The immuno-oncology drugs Opdivo and Keytruda have opened a new page in the first-line treatment of gastric, esophageal, and gastroesophageal junction cancers, traditionally aggressive and very poorly treated malignancies. However, we cannot yet speak of any breakthrough achievements in treatment; clinical outcomes have improved, but not by much.

In mid-April 2021, Opdivo (nivolumab), Bristol-Myers Squibb’s PD-1 blocker, received FDA approval for first-line treatment of patients with advanced or metastatic gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Regulatory approval is conditional, meaning that Opdivo has yet to definitively confirm its own unconditional efficacy.

In March 2021, Keytruda (pembrolizumab), Merck & Co.’s PD-1 blocker, received FDA approval for the first-line treatment of patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) [tumors with epicenter 1 to 5 centimeters above the GEJ] carcinoma that is not amenable to surgical resection or definitive chemoradiation, in combination with platinum- and fluoropyrimidine-based chemotherapy.

 

Opdivo’s Efficacy in First-line Treatment of Gastric and Esophageal Cancers

The CheckMate-649 (NCT02872116) phase 3 clinical trial (randomized, open-label, placebo-controlled, multicenter, international) tested the combination of nivolumab with chemotherapy (capecitabine + oxaliplatin [CapeOX] or fluorouracil + leucovorin + oxaliplatin [FOLFOX]) in the first-line treatment of adult patients (n=1581) with inoperable (advanced or metastatic) non-HER2-mutated gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma.

Among the main inclusion criteria: participants should not have previously received systemic therapy (chemotherapy, radiation) for a disseminated or metastatic indication and should not have received neoadjuvant or adjuvant treatment in the past 6 months.

The comparison was made with the group of patients who received chemotherapy alone.

After a median follow-up of 12.1 months, it was found that in the entire patient population (without considering PD-L1 tumor expression status), immuno-oncology treatment with Opdivo brought the median overall survival (OS) to 13.8 months (95% CI: 12.6–14.6) — versus 11.6 months (95% CI: 10.9–12.5) in the control group. Adding nivolumab to standard therapy reduced the risk of death by 20% (hazard ratio [HR] 0.80 [95% CI: 0.71–0.90]; p=0.0002).

Median progression-free survival (PFS) stopped at 7.7 months (95% CI: 7.1–8.5) — vs. 6.9 months (95% CI: 6.6–7.1). The risk of disease progression or death was reduced by 23% (HR 0.77 [95% CI: 0.68–0.87]).

The median duration of response (DoR) was 8.5 months (95% CI: 7.2–9.9), ranging from 1.0+ to 29.6+ months — vs. 6.9 months (95% CI: 5.8–7.2), being limited to a range of 1.2+ to 30.8 months.

nct02872116 results 01 - Opdivo and Keytruda: First-line Immunotherapy for Gastric Cancer and Esophageal Cancer

In patients with increased levels of tumor PD-L1 expression, slightly better clinical outcomes were recorded.

PD-L1 CPS≥1 (n=1296)

  • median OS: 14.0 months (95% CI: 12.6–15.0) — vs. 11.3 months (95% CI: 10.6–12.3), equivalent to a 23% reduction in likelihood of death (HR 0.77 [95% CI: 0.68–0.88]; p<0.0001)
  • median PFS: 7.5 months (95% CI: 7.0–8.4) — vs. 6.9 months (95% CI: 6.1–7.0), meaning a 26% reduction in risk of disease progression or death (HR 0.74 [95% CI: 0.65–0.85])
  • ORR: 49% (95% CI: 45–53), including CR 10% and PR 39% — vs. 38% (95% CI: 34–42), including CR 6% and PR 32%
  • median DoR: 8.5 months (95% CI: 7.7–10.3) with a range of 1.1+ to 29.6+ months — vs. 6.9 months (95% CI: 5.8–7.6) with a range of 1.2+ to 30.8+ months.

PD-L1 CPS≥5 (n=955)

  • median OS: 14.4 months (95% CI: 13.1–16.2) – vs. 11.1 months (95% CI: 10.0–12.1), equivalent to a 29% reduction in the likelihood of dying (HR 0.71 [95% CI: 0.61–0.83]; p<0.0001)
  • median PFS: 7.7 months (95% CI: 7.0–9.2) — vs. 6.0 months (95% CI: 5.6–6.9), meaning a 32% reduction in risk of disease progression or death (HR 0.68 [95% CI: 0.58–0.79]; p<0.0001)
  • ORR: 50% (95% CI: 46–55), including CR 12% and PR 38% — vs. 38% (95% CI: 34–43), including CR 7% and PR 31%
  • median DoR: 9.5 months (95% CI: 8.1–11.9) with a range of 1.1+ to 29.6+ months — vs. 6.9 months (95% CI: 5.6–7.9) with a range of 1.2+ to 30.8+ months.
nct02872116 results 02 - Opdivo and Keytruda: First-line Immunotherapy for Gastric Cancer and Esophageal Cancer

 

Expert Comments

The therapeutic efficacy of Opdivo looks acceptable but it all rests on the presence of PD-L1 tumor expression: its absence or weak expression will result in very modest improvements in clinical outcomes.

