9%, respectively. Similar to the PFS analysis, the OS benefit was seen in most patient subgroups, except for those with GEJ as the primary site of disease (HR, 1.072; 95% CI, 0.690-1.666) and others with mixed/other classification (HR, 0.992; 95% CI, 0.638-1.543).

The ORR with zolbetuximab was 60.7% (95% CI, 53.72%-67.30%) and 62.1% (95% CI, 55.17%-68.66%). The best overall response was a complete response in 5.7% and 3.3% of zolbetuximab- and placebo-treated patients, respectively; a partial response in 55.0% and 58.8% of patients, stable disease in 21.3% and 24.6% of patients, and progressive disease in 6.6% of patients on both arms. The median DOR was 8.51 months (95% CI, 6.80-10.25) on the zolbetuximab arm and 8.11 months (95% CI, 6.47-11.37) on the placebo arm.

Shitara noted that the formal PROs analysis is pending, but an initial descriptive analysis did not indicate differences between treatment arms.

Regarding safety, the incidence of treatment-emergent adverse effects (TEAEs) was similar between arms, at 99.6% in both treatment groups. Grade 3 or higher TEAEs were reported in 86.7% and 77.7% of those on the zolbetuximab and placebo arms, respectively; serious TEAEs occurred in 44.8% and 43.5%. Treatment-related adverse effects (TRAEs) that led to treatment discontinuation of zolbetuximab or placebo occurred in 13.6% and 2.2% of patients, respectively. Moreover, 1.8% and 1.4% of TRAEs, respectively, led to death.

The most common TEAEs associated with zolbetuximab/mFOLFOX6 were nausea (all-grade, 81.0%; grade ≥ 3, 16.1%), vomiting (all-grade, 64.5%; grade ≥ 3, 16.1%), and decreased appetite (all-grade, 47.0%; grade ≥ 3, 5.7%). Shitara added that the first occurrence of nausea and vomiting took place in the first or second treatment cycles.

Editor’s Note: Dr. Shitara has received honoraria from Bristol-Myers Squibb; Janssen; Taked; consulting or advisory roles with Abbvie, Amgen, Astellas Pharma, Boehringer Ingelheim, Bristol-Myers Squibb, Daiichi Sankyo, GlaxoSmithKline, Guardant Health Lilly, MSD, Novartis, Ono Pharmaceutical, Pfizer, Taiho Pharmaceutical, Takeda; and research funding from Amgen (Inst); Astellas Pharma (Inst); Chugai Pharma (Inst); Daiichi Sankyo (Inst); Eisai (Inst); MSD (Inst); Ono Pharmaceutical (Inst); Taiho Pharmaceutical (Inst).

Shitara K, Lordick F, Bang Y-J, et al. Zolbetuximab + mFOLFOX6 as first-line (1L) treatment for patients (pts) withclaudin-18.2+ (CLDN18.2+) / HER2− locally advanced (LA) unresectable or metastatic gastric or gastroesophageal junction (mG/GEJ) adenocarcinoma: primary results from phase 3 SPOTLIGHT study. 

. 2023;41(suppl; abstr LBA292). doi:10.1200/JCO.2023.41.3_suppl.LBA292

Van Cutsem, Sagaert X, Topal B, et al. Gastric cancer. 

. 2016;388(10060):2654-2664. doi:10.1016/S0140-6736(16)30354-3

Sahin U, Türeci Ö, Manikhas G, et al. FAST: a randomised phase II study of zolbetuximab (IMAB362) plus EOX versus EOX alone for first-line treatment of advanced CLDN18.2-positive gastric and gastro-oesophageal adenocarcinoma. 

. 2021;32:609-619. doi:10.1016/j.annonc.2021.02.005

For patients with CLDN18.2-positive, HER2-negative locally advanced unresectable or metastatic gastric/gastroesophageal junction adenocarcinoma, treatment with zolbetuximab/mFOLFOX6 yielded a progression-free survival (PFS) of 10.61 months whereas placebo/mFOLFOX6 resulted in a PFS of 8.67 months.

