Nivolumab/Ipilimumab and Nivolumab/Chemo Indications Enhance ESCC Treatment Landscape

Jaffer A. Ajani, MD

The approval of 2 nivolumab (Opdivo)-containing combinations for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) have opened the doors for immunotherapy to enter the landscape for this population allowing clinicians options to help patients to meet their individual treatment goals.¹

Results from the phase 3 CheckMate 648 trial (NCT03143153) supported the approval of nivolumab in combination with fluoropyrimidine- and platinum-based chemotherapy and nivolumab plus ipilimumab (Yervoy) for the first-line treatment of patients with advanced or metastatic ESCC. Data from the study showed that that both combinations elicited superior survival benefits and increased response rates compared with chemotherapy alone.^1,2

The overall response rate was 47.4% (95% CI, 41.8%-53.0%), 27.7% (95% CI, 22.9%-32.9%), and 26.9% (95% CI, 22.1%-32.0%), for nivolumab plus chemotherapy, nivolumab plus ipilimumab, and chemotherapy alone., respectively. Additionally, the median overall survival (OS) was 13.2 months (95% CI, 11.1-15.7), 12.8 months (95% CI, 11.3-15.5), and 10.7 months (95% CI, 9.4-11.9), respectively. These OS improvements resulted in a reduced risk of death of 16% and 12% in the nivolumab plus chemotherapy arm and nivolumab plus ipilimumab arm, respectively.²

In an interview with OncLive^®, Jaffer A. Ajani, MD, a professor in the department of gastrointestinal (GI) medical oncology in the Division of Cancer Medicine at The University of Texas MD Anderson Cancer Center in Houston, spoke on this unique trial and approval.

What does the current treatment landscape look like for patients with ESCC?

The only agent approved right now is pembrolizumab [Keytruda]. Although, the FDA has approved pembrolizumab plus chemotherapy for all untreated patients with ESCC in the advanced setting, it is more effective if the PD-L1 combined positive score [CPS] is 10 or higher. This is based on the KEYNOTE-590 study [NCT03189719].

That is the only thing available to us right now. The National Comprehensive Cancer Network guidelines also recommend pembrolizumab plus chemotherapy if the CPS score is 10 or higher.

What stood out to you about the efficacy data in Checkmate 648?

This is a very remarkable and unique study because it had 2 experimental arms. [There was also] a chemotherapy arm as control, chemotherapy plus nivolumab as one of the experimental arms, and the other [arm] was without any chemotherapy [but with nivolumab plus ipilimumab].

The comparison of both experimental arms was made to chemotherapy not to each other and both experimental arms were better than chemotherapy. This is unique that we have a nonchemotherapy option.

The chemotherapy option with nivolumab was better than chemotherapy. [However,] it could be reserved for certain patients who are very symptomatic with a lot of tumor who cannot wait for a response and need an immediate response. The immediate response comes from chemotherapy rather than with immunotherapy.

One thing to recognize is the study was not designed to figure out which patients should get which experimental arm. That is something we [must] figure out in the clinic. There is kind of a general notion that my colleagues might agree with that for an asymptomatic patient with very low tumor burden, you could consider the nonchemotherapy arm for those provided, there is no contraindication.

This approval encompasses 2 different combinations with nivolumab, how are you approaching treatment selection in clinical practice?

In my clinical practice, what I am hoping to do is, in some patients, to use a combination of immunotherapy drugs without chemotherapy because chemotherapy will consistently reduce quality of life and cause some irreversible adverse effects [AEs]. Immunotherapy can also do some of those things [but it is] a different group of AEs.

If you were to add chemotherapy to immunotherapy you are causing increased risk to the patient. You are giving [the patient] chemotherapy AEs and immunotherapy [AEs]. Yet, chemotherapy plus nivolumab has its own benefit. If a patient has never been treated and they are very symptomatic, they need quick relief. For [those patients] I am going to use nivolumab plus chemotherapy.

But there are some patients that do not need immediate relief, they do not have a lot of symptoms. For [these patients], if you can avoid chemotherapy, you can maintain a fairly good quality of life for them.

Are there any unique factors to consider regarding AEs among this patient population?

Both nivolumab and ipilimumab have been around for more than 10 years. Most general oncologists are familiar with these drugs because they are approved for multiple tumor types in multiple conditions. This [approval] is not going to impose a lot of burden on the oncologist as to how to manage the AEs.

The question is: how do you manage [the AEs] in this group of patients? The first cycle is the most important, where you really try to explain [the treatment to] the patient and family. They usually cannot grasp that because there is lots of stress already. When they first [receive a] diagnosis, they want to be treated that day. And when they come to the clinic and you start to explain the AEs, they tune out. You [must] be very careful in the first cycle to monitor the patient closely and educate the caregiver.

You need to have this kind of approach where you utilize all the resources that are available. After the first cycle, [you can learn some of] the spectrum of AEs a given patient is going to experience and then you adjust everything accordingly. The same thing [applies] for the nonchemotherapy arm, which was not necessarily more toxic than the chemotherapy arm, it was very similar to chemotherapy arm in terms of [the types of] AEs and the levels of [incidence].

Every patient can have a very different outcome in terms of efficacy and toxicity because they have never received these treatments. These are first-line treatments. So, some degree of extra care is needed in the first cycle.

How does this approval potentially shift the treatment paradigm in ESCC?

It will make it a little simpler because the discrimination of PD-L1 expression was different than in KEYNOTE-590. Here, they looked at the [tumor proportion score] TPS and the cut off was 1 or higher as positive and less than 1 as negative. So, it was not 10. Approximately 55% of patients had a TPS of at least 1.

It will be easier to select patients [for these regimens], although the FDA has approved it irrespective of TPS. The FDA label says you use nivolumab plus chemotherapy on every patient in this setting or use nivolumab plus ipilimumab in this setting. We [must] make some discrimination based on the details of this study. I believe it will make it easier.

What does the future hold for nivolumab?

Since a lot of oncologists are very familiar with nivolumab and pembrolizumab, those are the drugs that we will be leaning on [for this patient population]. There are other PD-1 inhibitors and several trials, these molecules are coming from China, and how they are going to fit into the [treatment] landscape is unclear.

Those are all late-comers, pembrolizumab and nivolumab have been here for a long time. It is going to be interesting, but no other trial has really done a nonchemotherapy approach. This is the first and only, and this is the largest trial conducted for patient with untreated metastatic ESCC. It is almost 950 patients, most other trials are under 600 patients.

it is a nice challenge because previously we did not have multiple options. If you have a patient in front of you, we had only 1 treatment that we could give them. The standard of care was only 1 option. Now we have several options. We can give either pembrolizumab plus chemotherapy, we can give nivolumab plus chemotherapy, or we can give nivolumab plus ipilimumab. It is going to be a very interesting learning curve going forward and I look forward to that.

References

1. Opdivo. Prescribing information. Bristol-Myers Squibb; 2022. Accessed June 2, 2022. bit.ly/3NjJhnN
2. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line esophageal squamous cell carcinoma indications. FDA. May 27, 2022. Accessed June 2, 2022. bit.ly/3zixPVg