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Key Studies in Gastrointestinal Cancers: Independent Conference Coverage of the 2021 ASCO Annual Meeting

Manish A. Shah, MD
Released: July 27, 2021

Key Studies from ASCO 2021


Manish A. Shah, MD:
At the 2021 ASCO annual meeting, several practice‑changing studies were presented for GI cancers. I would like to begin my discussion by highlighting 2 important presentations of data surrounding treatment for patients with metastatic colorectal cancer (mCRC).

KEYNOTE-177 Final Analysis: First-line Pembrolizumab vs Chemotherapy for MSI-H/dMMR mCRC

Manish A. Shah, MD:
PD‑L1 blockade has been associated with significant benefit for patients with numerous solid tumor types, with particular efficacy in patients with colorectal cancers who have mismatch repair deficiency (dMMR)/MSI-H.[Le 2015; Sahin 2019] Pembrolizumab, an anti–PD-1 antibody, has a tumor-agnostic indication for treating patients with unresectable/metastatic dMMR/MSI-H solid tumors that progressed following prior treatment with no satisfactory alternative treatment options.[Pembrolizumab PI]

The KEYNOTE-177 trial specifically assessed first-line pembrolizumab for patients with MSI-H or dMMR mCRC.[André 2021] The final analysis of this phase III study, which randomized 307 patients with previously untreated MSI-H/dMMR mCRC to pembrolizumab 200 mg IV every 3 weeks or investigator’s choice of standard chemotherapy (mFOLFOX6 or FOLFIRI, with or without bevacizumab or cetuximab) IV every 2 weeks, was presented at ASCO 2021. The study had coprimary endpoints of PFS and OS, and crossover was permitted from the chemotherapy arm to the pembrolizumab arm upon disease progression.

The report presented at ASCO 2021 was our first look at the OS data from this study. Interim results from KEYNOTE-177 were previously reported and showed that the median PFS for patients treated with pembrolizumab was twice as long as for patients treated with chemotherapy (16.5 vs 8.2 months; HR: 0.60; 95% CI: 0.45-0.80; P = .0002).[André 2020] In other words, there was a 40% reduction in risk of progression with pembrolizumab compared with chemotherapy. Additionally, there was a lower incidence of significant adverse events (AEs) and an improvement in quality of life. These results changed practice and resulted in pembrolizumab’s approval as a first‑line treatment for patients with unresectable or metastatic MSI‑high or dMMR CRC.[Casak 2021]

KEYNOTE-177 Final Analysis: Baseline Characteristics

Manish A. Shah, MD:
Baseline characteristics in KEYNOTE-177 were balanced. This was a global study, but most patients were enrolled in North America and western Europe. Approximately two thirds of patients in the study had right‑sided colon cancer. Regarding mutation status, approximately one quarter of patients were wild type for BRAF, KRAS, and NRAS, one quarter had a BRAFV600E mutation, and one quarter had a KRAS or NRAS mutation. In the chemotherapy arm, 51.9% of patients received FOLFOX either alone or with bevacizumab or cetuximab, 38.9% received FOLFIRI either alone or with bevacizumab or cetuximab, and 7.1% of patients received no treatment. 

KEYNOTE-177 Final Analysis: PFS and PFS2

Manish A. Shah, MD:
In this final analysis of KEYNOTE-177, there was a sustained significant improvement in PFS with pembrolizumab compared with chemotherapy, with a median PFS of 16.5 vs 8.2 months (HR: 0.59; 95% CI: 0.45-0.79) and median PFS2 of 54.0 vs 24.9 months (HR: 0.61; 95% CI: 0.44-0.83).

KEYNOTE-177 Final Analysis: Response and Subsequent Therapy

Manish A. Shah, MD:
It is important to note that this study was performed after pembrolizumab was approved in later‑line settings for dMMR/MSI-H tumors, and 60% of patients in the chemotherapy arm went on to receive an anti─PD‑1 or anti─PD‑L1 therapy as their second‑line treatment. This certainly merits some consideration in the interpretation of the data from this study, as we will discuss below with the OS findings.

