Nivolumab/ipilimumab and nivolumab/chemo indications improve the ESCC treatment landscape

Approval of 2 nivolumab-containing combinations for patients with advanced or metastatic esophageal squamous cell carcinoma has opened the doors for immunotherapy to enter the landscape in this population, providing clinicians with options to help patients achieve their individual treatment goals.

Approval of 2 combinations containing nivolumab (Opdivo) for patients with advanced or metastatic esophageal squamous cell carcinoma (ESCC) has opened the doors for immunotherapy to enter the landscape for this population, providing clinicians with options to help patients achieve 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 CCHS. The study data showed that both combinations caused superior survival benefits and increased response rates compared to 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 improvements in OS resulted in a 16% and 12% reduction in the risk of death in the nivolumab plus chemotherapy arm and the nivolumab plus ipilimumab arm, respectively.2

In an interview with Live®Jaffer A. Ajani, MD, 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 about this unique trial and its endorsement .

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

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

It’s the only thing we currently have. 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 Checkmate 648 efficacy data?

This is a very remarkable and unique study because it had 2 experimental arms. [There was also] one 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 the two experimental arms was made to chemotherapy and not to each other and both experimental arms were better than chemotherapy. It’s unique that we have a no-chemo option.

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

One thing to recognize is that the study was not designed to determine which patients should get which experimental arm. It’s something that we [must] understand at the clinic. There’s kind of a general notion that my colleagues might agree that for an asymptomatic patient with a very low tumor burden you might consider the non-chemo arm for those provided there’s no contraindication.

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

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

If you were to add chemotherapy to immunotherapy, you increase the risk to the patient. You give [the patient] AE of chemotherapy and immunotherapy [AEs]. Still, chemotherapy combined with nivolumab has its own benefits. If a patient has never been treated and is very symptomatic, they need fast relief. For [those patients] I’m going to use nivolumab plus chemotherapy.

But there are patients who don’t need immediate relief, they don’t have many 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?

Nivolumab and ipilimumab have been around for over 10 years. Most general oncologists are familiar with these drugs because they are approved for multiple types of tumors in multiple conditions. This [approval] is not going to place a lot of burden on the oncologist as to how to manage 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 his family. They usually cannot understand this because there is already a lot of stress. When they first [receive a] diagnosis, they want to be treated that day. And when they come to the clinic and you start explaining AEs, they disconnect. You [must] be very careful in the first cycle to closely monitor the patient and educate the caregiver.

You have to have that kind of approach where you use all available resources. 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 no chemotherapy arm, which was not necessarily more toxic than the chemotherapy arm, it was very similar to the chemotherapy arm in terms of [the types of] AEs and levels of [incidence].

Each patient may have a very different outcome in terms of efficacy and toxicity because they have never received these treatments. These are first-line treatments. Thus, a certain degree of extra care is required during the first cycle.

How does this approval potentially change the treatment paradigm in CCHS?

This will make it a bit simpler because the discrimination of PD-L1 expression was different than KEYNOTE-590. Here they watched the [tumor proportion score] TPS and the threshold was 1 or more because positive and less than 1 as negative. So it wasn’t 10. About 55% of patients had a GST of at least 1.

It will be easier to select patients [for these regimens], although the FDA has approved it independently 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 that will make things easier.

What future for nivolumab?

Since many oncologists are very familiar with nivolumab and pembrolizumab, these are the drugs we will rely on [for this patient population]. There are other PD-1 inhibitors and several trials, these molecules come from China, and how they will fit into the [treatment] the landscape is not clear.

These are all latecomers, pembrolizumab and nivolumab have been around for a long time. This is going to be interesting, but no other trial has really taken a non-chemotherapeutic approach. This is the first and only, and largest trial conducted for patients with untreated metastatic CCHS. This is about 950 patients, most other trials involve less than 600 patients.

it’s a nice challenge because before we didn’t have several options. If you have a patient in front of you, we only had one treatment we could give them. Standard of care was only one option. Now we have several options. We can give either pembrolizumab plus chemotherapy, or nivolumab plus chemotherapy, or nivolumab plus ipilimumab. It will be a very interesting learning curve in the future and I look forward to it.


  1. Opdivivo. Prescribing Information. Bristol-Myers Squibb; 2022. Accessed June 2, 2022.
  2. FDA approves Opdivo in combination with chemotherapy and Opdivo in combination with Yervoy for first-line indications of esophageal squamous cell carcinoma. FDA. May 27, 2022. Accessed June 2, 2022.

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