Thus, according to an exploratory analysis, in patients with PD-L1 CPS<1 (n=265) the median OS was 13.1 months (95% CI: 9.8–16.7) in the nivolumab group — versus 12.5 months (95% CI: 10.1–13.8) in the chemotherapy group. The risk of death was reduced by 15% (HR 0.85 [95% CI: 0.63–1.15].

In patients with PD-L1 CPS<5 (n=606), the median OS was 12.4 months (95% CI: 10.6–14.3) in the nivolumab group — vs. 12.3 months (95% CI: 11.0–13.2) in the chemotherapy group. The risk of death was reduced by 6% (HR 0.94 [95% CI: 0.78–1.14].

As we can see, the relatively small increase in the probability of not dying is accompanied by a wide range of confidence intervals. In other words, we can be certain that Opdivo will be useful in the treatment of gastric, esophageal, or gastroesophageal junction cancer only when PD-L1 tumor expression is significant (CPS≥5).

Doubts are also added by the results of the ATTRACTION-4 (NCT02746796) phase 2/3 clinical trial, similar in design to CheckMate-649, but including exclusively Asian (Japan, Taiwan, Korea) patients (n=724).

Follow-up for a median of 26.6 months revealed no benefit of adding Opdivo to chemotherapy (either oxaliplatin and tegafur + gimeracil + oteracil [SOX] or the CapeOX regimen) in terms of prolonging overall survival in the first-line treatment of advanced or recurrent HER2-negative gastric or gastroesophageal junction cancer.

The median OS was 17.45 months (95% CI: 15.67–20.83) — versus 17.15 months (95% CI: 15.18–19.65) in the control group that received only indicated chemotherapy (HR 0.90 [95% CI: 0.75–1.08]; p=0.257).

PFS, on the other hand, was prolonged: after a median of 11.6 months, it was equal to the median of 10.45 months (95% CI: 8.44–14.75) — vs. 8.34 months (95% CI: 6.97–9.40), thereby reflecting a 32% reduced risk of disease progression or death (HR 0.68 [98.5% CI: 0.51–0.90]; p=0.0007). PFS at one year was recorded for 45.4% of patients — vs. 30.6%.

Administration of nivolumab improved (p=0.0088) response to treatment: ORR 57% (95% CI: 52–62), including CR 19% and PR 38% — vs. ORR 48% (95% CI: 43–53), including CR 13% and PR 35%. Median DoR came out to 12.9 months (95% CI: 9.9–16.6) — vs. 8.7 months (95% CI: 7.2–11.4).

 

Opdivo’s Efforts in First-line Therapy for Esophageal Cancer

At this time, Opdivo is approved for the first-line treatment of esophageal adenocarcinoma. However, the esophageal cancer may present with a different histology, squamous cell carcinoma. Epidemiologic data are that esophageal adenocarcinoma is more common in Western Europe and North America, squamous cell carcinoma in Eastern Europe and Asia.

In early April 2021, Bristol-Myers Squibb announced the success of the CheckMate-648 (NCT03143153) phase 3 clinical trial (randomized, open-label, placebo-controlled, multicenter, international) in which Opdivo was evaluated in the first-line treatment of patients (n=939) with inoperable advanced, recurrent or metastatic esophageal squamous cell carcinoma.

Participants were randomized into three groups treated with standard chemotherapy (cisplatin + fluorouracil), its and Opdivo, its and a combination of Opdivo and Yervoy (ipilimumab), a CTLA-4 blocker.

As a result, the experimental treatment statistically significantly outperformed standard chemotherapy, prolonging overall survival among patients with PD-L1 tumor expression and in the entire patient population. The addition of Opdivo also resulted in a statistically significant prolongation of progression-free survival among PD-L1-positive subjects, whereas the addition of Opdivo and Yervoy did not.

 

Extras

Opdivo (nivolumab). Prescribing information. US. [PDF]

 

Keytruda’s Efficacy in First-line Treatment of Esophageal Cancer

The KEYNOTE-590 (NCT03189719) phase 3 clinical trial (randomized, double-blind, placebo-controlled, multicenter, international) checked the feasibility of adding pembrolizumab to standard chemotherapy (cisplatin with fluorouracil) in first-line treatment of adult patients (n=749) who were diagnosed with either locally advanced unresectable or metastatic esophageal carcinoma (including adenocarcinoma or squamous cell carcinoma) or advanced and/or metastatic adenocarcinoma of the gastroesophageal junction (Siewert type I).