Interestingly, among patients who went on to receive chemotherapy after pembrolizumab, the response rate was 23% vs 13% in those who received second‑line chemotherapy after first‑line chemotherapy.

KEYNOTE-177 Final Analysis: OS

Manish A. Shah, MD:
Importantly, in the final analysis of KEYNOTE-177, though a numeric OS improvement was observed with pembrolizumab (HR: 0.74; 95% CI: 0.53-1.03), this was not found to be statistically significant. The 3‑year survival rate with pembrolizumab compared with chemotherapy was 61% vs 50%.

The main explanation given by the authors as to why the OS data were not significant was the high crossover rate of patients receiving chemotherapy into the pembrolizumab arm. In spite of these nonsignificant OS findings, data were found to be consistent and compelling to support the use of pembrolizumab as first‑line therapy for this patient population.

KEYNOTE-177 Final Analysis: OS in Key Subgroups

Manish A. Shah, MD:
Investigators also evaluated survival across patient subgroups and observed an OS benefit across most patient subgroups favoring pembrolizumab over chemotherapy. 

Notably, patients with KRAS- or NRAS‑mutant tumors did not appear to experience the same magnitude of benefit with pembrolizumab seen with other subgroups. I think these data are preliminary and additional studies will be needed to better understand these findings.

KEYNOTE-177 Final Analysis: Safety

Manish A. Shah, MD:
As in previous reports, and as expected, treatment with pembrolizumab was well tolerated.[André 2020] Rates of any treatment-related adverse events (TRAEs) were lower with pembrolizumab when compared with chemotherapy (79.7% vs 98.6%). Similarly, rates of grade ≥3 AEs were lower with pembrolizumab at 21.6% compared with 66.4% in those receiving chemotherapy.

KEYNOTE-177 Final Analysis: Clinical Implications

Manish A. Shah, MD:
KEYNOTE-177 is a practice‑changing study, and the final analyses presented at ASCO 2021 reaffirmed our current management in this setting. The data presented at ASCO 2021 showed that pembrolizumab can yield improved PFS (and likely OS if not for the crossover) with much lower toxicity compared with previous standard-of-care chemotherapy.

DESTINY-CRC01: T-DXd for Patients With HER2-Expressing Metastatic CRC

Manish A. Shah, MD:
The next study that I would like to highlight was a phase II study of trastuzumab deruxtecan (also known as T-DXd or DS-8201) for patients with mCRC. Trastuzumab deruxtecan is a novel antibody–drug conjugate targeting HER2 and has received FDA approval for treating breast cancer and gastric cancers.[Trastuzumab Deruxtecan PI] Approximately 3% to 14% of colon cancers harbor amplifications in HER2.[NCCN 2021] These tumors are often located in the distal colon and can potentially be treated with HER2-targeting agents.

DESTINY-CRC01 Final Results: T-DXd for Patients With HER-2 Expressing Metastatic CRC

Manish A. Shah, MD:
At ASCO 2021, the final results from the multicenter, multicohort, phase II DESTINY‑CRC01 trial were presented. This study evaluated trastuzumab deruxtecan in 86 patients with HER2‑expressing mCRC who had progressed on 2 or more previous regimens, excluding patients with prior history of, currently with, or suspected of having interstitial lung disease.[Yoshino 2021] All patients received trastuzumab deruxtecan 6.4 mg/kg intravenously every 3 weeks, as part of 3 different cohorts: cohort A included 53 patients with HER2-positive colon cancer (IHC 3+ or IHC 2+ and FISH-positive); cohort B included 15 patients who were HER2 IHC 2+ and FISH-negative (therefore, not HER2 overexpressing); and cohort C consisted of 18 patients who were HER2 IHC 1+. The primary endpoint of this study was objective response rate per Response Evaluation Criteria in Solid Tumors (RECIST) in cohort A. Secondary endpoints included ORR per RECIST in cohorts B and C, PFS, OS, duration of response (DoR), disease control rate (DCR), and safety and tolerability.