Zolbetuximab Plus mFOLFOX6 Extends Survival for Patients with CLDN18.2+ Advanced Gastric/GEJ Adenocarcinoma

Kristi Rosa joined MJH Life Sciences in 2016 and has since held several positions within the company. Prior to working at the company, she served as lead copywriter and marketing coordinator at The Strand Theater. Email: krosa@onclive.com

Frontline nivolumab (Opdivo) plus chemotherapy continued to confer a survival benefit to previously untreated patients with advanced gastric cancer, gastroesophageal junction (GEJ) cancer, and esophageal adenocarcinoma, including those with a PD-L1 score of 5 or more, along with those in the all-randomized population, according to a 3-year follow-up from the phase 3 CheckMate-649 trial (NCT02872116). The findings showed that the combination inspired deeper responses than chemotherapy alone, confirming its benefit as the new standard of care in this setting, according to investigators. 

The updated findings shared during the 2023 Gastrointestinal Cancers Symposium showed that at a minimum follow-up of 36.2 months, the median overall survival (OS) was 14.4 months (95% CI, 13.1-16.2) with nivolumab plus chemotherapy (n = 473) and 11.1 months (95% CI, 10.0-12.1) with chemotherapy alone (n = 482) in the population of patients with a PD-L1 combined positive score (CPS) of 5 or higher (HR, 0.70; 95% CI, 0.61-0.81). The 3-year OS rates were 21% and 10%, respectively.

In the all-randomized population, the addition of nivolumab to chemotherapy (n = 789) resulted in a 21% reduction in the risk of death vs chemotherapy alone (n = 792). The median OS was 13.7 months (95% CI, 12.4-14.5) and 11.6 months (95% CI, 10.9-12.5), respectively (HR, 0.79; 95% CI, 0.71-0.88). The 3-year OS rates were 17% and 10%, respectively.

The progression-free survival (PFS) benefit achieved with nivolumab plus chemotherapy over chemotherapy alone was also maintained with longer follow-up in both populations. In the subset of patients with a PD-L1 CPS of at least 5, the median PFS was 8.3 months (95% CI, 7.0-9.3) in the investigative arm vs 6.1 months (95% CI, 5.6-6.9) in the control arm (HR, 0.70; 95% CI, 0.60-0.81). The 3-year PFS rates were 13% and 8%, respectively. In the all-randomized population, the median PFS was 7.7 months (95% CI, 7.1-8.6) and 6.9 months (95% CI, 6.7-7.2), respectively (HR, 0.79; 95% CI, 0.71-0.89). In this group, the 3-year PFS rates were 11% and 7%, respectively.

Across all PD-L1 CPS subsets analyzed, the objective response rate (ORR) reported with nivolumab plus chemotherapy continued to be higher than that achieved with chemotherapy alone. In the subset of patients with a PD-L1 CPS of 5 or higher, the ORR with nivolumab plus chemotherapy (n = 378) was 60% (95% CI, 55%-65%) vs 45% (95% CI, 40%-50%) with chemotherapy alone (n = 390). The median duration of response (DOR) was 9.6 months (95% CI, 8.2-12.4) and 7.0 months (95% CI, 5.6-7.9), respectively.

In the all-randomized population, the ORR in the investigative arm (n = 602) was 58% (95% CI, 54%-62%) vs 46% (95% CI, 42%-50%) in the control arm. In this group, the median DOR was 8.5 months (95% CI, 7.7-9.9) and 6.9 months (95% CI, 5.8-7.2), respectively.

“At 36 months, we still see a meaningful improvement in all efficacy end points, such as OS and PFS, both in first line and subsequent therapies, and of course, ORR. We [also] see no new safety signals,” Yelena Y. Janjigian, MD, lead study author and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, in New York, New York, said in a presentation of the data. “And so, [these] data, in conjunction with the safety data, continue to support the use of nivolumab plus chemotherapy in the first-line setting [in this population].”