The comparison was made with a group of patients who received only standard chemotherapy.

At a median follow-up of 10.8 months, the overall survival (OS) rate in the Keytruda group came out to the median of 12.4 months (95% CI: 10.5–14.0) — versus 9.8 months (95% CI: 8.8–10.8) in the control group. The risk of death was reduced by 27% (hazard ratio [HR] 0.73 [95% CI: 0.62–0.86]; p<0.0001).

nct03189719 results 01 - Opdivo and Keytruda: First-line Immunotherapy for Gastric Cancer and Esophageal Cancer

The median progression-free survival (PFS) was 6.3 months (95% CI: 6.2–6.9) — vs. 5.8 months (95% CI: 5.0–6.0), with a 35% reduction in the chance of disease progression or death (HR 0.65 [95% CI: 0.55–0.76]; p<0.0001).

The combination of Keytruda with chemotherapy provided an improved overall response rate (ORR) to treatment (p<0.0001): 45.0% (95% CI: 39.9–50.2) — vs. 29.3% (95% CI: 24.7–34.1). The median duration of response (DoR) was 8.3 months (1.2+ — 31.0+) — vs. 6.0 months (1.5+ — 25.0+).

nct03189719 results 02 - Opdivo and Keytruda: First-line Immunotherapy for Gastric Cancer and Esophageal Cancer

The subgroup of subjects with high PD-L1 tumor expression (CPS≥10) demonstrated enhanced therapeutic efficacy. Thus, the median OS among those receiving combined immuno-oncology treatment reached 13.5 months (95% CI: 11.1–15.6) — vs. 9.4 months (95% CI: 8.0–10.7) among those receiving chemotherapy alone: a 38% risk reduction (HR 0.62 [95% CI: 0.49–0.78]; p<0.0001). Median PFS was determined to be 7.5 months (95% CI: 6.2–8.2) — versus 5.5 months (95% CI: 4.3–6.0) in the control group: a 49% risk reduction (HR 0.51 [95% CI: 0.41–0.65]; p<0.0001).

In comparison, in the subgroup of participants with lowered PD-L1 tumor expression (CPS<10), the median OS was 10.5 months (95% CI: 9.7–13.5) — vs. 10.6 months (95% CI: 8.8–12.0): HR 0.86 (95% CI: 0.68–1.10).

In patients with esophageal carcinoma with squamous cell histology, administration of pembrolizumab brought the median OS to 12.6 months (95% CI: 10.2–14.3) — vs. 9.8 months (95% CI: 8.6–11.1) in the control group (HR 0.72 [95% CI: 0.60–0.88]; p=0.0006). The median PFS was 6.3 months (95% CI: 6.2–6.9) — vs. 5.8 months (95% CI: 5.0–6.1) in the chemotherapy group (HR 0.65 [95% CI: 0.54–0.78]; p<0.0001).

Patients with esophageal squamous cell carcinoma and high PD-L1 tumor expression (CPS≥10) benefited the most from the addition of Keytruda to the standard chemotherapy regimen: median OS was recorded at 13.9 months (95% CI: 11.1–17.7) — vs. 8.8 months (95% CI: 7.8–10.5), resulting in a 43% reduction in the risk of death (HR 0.57 [95% CI: 0.43–0.75]; p<0.0001).

 

Expert Comments

Expert consensus is that the addition of pembrolizumab to standard chemotherapy should become the new standard of first-line treatment for patients with unresectable locally advanced or metastatic esophageal cancer, including gastroesophageal junction cancer, regardless of histology and biomarkers.

Indeed, prolongation of overall survival was observed in all patient populations, including esophageal squamous cell carcinoma, esophageal adenocarcinoma, and gastroesophageal junction tumors. However, the inclusion of patients whose tumors were characterized by different histology (73% of subjects had squamous cell carcinoma and 27% had adenocarcinoma) in a single clinical trial makes the interpretation of treatment results very confusing and ambiguous.

Again, prolongation of overall survival was observed without any reference to the level of PD-L1 tumor expression, although the latter was not used as a stratification factor prior to randomization, despite being included in the comprehensive stepwise statistical design of the study. In other words, there are concerns about overestimating favorable outcomes for all patients because the group of respondents with high levels of PD-L1 tumor expression showed the best outcomes.

KEYNOTE-590 also left open the question of treatment efficacy in the presence of tumors with microsatellite instability (MSI) and/or high tumor mutation burden (TMB). These biomarkers must necessarily be taken into account when therapy is established.

 

Extras

Keytruda (pembrolizumab). Prescribing information. US. [PDF]

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Mark Gubar

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Mark has long been the most closely involved in the entire process of drug approval. His professional interests include phenotypic screening in vitro, sequencing technologies, predictors of clinical relevance, and patient compliance.

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