DESTINY-CRC01 Final Results: Baseline Characteristics

Manish A. Shah, MD:
DESTINY-CRC01 was a global study and patients were enrolled across Europe (53.5%), Asia (30.2%), and North America (16.3%). Overall, 98.8% of patients had BRAF V600E wild-type cancer and 97.7% had RAS wild-type cancer; 80.2% of tumors were MSI-stable and 19.8% had unknown MSI status.

Regarding HER2 status, in cohort A, 75% were IHC 3+, 25% were IHC 2+, and 98.1% were FISH-positive; in cohort B, 100% were IHC 2+ and all were FISH-negative; and in cohort C, 100% of patients had IHC 1+ and 22.2% were FISH-positive.

DESTINY-CRC01 Final Results: Response

Manish A. Shah, MD:
The initial interest in trastuzumab deruxtecan came from its unique mechanism of action and drug-to-antibody ratio of 8. This suggested that this agent could potentially exert anti-neoplastic activity even in tumors with low HER2 expression, which was the rationale behind exploring trastuzumab deruxtecan activity in cohorts B and C.

In patients with HER2 overexpression in cohort A, the response rate was quite remarkable, with 24 of 53 (45%) patients achieving a partial response (PR) per independent central review. The DCR in cohort A was 83.0%, and a median DoR of 7.0 months, which was very encouraging.

However, in low–HER2-expressing cohorts (cohorts B and C), some activity was observed, but this was not as high as in cohort A. In cohort B, 9 out of 15 patients (60%) achieved stable disease, none had a PR, and the DCR was 60%. In cohort C, 4 out of 18 (22.2%) patients achieved stable disease, none had a PR, and 10 (55.6%) patients had disease progression. Five patients had a response lasting more than a year to date. 

Together, response data for trastuzumab deruxtecan in the final analysis of DESTINY-CRC01 suggest that there is clear activity in HER2-overexpressing mCRC.

DESTINY-CRC01 Final Results: PFS and OS

Manish A. Shah, MD:
The median PFSs for patients in cohort A, cohort B, and cohort C were 6.9 months, 2.1 months, and 1.4 months, respectively; median OSs for patients in cohort A, cohort B, and cohort C were 15.5 months, 7.3 months, and 7.7 months, respectively. Again, patients with high–HER2-positive mCRC had a better PFS and OS than those with low or intermediate expression. I find the median OS of 15.5 months in cohort A most compelling, yet it is important to note that this was not a randomized study.

DESTINY-CRC01 Final Results: Safety

Manish A. Shah, MD:
In cohort A, which was the largest cohort (n = 53), 66.0% of patients experienced grade 3 or higher treatment-emergent adverse events (TEAEs). Notable TEAEs of any grade in cohort A included nausea (69.8%), anemia (39.6%), fatigue (39.6%), platelet count decrease (32.1%), and neutrophil count decrease (37.7%). TRAEs of grade 3 or higher in the overall population (N = 86) were seen in 65.1% of patients across all cohorts and included anemia (14.0%), platelet count decrease (9.3%), and neutrophil count decrease (22.1%).

DESTINY-CRC01 Final Results: Interstitial Lung Disease (ILD)

Manish A. Shah, MD:
A particular safety concern with trastuzumab deruxtecan is the potential for drug‑related interstitial lung disease (ILD). And, as mentioned earlier, patients with prior history or, currently with, or suspected of ILD were excluded for enrollment in the study. There were 8 ILD events (9.3%) of any grade reported. The median time to onset of ILD was 61 days (range, 9 to 165 days). All 8 cases of ILD were managed with corticosteroids, with 4 patients with grade 2 ILD recovering to grade 1; 1 patient with grade 3 ILD did not recover and later died due to disease progression. There were 3 patient deaths attributed to grade 5 drug-related ILD, which occurred within 120 days and between 1 to 3 weeks from the diagnosis of ILD.  Because of these findings, ILD guidelines were updated with recommendations for monitoring for symptoms, interrupting or holding the treatment, conducting imaging (as clinically indicated), and starting steroids as soon as possible for suspected ILD.

