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ESMO GI 2022 Highlights

CME

Key Studies in Gastrointestinal Cancers: Independent Conference Coverage of the ESMO World Congress on Gastrointestinal Cancer 2022

Physicians: Maximum of 1.00 AMA PRA Category 1 Credit™

Released: October 04, 2022

Expiration: October 03, 2023

CME/CE Information

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1
Course Completed

CheckMate 648 Study of First-line Nivolumab Plus Chemotherapy or Ipilimumab vs Chemotherapy in Advanced ESCC

Rachna T. Shroff, MD, MS:
More than one half of upper GI cancers including ESCC are diagnosed in later stages. Combination cytotoxic CT has been the standard of care, but the OS with most regimens has been approximately 1 year.9 The addition of immunotherapy to CT is shifting the practice paradigm based on CheckMate648 and other relevant trials.9 CheckMate 648 was an open‑label, randomized phase III trial investigating nivolumab with CT vs nivolumab and ipilimumab vs CT alone in individuals with unresectable and advanced, recurrent, or metastatic ESCC. The dual primary endpoints were OS and PFS.10 Participants in the CheckMate 648 trial had unresectable and advanced, recurrent, or metastatic ESCC with no previous systemic therapy. They were randomized to 1 of 3 arms: fixed-dose nivolumab with CT, weight-based nivolumab plus ipilimumab, or CT alone. The endpoints evaluated in this analysis were DoR and time from randomization to progression after subsequent systemic therapy, initiation of second subsequent systemic therapy, or death (PFS2).11

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CheckMate 648: Baseline Characteristics

Rachna T. Shroff, MD, MS:
The treatment arms appeared to be well balanced. Most patients were Asian (70%) and male (79%-85%) with a median age of 63-64 years. Approximately one half (48%) of the patients had tumor cell PD-1 expression ≥1%.

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CheckMate 648: Updated Efficacy and Safety

Rachna T. Shroff, MD, MS:
After 13 months of follow-up, immunotherapy demonstrated statistically significant beneficial PFS2 with nivolumab and CT (HR: 0.64; 95% CI: 0.54-0.77) and nivolumab and ipilimumab (HR: 0.74; 95% CI: 0.62-0.88) compared with CT alone. The ORRs were 47% with nivolumab and CT, 28% with nivolumab and ipilimumab, and 27% with CT alone. Of importance, the nivolumab and CT arm had a DoR of 12 months or longer in 39% of patients. As we typically see with immunotherapy, those who respond have a prolonged period of response time.

Treatment-related adverse events (TRAEs) were mostly grade 1/2, and there were no surprising safety signals. Nonendocrine‑selected TRAEs resolved in most patients quite quickly with specific management algorithms.

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CheckMate 648: Implications

Rachna T. Shroff, MD, MS:
The authors concluded that in patients with previously untreated advanced ESCC, nivolumab and CT or nivolumab and ipilimumab both improved PFS2 compared with CT alone. A higher proportion of patients who received nivolumab with CT or nivolumab and ipilimumab had impressive median DoRs of 12 months or longer compared with CT alone. The addition of immunotherapy should be considered as a potential first‑line standard of care in ESCC, either with a dual immunotherapy-based regimen or CT plus immunotherapy. These findings further emphasize the utility of immunotherapy in newly diagnosed ESCC patients. CT is a vital backbone that can and should be considered. For patients who cannot tolerate CT, there is the nivolumab and ipilimumab option. Adding nivolumab to CT seems to result in a durable response that we typically do not see with CT alone.

Joleen Hubbard, MD:
This updated analysis really supports the use of nivolumab in combination with CT or nivolumab plus ipilimumab in the first‑line setting for advanced ESCC. I like combining CT with nivolumab in the first‑line setting for these patients because there does seem to be an improved response rate and it is well tolerated for our patients. This is my choice if there’s no contraindication to systemic CT.

RATIONALE-306 study of Tislelizumab Plus CT vs CT in Advanced/Metastatic ESCC: Background

Joleen Hubbard, MD:
The RATIONALE‑306 trial is another study in ESCC of a CT with immunotherapy combination approach vs the standard of CT alone. Tislelizumab is an anti–PD-1 antibody designed to minimize binding to the Fcγ receptor and, potentially, maximize its therapeutic inhibition. It has shown activity in various solid tumor types.12 Participants in RATIONALE‑306 were newly diagnosed with locally advanced or metastatic ESCC and had received no previous systemic therapy.13 Stratification factors included region and investigator-chosen CT. Patients were randomized to receive CT with either tislelizumab or placebo every 3 weeks until disease progression or toxicity. The primary outcome was OS.

