Nivolumab Plus Chemo or Ipilimumab Represent Potential First-Line Standards in Advanced ESCC


Nivolumab plus chemotherapy or ipilimumab showcased superior overall survival over chemotherapy alone in previously untreated patients with advanced esophageal squamous cell carcinoma.

Ian Chau, MD

Ian Chau, MD

Nivolumab (Opdivo) plus chemotherapy or ipilimumab (Yervoy) showcased superior overall survival (OS) over chemotherapy alone in previously untreated patients with advanced esophageal squamous cell carcinoma (ESCC), according to Ian Chau, MD, who added that certain factors will need to be considered to appropriately choose among these regimens should regulatory authorities approve them for use in clinical practice.

Data from the phase 3 CheckMate-648 trial (NCT03143153) showed that the median OS with nivolumab plus chemotherapy in all randomized patients (n = 321) was 13.2 months (95% CI, 11.1-15.7) vs 10.7 months (95% CI, 9.4-11.9) with chemotherapy alone (n = 324; HR, 0.74; 99.1% CI, 0.58-0.96; P = .0021). The median OS was also superior with nivolumab/ipilimumab in the all-randomized patients over chemotherapy alone, at 12.8 months (95% CI, 11.3-15.5).

In a subset of patients with a PD-L1 of 1% or higher, the median OS with nivolumab plus chemotherapy (n = 158) and chemotherapy alone (n = 157) was 15.4 months (95% CI, 11.9-19.5) vs 9.1 months (95% CI, 7.7-10.0), respectively (HR, 0.54; 99.1% CI, 37.0-0.80; P <.0001). Again, the OS was also superior with the dual immunotherapy regimen vs chemotherapy alone, at 13.7 months (95% CI, 11.2-17.0)

“Now, the question is, do I give [nivolumab] with chemotherapy, or do I give it with a second immunotherapy drug? That is probably the most important [thing to consider],” Chau said. “It is also important to highlight that many of the patients who develop this cancer have other medical conditions. They might have kidney impairment or heart disease, and some cannot receive chemotherapy. In fact, some patients would previously be denied any treatment because they could not receive chemotherapy. Now we have a chemotherapy-free option with nivolumab/ipilimumab; this would be a good treatment option for these patients.”

In an interview with OncLive®, Chau, a consultant medical oncologist at the Royal Mardsen Hospital in the United Kingdom, further discussed the CheckMate-648 trial examining nivolumab-based combinations in patients with ESCC, the differences between the study regimens, and remaining questions to address with future efforts.

OncLive®: What was the rationale for the phase 3 CheckMate-648 trial, and what was the design of this research?

Chau: Cancer of the esophagus carries a poor prognosis. Each year, approximately half a million patients will die from this disease. In this study, we [examined] a subtype called squamous cell cancer, [which] is the most predominant type of this disease. For decades, there has been no improvement in treatment outcomes for our patients. For patients [in whom] the cancer has already spread, the average [prognosis] is only approximately 10 months or less. As such, we have a lot that we need to improve on.

We performed this study, called CheckMate-648, [where we enrolled patients with unresectable advanced, recurrent, or metastatic cancer]. Patients were [randomized to 1 of] 3 different groups: a standard [arm] with chemotherapy alone, which has been the standard for decades; nivolumab [plus] standard chemotherapy; and a chemotherapy-free option where we utilized the 2 immunotherapy drugs nivolumab and ipilimumab. This global study is the largest that has ever been conducted in this disease setting. A total of 970 patients were enrolled.

What were some of the key takeaways from this trial?

We found that patients who received the immunotherapy, the group who received nivolumab plus chemotherapy and the group [who received dual immunotherapy], showed a significantly [improved] survival compared with those who received chemotherapy alone. [As such, we now] have not just 1, but 2 new treatment options for our patients. [In addition to] improving their survival, we also found that there were longer-term survivors in the immunotherapy-containing arms. We also saw that in patients who [experienced] tumor shrinkage with immunotherapy, the shrinkage lasted for much longer than the that achieved with chemotherapy alone.

What were the differences in efficacy between nivolumab plus chemotherapy and nivolumab plus ipilimumab?

Both regimens resulted in improved survival compared with chemotherapy alone. [However,] nivolumab and ipilimumab, take a bit longer to start to work. [As such], if patients have a very high symptom burden, it is probably better to start with the chemotherapy plus nivolumab rather than nivolumab/ipilimumab. If you look at longer-term survival [benefit, it was about] the same in these 2 arms. At the beginning, [however,] perhaps the chemotherapy plus nivolumab did do better.

As these treatments become more available, and we are able to treat more patients, we will learn from that experience [and be able to] further refine what the best [approach will be] for [each] patient.

What was learned in terms of safety?

Immunotherapy is often used in different types of cancer. In this study, the adverse effects [AEs] were what we expected. In the groups of patients who received chemotherapy, [the more prominent AEs] came from the chemotherapy drugs, whereas the group that was chemotherapy free [experienced] some immune-related AEs. Again, these kinds of drug combinations have been used quite widely in other cancers, so there are very well-established treatment algorithms to deal with the AEs [that come with them].

What are the clinical implications of these results? What kind of factors would you consider when choosing between the approaches?

Now that have these study results, which are very encouraging, when these drugs have the relevant approval from the regulatory authorities, and they are available to our patients, then I would consider giving nivolumab to the [appropriate] patient.

For patients who have a lot of symptoms [when they are diagnosed]—if their swallowing is poor, they are losing weight, etc.—it is better, if they are otherwise fit enough, for them to receive chemotherapy with the immunotherapy because the tumor shrinkage is greater in that situation; it is perhaps more rapid, as well. That would be a suitable [approach] for that group of patients. However, with the survival benefit we see with these 2 new treatment options, we now have a breakthrough advancement for our patients with esophageal cancer.

What are the next steps for this research? Are any subsequent analyses planned?

[A question] that was not addressed by this study is determining whether in those patients who are very symptomatic, we can start with chemotherapy plus nivolumab, and after a few weeks or a couple months of treatment, we can just continue with nivolumab/ipilimumab. Perhaps that could be a strategy, because if we [control the disease], we then have time for the immunotherapy to work. [Patients] can then be spared from the AEs [experienced with] the chemotherapy.

Also, in future meetings, we will be presenting some quality-of-life [QoL] data that were generated in this study. From there, we will see whether patients [who receive] a chemotherapy-free option [will have a very good] QoL. That is certainly something that we would [investigate further].

Lastly, the chemotherapy used in this trial is the standard treatment [that is used] across the world: cisplatin and 5-fluorouracil. Between those 2 chemotherapy drugs, cisplatin is the harsher chemotherapy. As such, in this study, if [we choose] to stop 1 of the drugs, we will always try to stop cisplatin. Maybe in the future, we can investigate how much cisplatin is necessary [for these patients].


  1. Chau I, Doki Y, Ajani JA, et al. Nivolumab (NIVO) plus ipilimumab (IPI) or NIVO plus chemotherapy (chemo) versus chemo as first-line (1L) treatment for advanced esophageal squamous cell carcinoma (ESCC): first results of the CheckMate 648 study. J Clin Oncol. 2021;39(suppl 15):LBA4001. doi:10.1200/JCO.2021.39.15_suppl.LBA4001
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