DESTINY-CRC01 Final Results: Clinical Implications

Manish A. Shah, MD:
Overall, I think this is an important study because it reinforces and validates the notion that HER2 is an important target in patients with colon cancer. Even though only 3% to 14% of colon cancers harbor amplifications in HER2, colon cancer is among the most prevalent GI diseases that GI oncologists see. Thus, testing for HER2 is important. Trastuzumab deruxtecan may potentially be approved in the near future, but in the meantime, trastuzumab, pertuzumab, and other HER2-targeted agents may be considered for patients with HER2-positive mCRC.[NCCN 2021]

Gastroesophageal Cancer Studies

Manish A. Shah, MD:
Now I would like to transition to key esophageal cancer studies presented at ASCO 2021. Esophageal cancer is a relatively prevalent disease in the United States, with approximately 19,000 new cases diagnosed every year[ACS 2021]; approximately 450,000 patients are diagnosed with the disease globally.[Zhang 2013] Most patients with esophageal cancer are diagnosed with locally advanced disease, present with dysphagia, and, in those who are candidates, receive preoperative chemotherapy and radiation followed by surgery.

CheckMate 577 Update: Adjuvant Nivolumab in Resected Esophageal or Gastroesophageal Junction Cancer After Neoadjuvant Chemotherapy

Manish A. Shah, MD:
The first study in esophageal cancer that I would like  to highlight from ASCO 2021 is the randomized, phase III CheckMate 577 study, in which 794 patients with resected stage II/III esophageal or gastroesophageal junction (GEJ) cancer and residual pathologic disease after neoadjuvant chemoradiotherapy were randomized 2:1 to receive either adjuvant nivolumab 240 mg every 2 weeks for 16 weeks, then 480 mg every 4 weeks, or placebo.[Kelly 2021] Patients received treatment for 1 year, until disease progression, unacceptable toxicity, or withdrawal of consent. Notably, patients who had a complete response after preoperative therapy were not enrolled or evaluated.

The primary endpoint was disease‑free survival (DFS).  Secondary endpoints included OS and OS rate at year 1, 2, and 3. Exploratory endpoints included safety, distant metastasis-free survival, PFS2, and quality of life.

CheckMate 577 Update: Baseline Characteristics

Manish A. Shah, MD:
Baseline characteristics were balanced between arms. In both arms, 71% of patients had adenocarcinoma and 29% of patients had squamous cell cancer histology. Approximately 60% of patients had esophageal cancer and 40% had GEJ cancers, and 70% to 75% had tumor PD‑L1 <1% expression.

CheckMate 577 Update: Efficacy and Quality of Life

Manish A. Shah, MD:
Investigators reported a highly significant median DFS improvement with adjuvant nivolumab vs placebo (22.4 vs 11.0 months; HR: 0.69; P = .0003). For the first time, investigators also reported an improved median distant metastasis‑free survival with adjuvant nivolumab (28.3 vs 17.6 months; HR: 0.74). Investigators also reported a DFS benefit with adjuvant nivolumab across multiple patient subgroups.

CheckMate 577 Update: Safety

Manish A. Shah, MD:
Regarding safety, the percentage of grade 3/4 serious AEs was the same in the nivolumab and placebo arms (20% vs 20%), suggesting that nivolumab did not appear to add significant toxicity for this patient population. Immune‑related AEs were infrequent, with most grade 3/4 events reported in fewer than 1% of patients.

CheckMate 577 Update: Clinical Implications

Manish A. Shah, MD:
This was another practice‑changing study. In May 2021, the FDA approved nivolumab for patients with completely resected esophageal or GEJ cancer with residual pathologic disease after neoadjuvant chemoradiotherapy.[Nivolumab PI] Based on these data, I believe that patients with residual disease should receive nivolumab if they are a good candidate for it. Of importance, CheckMate 577 showed there is a 31% reduction in risk of recurrence and doubling of the median DFS with adjuvant nivolumab compared with placebo. We eagerly await OS data, which may be presented at a future congress.