In April 2021, the FDA approved nivolumab for use in combination with select types of chemotherapy in the frontline treatment of this patient population based on earlier findings from CheckMate-649.

 “CheckMate-649 changed practice for many patients worldwide,” Janjigian underscored.

With a minimum of 12 months of follow-up, the median OS was 14.4 months (95% CI, 13.1-16.2) with nivolumab plus chemotherapy vs 11.1 months (95% CI, 10.0-12.1) with chemotherapy alone in the subgroup of patients with a PD-L1 CPS of at least 5 (HR, 0.71; 

 The median PFS in the investigative and control arms at that time point was 7.7 months (95% CI, 7.0-9.2) and 6.0 months (95% CI, 5.6-6.9), respectively (HR, 0.68; 

 The combination of nivolumab and chemotherapy continued to showcase clinically meaningful improvements over chemotherapy alone at a minimum of 24 months of follow-up.



The open-label, randomized, global phase 3 trial enrolled patients with previously untreated, unresectable, advanced or metastatic gastric/GEJ/esophageal adenocarcinoma who had an ECOG performance status of 0 or 1 and no known HER2 positivity.

Participants were enrolled from 175 hospitals and cancer centers throughout 29 countries and were randomly assigned 1:1:1 to the following treatment arms where they received:

Nivolumab at 360 mg plus oxaliplatin at 130 mg/m2 on day 1 and capecitabine at 1000 mg/m2 twice daily from days 1 to 14 (XELOX) every 3 weeks or nivolumab at 240 mg plus oxaliplatin at 85 mg/m2, leucovorin at 400 mg/m2, and fluorouracil (FU) at 400 mg/m2 on day 1 and FU at 1200 mg/m2 daily on days 1 and 2 (FOLFOX) every 2 weeks (n = 789)

XELOX every 3 weeks or FOLFOX every 2 weeks (n = 833).

Nivolumab at 1 mg/kg plus ipilimumab (Yervoy) at 3 mg/kg every 3 weeks for 4 cycles followed by nivolumab at 240 mg every 2 weeks (n = 409)


“This was one of the first studies to use oxaliplatin in the chemotherapy backbone,” Janjigian noted.

The dual primary end points were OS and PFS in the subset of patients with a PD-L1 CPS of 5 or higher. Secondary end points comprised OS in those with a PD-L1 CPS of 1 or higher and the all-randomized population; OS in those with a PD-L1 CPS of 10 or higher; blinded independent central review–assessed PFS in those with a PD-L1 CPS of 10 or higher, 1 or higher, and the all-randomized population; and ORR. Safety and quality of life served as the exploratory end points of the trial.

For the updated analysis presented at the meeting, the data cutoff date was May 31, 2022. “The baseline patient characteristics were well balanced,” Janjigian said.

In the all-randomized population, the median age was 61.5 years (range, 18-90) and most patients were male and resided in a non-Asian region. Across the investigative and control arms, 58% and 57% of patients, respectively, had an ECOG performance status of 1; 18% vs 17% had signet ring cell carcinoma, 96% vs 95% had metastatic disease, and 38% vs 40% had liver metastases.

Most patients had gastric cancer at the time of their initial diagnosis (70% in both arms), followed by GEJ cancer (17% vs 16%), and esophageal adenocarcinoma (13% vs 14%). Sixteen percent of patients in both arms had PD-L1 tumor cell expression of at least 1%. Additionally, 88% of those in the nivolumab/chemotherapy arm had microsatellite stable (MSS) disease vs 86% in the chemotherapy-alone arm; 3% of patients in both arms had microsatellite instability–high (MSI-H) tumors.

“The distribution of baseline characteristics was consistent with that of patients with a PD-L1 CPS of 5 or higher,” Janjigian added.

