PD-L1 CPS Plays Role in Selecting Treatment for Gastric Cancer

Syma Iqbal, MD (Moderator)

Associate Professor of Clinical Medicine

Keck School of Medicine of USC

Medical Director, Inpatient Services, Norris Cancer Hospital

Los Angeles, CA

CASE SUMMARY

A 60-year-old man presented with abrupt 10-pound weight loss, dyspepsia, bloating after meals, and loss of appetite, with all symptoms worsening over the past 3 months​. His father died of gastric cancer at 50 years old.

The patient was overweight, with Barrett esophagus. ​Esophagogastroduodenoscopy showed a 2-cm protruding mass in the body of the stomach, without ulceration​. A biopsy revealed poorly differentiated adenocarcinoma​. Molecular testing showed he was HER2/neu–negative; mismatch repair proficient/microsatellite stable; PD-L1 combined positive score (CPS) 5; and NTRK alteration negative​.

A CT scan of the abdomen and chest revealed a gastric polypoid mass and thickening; no ascites; 2 lesions in the left lung lower lobe​. Lung biopsy confirmed metastatic adenocarcinoma consistent with gastric primary. PET/CT scan confirmed metastatic disease​. He received a diagnosis of stage IV gastric adenocarcinoma and was started on FOLFOX (folinic acid, 5-fluorouracil, and oxaliplatin) plus nivolumab​ (Opdivo).

DISCUSSION QUESTIONS

• Do you agree with the choice of first-line nivolumab plus FOLFOX for this patient? ​
• At what PD-L1 expression threshold do you consider adding an immune checkpoint inhibitor to chemotherapy for HER2- advanced/metastatic gastric/gastroesophageal junction (GEJ) cancers? ​
• What if the patient in our case had a PD-L1 CPS of 3 or 4 instead of 5? What would you most likely recommend as first-line therapy?​
• What if the PD-L1 testing had not been performed or was unknown for some reason? Would you have initiated nivolumab plus chemotherapy or order a PD-L1 test (if tissue available/accessible) before starting nivolumab?​

SYMA IQBAL, MD: Do you agree with the first choice, nivolumab and FOLFOX? And then what do you think about the CPS score? Would you treat a [patient with a] CPS score of less than 5?

SHIVEN PATEL, MD: The data were presented in a clever way to get it approved for all comers, but they weren’t presented specifically for the subgroups.¹ Looking at the [Kaplan-Meier] curves [for overall survival for patients with CPS of at least 1 versus all patients], there are clearly those with CPS greater than 5 who created the benefit in all comers and in those with CPS greater than 1. I think if you had specific charts looking at the CPS 1 to 4 and the CPS less than 1—which would be small numbers, underpowered—I don’t think you’d see any benefit in those with CPS less than 1, and I think those with CPS 1 to 4 would be questionable. I still offer it if [their CPS score is] greater than 1.

IQBAL: There have been retrospective data presented looking at those low CPS scores from CheckMate 649 [NCT02872116]. You’re absolutely right. This study was enriched. Surprisingly, I think it was at least 60% of patients who had a CPS score of 5 or greater, so it skewed the all-comers. But it looks like that those patients whose CPS was less than 5 didn’t appear to benefit from the addition of the immunotherapy in some of these retrospective evaluations of these low scores.²

ADITI CHOUDHRY, MD: Do you think the FDA might change the on-label indication? Because patients ask about that. The on-label is for everybody. It’s for all comers.

PATEL: It was an accelerated approval so they can change it down the road just like they took away the…indications [for pembrolizumab (Keytruda)].³

IQBAL: I’m sure it will get reviewed. They did take away the third-line indication for single-agent [pembrolizumab], so there may be some revision to the FDA label [for nivolumab].

CHOUDHRY: What do you do in your practice, Dr Iqbal?

IQBAL: I do what’s been described. If they have a CPS score of 5 or greater, they get immunotherapy. If they’re between 1 and 4, even though the retrospective data shows that they probably aren’t benefitting, I do tend to use it in my practice. If their CPS is 0, I don’t use it at all.

CHOUDHRY: What do you do with somebody with squamous histology, CPS of 1 and TMB [tumor mutational burden] of 8? Would you use it?

