Ajani Discusses Immune Checkpoint Inhibition in HER2-Negative Upper GI Cancer

Jaffer A. Ajani, MD

Professor, Department of Gastrointestinal Medical Oncology

Division of Cancer Medicine

The University of Texas MD Anderson Cancer Center

Houston, TX

Targeted Oncology^TM: What are the approved immune checkpoint inhibitors (ICIs) for treating a patient such as this with HER2-negative upper gastrointestinal cancer? What role does PD-L1 status have in treatment?

AJANI: Both pembrolizumab [Keytruda] and nivolumab [Opdivo] are approved to treat [esophageal squamous cell carcinoma and adenocarcinoma].^1,2 Nivolumab was approved based on data from CheckMate 648 [NCT03143153] and [then approved] for adenocarcinoma based on CheckMate 649 [NCT02872116].^3,4 Both were approved by the FDA without any regard to CPS or PD-L1 status, and I think that’s a mistake. Nivolumab has approval for esophageal adenocarcinoma, including GEJC [gastroesophageal junction cancer] type I, II, III, and gastric cancer.¹ The pembrolizumab approval is restricted to GEJC type I.² There were some patients with GEJC [who were studied], so I think if you like to use pembrolizumab for type II, you should be able to get the drug.

Pembrolizumab has approval for HER2-positive [locally advanced or unresectable gastric cancer or GEJC].² Nivolumab is approved for all adenocarcinomas, also for squamous carcinoma in the untreated setting and in the second line if the patient has not received [it] in the first line.¹ Pembrolizumab has a new indication that if the tumor is untreated, metastatic, and HER2-positive, you can add pembrolizumab to chemotherapy plus trastuzumab.²

Then for metastatic adenocarcinoma, it is restricted to GEJC type I and approved for squamous cell carcinoma. But the benefit is limited to a CPS of 10, which occurs in about 45% of cases, so it’s pretty restrictive. But nivolumab you can use for all patients of squamous carcinoma. In that New England Journal of Medicine paper, 91% of patients with advanced squamous cell carcinoma are PD-L1 positive and they all seem to benefit with nivolumab.³

I wanted to point out 1 area of a lot of discussion as far as the nivolumab is concerned. The National Comprehensive Cancer Network panel now has 32 institutions and there’s always a lot of debate, but everyone agreed that if the CPS score is 5 or higher, nivolumab should be added. But the argument comes when PD-L1 is less than 5, and that includes 0. But there are some members that feel like we should use nivolumab plus chemotherapy even in this category, and then there are others who say that you shouldn’t.

What were the results of the CheckMate 649 arm investigating nivolumab in combination with chemotherapy?

[I will note that in CheckMate 649], the nivolumab plus ipilimumab [Yervoy] arm was a negative arm compared with chemotherapy alone.⁴ Nobody should be using nivolumab/ipilimumab in adenocarcinoma. But this was a large trial, with more than 1500 patients in just the nivolumab/chemotherapy and chemotherapy alone arms—mostly a White population and [with] good performance status.

It had a coprimary end point of OS [overall survival] and PFS [progression-free survival]. In the middle of the trial, [they] decided [to] change it to CPS of 5 or higher, and then a secondary end point was any CPS score.

The [12-month] OS rate for select populations of PD-L1 5% [or] higher was 57% of patients receiving nivolumab [vs 46% with only chemotherapy].⁴ It turned out that they had a high CPS score, the Kaplan-Meier curve separates very early on, and there is a tail.

Now we have 36-month follow-up data [Table⁵]. These are all patients with metastatic untreated disease and there is a significant tail at 36-month follow-up, so it looks like we’re changing the landscape entirely. When I communicate with patients and families, they always ask what the chance of cure is, how long they are going to live. For years it was a 3% cure rate among all comers in previous data. Now that is going to change. I think we will be able to say to them if the PD-L1 CPS is 5 or higher, there is maybe a 15% to 18% chance of cure, which is quite a change.

What were the data with respect to PFS and response rates?

With the PFS, after about 2 months there is delay in progression.⁴ You don’t see the tail [at this time] because it is relatively early. In the 36-month data, those curves started to separate quite a bit.⁵

Then we have data on all comers. In the ITT [intention-to-treat] population, there is also an advantage.⁴ In CPS 1 there appears to be an advantage, but I should clarify that the PD-L1 CPS 1% or higher population also has the CPS 5 and higher population, so it captures everything. The same thing in all patients is [that] we have CPS of 5 and higher patients. If you take it out— suppose you just focus on those with a CPS of 0 to 4—then you see response advantage but you don’t see PFS or survival advantage.6 Those data were published in the journal Nature.

The CR rate in the population that has a CPS of 5 or higher is 12% with nivolumab/chemotherapy, and in all patients, it is 10%; in chemotherapy [it] is around 7% for each group.⁴ So there is a little bit of a bump. The objective response rate with nivolumab was 15% higher with both populations compared with chemotherapy alone [in the CPS 5 and higher group]. In all patients, there is a 12% advantage. The duration of response is also longer with immunotherapy.

What safety concerns should clinicians be aware of with nivolumab in a regimen such as this?

As far as safety is concerned, patients will get some signals from immunotherapy in addition to chemotherapy. There was nothing alarming. In other words, the immunotherapy addition did not exacerbate toxicity when combined with chemotherapy.⁴ I think most patients seem to tolerate this very well. Hepatotoxicity [was more frequent] with nivolumab compared with chemotherapy alone. The oxaliplatin can also exacerbate hepatoxicity when nivolumab is used.

_REFERENCES

_{1. Keytruda. Prescribing information. Merck Sharp & Dohme Corp; 2023. Accessed February 8, 2023. https://bit.ly/3xdYO1X}

_{2. Opdivo. Prescribing information. Bristol-Myers Squibb Company; 2022. Accessed February 8, 2023. https://bit.ly/40Jx7M5}

_{3. Doki Y, Ajani JA, Kato K, et al; CheckMate 648 Trial Investigators. Nivolumab combination therapy in advanced esophageal squamous-cell carcinoma. N Engl J Med. 2022;386(5):449-462. doi:10.1056/NEJMoa2111380}

_{4. 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}

_{5. Janjigian YY, Shitara K, Moehler M, et al. Nivolumab (NIVO) plus chemotherapy (chemo) vs chemo as first-line (1L) treatment for advanced gastric cancer/gastroesophageal junction cancer/esophageal adenocarcinoma (GC/GEJC/EAC): 3-year follow-up from CheckMate 649. J Clin Oncol. 2023;41(suppl 4):abstr 291. doi:10.1200/JCO.2023.41.3_suppl.291}

_{6. Shitara K, Ajani JA, Moehler M, et al. Nivolumab plus chemotherapy or ipilimumab in gastro-oesophageal cancer. Nature. 2022;603(7903):942-948. doi:10.1038/s41586-022-04508-4}