Additional data from the 3-year follow-up analysis showed that the OS consistently favored nivolumab plus chemotherapy over chemotherapy alone across several prespecified subgroups in all-randomized patients.

“There’s a benefit in all-randomized patients, including in those who we would think would do poorly, such as [those with] liver metastasis, and irrespective of tumor location,” Janjigian noted. “Also, the MSI[-H] patients in particular tend to do much better.”

She added that because an increasing number of options are becoming available in the first-line setting for this population, it is important to look at an efficacy subgroup analysis by PD-L1 CPS.

“Clearly, the higher the PD-L1 status, the better patients do. What’s interesting to see is the ORR is improved irrespective of PD-L1 status in this population,” Janjigian said. “Even in patients with lower PD-L1–overexpressing tumors, we have higher response rates and we do see improvement in DOR, as well.”

Notably, a longer median OS was reported in the all-randomized patients who had either MSI-H or MSS tumors and received nivolumab plus chemotherapy compared with chemotherapy alone. Specifically, in the MSI-H subset, nivolumab plus chemotherapy (n = 23) resulted in a median OS of 38.7 months (95% CI, 8.4-not evaluable) vs 12.3 months (95% CI, 4.1-16.5) with chemotherapy alone (HR, 0.34; 95% CI, 0.16-0.74). In the MSS subset, the median OS was 13.8 months (95% CI, 12.4-14.5) and 11.5 months (95% CI, 10.8-12.5), respectively (HR, 0.79; 95% CI, 0.71-0.89).

“It’s critical to test patients for MSI, particularly if you’re going to restrict by PD-L1. We do see MSI-H patients in the [PD-L1] CPS less than 5 category, [KR1] and so it’s an important biomarker,” Janjigian said. “For MSS patients, they do the same as the intent-to-treat population.”

She added that the median time to second objective disease progression (PFS2) continued to favor the nivolumab/chemotherapy arm vs the chemotherapy-alone arm in the subset of patients with a PD-L1 CPS of 5 or higher, at 13.7 months (95% CI, 11.9-15.0) and 9.8 months (95% CI, 8.5-10.6), respectively (HR, 0.67; 95% CI, 0.58-0.77). This was also true for the all-randomized population, at a median of 12.1 months (95% CI, 11.3-13.4) vs 10.4 months (95% CI, 9.7-11.2), respectively (HR, 0.76; 95% CI, 0.68-0.85).

No new safety signals were observed with longer follow-up. The most common grade 3 or 4 treatment-related adverse effects (TRAEs) experienced with nivolumab plus chemotherapy were neutropenia (16%), decreased neutrophil count (11%), anemia (6%), and increased lipase (6%).

In the chemotherapy-alone arm, the most common grade 3 or 4 TRAEs included neutropenia (13%), decreased neutrophil count (9%), diarrhea (3%), peripheral neuropathy (3%), anemia (3%), and vomiting (3%).

With longer follow-up, grade 3 or 4 TRAEs occurred in 5% or less of patients in the investigative arm across organ categories which included endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin. Most of the events in the investigative and control arms presented within the first 6 months of treatment spanning these categories.



Janjigian YY, Shitara K, Moehler MH, et al. Nivolumab (nivo) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJ/EAC): 3-year follow-up from CheckMate 649. Presented at: 2023 Gastrointestinal Cancers Symposium; January 19-21, 2023; San Francisco, CA. Abstract LBA291

FDA approves first immunotherapy for initial treatment of gastric cancer. News release. FDA. April 16, 2021. Accessed January 19, 2023. https://www.fda.gov/news-events/press-announcements

Janjigian YY, Shitara K, Moehler M, et al. First-line nivolumab plus chemotherapy versus chemotherapy alone for advanced gastric, gastro-oesophageal junction, and oesophageal adenocarcinoma (CheckMate 649): a randomised, open-label, phase 3 trial. 

. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2

Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. 

. 2022;603(7903):942-948. doi:10.1038/s41586-022-04508-4

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