IQBAL: Yes, for a CPS of 1 or greater in squamous [disease] I use it.

VANDANA AGARWAL, MD: How immunogenic are GEJ cancers? There are 2 tumor types which are highly immunogenic: melanoma and renal cell carcinoma. But GEJ cancers are not more immunogenic.

IQBAL: Not in the way that we’re seeing in the tumors you’ve described, but it’s [one of] the first things that we’ve been able to add to our armamentarium of treating these patients. Besides trastuzumab [Herceptin] and ramucirumab [Cyramza], we haven’t had anything to add to chemotherapy, and the addition of immunotherapy clearly benefits some patients. I do tend to use it. Are you finding limitations of getting it in your practice, based on CPS score?

AGARWAL: No.

IQBAL: What if you didn’t know the CPS score? What if you didn’t know the PD-L1 status of the patient?

AGARWAL: Then it’s difficult. We can’t get approval. If the CPS score is not available or PD-L1 or TMB is not there, then unless it’s a private insurance, it’s very difficult to get reimbursed or approved from the Health Maintenance Organizations.

DISCUSSION QUESTIONS

• For how long do you, or should you, continue nivolumab?​
• What are the options for next-line therapy for this patient? ​
• Given the high proportion of patients who do not go on to receive more than 1 line of therapy, how important is using the most effective therapy first? ​
• What do you view as the ideal scenario(s)/line of therapy for use of an immune checkpoint inhibitor for a patient with HER2- advanced/metastatic gastric or GEJ cancer? ​

IQBAL: How long do you continue therapy with nivolumab?

AGARWAL: One year or until progression or intolerance.

CHOUDHRY: Two years or until progression or intolerance.

ELIE FAHED, MD: Usually 2 years, but I don’t think I have had to make that decision yet.

NEEL TALWAR, MD: I would continue indefinitely until progression or toxicity. I think the issue is more the oxaliplatin; how long do you give that? Usually, I give 8 cycles of FOLFOX and nivolumab and then drop the oxaliplatin and keep them on maintenance 5-fluorouracil and nivolumab.

IQBAL: I think that’s a common practice. Many of the trials that are being designed now have accepted that as a standard approach, and extrapolating from the colon cancer data and dropping the oxaliplatin and continuing with the maintenance therapy plus the nivolumab.

FAHED: Is there a tail on the [Kaplan-Meier] curve? [Are] there any long responders?

IQBAL: There are tails on all these immunotherapy [Kaplan-Meier] curves. That is what we’re looking for in all these patients, to find that tail patient. In terms of how long to treat these patients, CheckMate 649 was 2 years. You’re lucky to have this problem, but I also usually continue until disease progression. [That is] something to keep in mind.

DIANA HANNA, MD: [I continue] usually until 2 years and then for that rare patient, I have a discussion with them if they want to continue or stop.

IQBAL: Yes. I think it’s also interesting we brought up the third-line [pembrolizumab] data where the FDA approval was retracted, if you will, based on ODAC’s [Oncologic Drugs Advisory Committee’s] recommendation. This [essentially] is the only opportunity to potentially expose patients to immunotherapy. The majority of patients don’t go on to second-line treatment. Does that affect your decision to use immunotherapy up front?

FAHED: To a degree it does. I always consider I have one shot at the goal here, and whatever I pick for my first line, [it is] probably very unlikely that I’ll go to second line. So I tend to use a lot of combinations based on FDA approval, chemoimmunotherapy and trastuzumab if the patient is HER2 positive.

_REFERENCES

_{1. 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. Lancet. 2021;398(10294):27-40. doi:10.1016/S0140-6736(21)00797-2}

_{2. Shitara K, Janjigian YY, Moehler M, et al. Nivolumab (NIVO) plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): Expanded efficacy, safety, and subgroup analyses from CheckMate 649. J Clin Oncol. 2022;40(4_suppl):240. doi:10.1200/JCO.2022.40.4_suppl.240}

_{3. Merck provides update on Keytruda® (pembrolizumab) indication in third-line gastric cancer in the US. Merck. July 1, 2021. Accessed November 16, 2022. https://bit.ly/3tBF9Hs}