CheckMate 648: Nivolumab + Ipilimumab or Chemotherapy vs Chemotherapy for First-line Treatment of Advanced Esophageal Squamous Cell Carcinoma


Manish A. Shah, MD:
Moving to advanced esophageal squamous cell carcinoma, data were presented at ASCO 2021 from the ongoing phase III CheckMate 648 study, in which 970 patients with unresectable, advanced, recurrent, or metastatic squamous esophageal cancer have been randomized to receive nivolumab 240 mg every 2 weeks with monthly chemotherapy (5-fluorouracil and cisplatin) or chemotherapy alone or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks.[Chau 2021] The coprimary endpoints are OS and PFS in patients with tumor cell PD-L1 expression of 1% or greater. Secondary endpoints include OS and PFS in all patients, and ORR.

CheckMate 648: Baseline Characteristics


Manish A. Shah, MD:
In this large study, approximately 70% of patients were Asian, which reflects the fact that the majority of esophageal squamous cell cancers occur in Asia, whereas in the West, there are more esophageal adenocarcinomas and gastroesophageal junction tumors. Nearly all patients in the overall study population had squamous esophageal cancer (>96%). Additionally, approximately half of the patients had PD-L1 expression ≥1%.

CheckMate 648: OS


Manish A. Shah, MD:
Results showed significantly improved median OS for patients with PD-L1 expression ≥1% who received nivolumab vs chemotherapy. For the combination of nivolumab and chemotherapy, the median OS was 15 months vs 9.1 months with chemotherapy alone (HR: 0.54; P <.0001). Nivolumab plus ipilimumab produced a similar median OS compared with nivolumab and chemotherapy (13.7 months).

In the overall population of randomized patients, the median OS was 10.7 months with chemotherapy, which is consistent with past experience, but still meaningfully shorter than the 13.2 months seen with the addition of nivolumab (HR: 0.74; P = .0021). Nivolumab plus ipilimumab also improved OS in all randomized patients (median 12.8 months; HR: 0.78; P = .0110). At 12 months, at least half of the patients treated with nivolumab remained alive vs 37%-44% with chemotherapy alone.

CheckMate 648: Responses


Manish A. Shah, MD:
Results also demonstrated a significant improvement in the ORR with the addition of nivolumab: In the PD-L1 ≥1% group, the ORR was 53% with nivolumab plus chemotherapy and 35% with nivolumab plus ipilimumab vs 20% with chemotherapy alone. In the overall population, the ORR was 47% with nivolumab plus chemotherapy, 28% with nivolumab plus ipilimumab, and 27% with chemotherapy alone.

CheckMate 648: TRAEs


Manish A. Shah, MD:
Rates of TRAEs were not significantly worse with the addition of immunotherapy to chemotherapy.

CheckMate 648: Clinical Implications

Manish A. Shah, MD:
CheckMate 648 is likely to be practice changing, demonstrating the efficacy of the first chemotherapy-free treatment regimen for advanced esophageal squamous cell carcinoma (nivolumab plus ipilimumab). A current question surrounds whether toxicity commonly associated with combined immunotherapy might make nivolumab plus chemotherapy a more preferable option.

It should also be noted that, based on the Kaplan-Meier OS curves, chemotherapy alone appeared to improve survival vs nivolumab plus ipilimumab until approximately 6 months of treatment, when the curves met; by 12 months, nivolumab plus ipilimumab was associated with improved OS in the PD-L1 ≥1% and all randomized patient groups. This may be another consideration when selecting between regimens for specific patients.

CheckMate 649: Additional Analysis of First-line Nivolumab + CT vs CT for Advanced Gastroesophageal Cancers

Manish A. Shah, MD:
Updated results were also presented at ASCO 2021 from the ongoing phase III CheckMate 649 study, in which 1581 patients with previously untreated advanced or metastatic gastric cancer, gastroesophageal junction cancer, or esophageal adenocarcinoma have been randomized to nivolumab 360 mg plus capecitabine/oxaliplatin (XELOX) or nivolumab 240 mg plus 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX) vs XELOX or FOLFOX. [Moehler 2021, Janjigian 2021] A third arm in this study randomized patients to nivolumab plus ipilimumab; however, data from this arm were not presented at ASCO 2021.