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RATIONALE-306: Baseline Characteristics

Joleen Hubbard, MD:
Many participants (65%) were enrolled in Asia, which seems to be characteristic of ESCC studies. Over one half of patients (55%) received platinum and paclitaxel CT, and the rest received platinum with 5-FU–based CT. In total, 50% of patients in both arms had a tumor PD‑L1 status of <10%.

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RATIONALE-306: Overall Survival

Joleen Hubbard, MD:

The addition of tislelizumab improved median OS and, quite quickly, you see a separation of the curves. The median OS with CT and placebo was 10.6 months vs 17.2 months with the addition of tislelizumab (HR: 0.66; 95% CI: 0.54-0.80). The OS benefit is observed already at 6 months and holds true all the way through 18 months with an 18‑month OS rate of 48.6% in the immunotherapy arm.

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RATIONALE-306: OS by Subgroup

Joleen Hubbard, MD:

The authors evaluated OS by subgroup, and the forest plot demonstrates that most patients derived benefit from tislelizumab. Of importance, a tumor PD‑L1 score ≥10% was a predictor for tislelizumab showing improvement, which is not surprising. Even patients with a tumor PD‑L1 score <10% seemed to benefit from the addition of immunotherapy.

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RATIONALE-306: Progression-Free Survival

Joleen Hubbard, MD:

PFS similarly improved from a median of 5.6 months up to 7.3 months with the addition of tislelizumab (HR: 0.62; 95% CI: 0.52-0.75). There is a quick separation of the curves with a 12‑month PFS rate of 30% in the CT with tislelizumab arm vs 15.7% in the placebo and CT arm.

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RATIONALE-306: Response

Joleen Hubbard, MD:

The ORR was also higher (63.6% vs 42.4%) and the DoR was longer (median 7.1 months vs 5.7 months) with the addition of immunotherapy to CT compared with placebo. A total of 19.3% of patients in the immunotherapy arm still had an ongoing response at the time of data cutoff.

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RATIONALE-306: Safety

Joleen Hubbard, MD:
TEAEs were presented and were as would be expected with immunotherapy. A total of 66.7% of participants in the immunotherapy and CT arm had a grade ≥3 treatment-related TEAE, but this was not dramatically higher than in the CT with placebo arm (64.5%).

Immune‑mediated adverse events of grade ≥3 were experienced in 8.6% of patients in the immunotherapy and CT arm, which was not surprising. There were no emerging safety signals that were truly surprising or unexpected. The most common TEAEs included anemia, decreased neutrophil count, decreased white blood cell count, and nausea.

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RATIONALE-306: Implications

Rachna T. Shroff, MD, MS:
In patients with previously untreated, unresectable ESCC, the addition of tislelizumab with CT improved median OS to 17.2 months compared with 10.6 months for placebo and CT. This benefit was consistent across subgroups, including PD‑L1 status. The safety and tolerability were manageable with no surprising safety signals. These findings support the suggestion that tislelizumab with CT could be a frontline approach in patients with advanced or metastatic ESCC. This is continued and consistent support of the addition of immunotherapy in newly diagnosed patients with ESCC. These 2 studies, taken together, demonstrate the impact of checkpoint inhibition with a CT backbone. This type of regimen really should be considered in all patients who are able to receive CT.

It is reassuring that findings are similar with low or high PD‑L1 scores. As more and more patients are instituted on these regimens, research can help determine factors to identify patients that could truly benefit more so or more durably from immunotherapy.

Joleen Hubbard, MD:
I am optimistic that tislelizumab may become another option for patients with metastatic ESCC. It looks potentially comparable with other checkpoint inhibitors. The question is how this PD‑1 inhibitor will fit in with the other checkpoint inhibitors that have been approved for use in this patient population.

Which of the following findings was reported from the RATIONALE-306 phase III trial of tislelizumab or placebo with investigator-chosen chemotherapy (CT) for patients with unresectable locally advanced or metastatic esophageal squamous cell carcinoma (ESCC)?
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