The coprimary endpoints are OS and PFS in patients with a PD-L1 combined positive score (CPS) of at least 5. Secondary endpoints include OS and PFS in all patients and those with a PD-L1 CPS ≥10, and ORR.

CheckMate 649: Baseline Characteristics

Manish A. Shah, MD:
CheckMate 649 was primarily a study in patients with gastric cancer, as patients with esophageal cancer made up just 10%-15% of the total population. Both arms were well balanced with regard to age, sex, and race, as well as tumor location. The vast majority (~87%) of patients’ tumors were mismatch repair proficient, that is, microsatellite stable. The arms were balanced in terms of FOLFOX or XELOX, which were received by approximately 54% and 46%, respectively, in both arms.

CheckMate 649: Overall OS and PFS

Manish A. Shah, MD:
Median OS was statistically improved with the addition of nivolumab to chemotherapy (13.8 vs 11.6 months with chemotherapy alone; HR: 0.80; P = .0002). Likewise, median PFS was slightly longer with nivolumab plus chemotherapy (7.7 months vs 6.9 months with chemotherapy alone; HR: 0.77). The minimum follow-up was 12.1 months at the time of reporting.

CheckMate 649: Response

Manish A. Shah, MD:
The ORR was improved with nivolumab plus chemotherapy vs chemotherapy alone (58% vs 46%). Complete responses were seen in 10% vs 6%, PRs in 48% vs 40%, and stable disease was achieved in 28% vs 33%, respectively. The median time to response was 1.5 months in both arms, but the median DoR was slightly longer with nivolumab plus chemotherapy at 8.5 months vs 6.9 months with chemotherapy alone.

CheckMate 649: Subgroup Analysis by PD-L1 CPS

Manish A. Shah, MD:
The investigators conducted an important subgroup analysis of both OS and PFS according to PD-L1 CPS. In patients with a PD-L1 CPS of 5 or greater, the median OS was 14.4 months with nivolumab plus chemotherapy vs 11.1 months with chemotherapy alone (HR: 0.70). Of note, the median OS with nivolumab plus chemotherapy and a CPS of less than 5 was 12.4 months (HR 0.94 vs chemotherapy alone).

Median PFS was not significantly different with nivolumab plus chemotherapy whether patients had a PD-L1 CPS of less than 5 (7.5 months) or 5 or greater (7.7 months). Likewise, the ORR was similar with nivolumab plus chemotherapy whether patients had a PD-L1 CPS of greater or less than 5.

CheckMate 649: TRAEs With Potential Immunologic Cause in Patients Treated With Nivolumab + CT

Manish A. Shah, MD:
Treatment-related toxicity was infrequent, with grade 3/4 toxicities affecting no more than 5% of patients, including endocrine, gastrointestinal, hepatic, pulmonary, renal, and skin AEs. The most common TRAEs (any grade) included gastrointestinal (34%), hepatic (26%), and skin (27%) events.

CheckMate 649: QoL

Manish A. Shah, MD:
The addition of nivolumab to chemotherapy did improve the time to symptom deterioration compared with chemotherapy alone. Median time to symptom deterioration was not reached in the nivolumab arm vs 21.0 months in the chemotherapy-alone arm (HR: 0.77; P = .0129). According to the FACT-Ga GP5 questionnaire, patients in both arms were not particularly bothered by TRAEs.

CheckMate 649: Clinical Implications

Manish A. Shah, MD:
Nivolumab is now FDA approved for all comers for patients with advanced or metastatic gastroesophageal adenocarcinoma (gastric cancer, gastroesophageal junction cancer, and esophageal adenocarcinoma) in combination with chemotherapy.[Nivolumab PI] Of note, adding nivolumab to chemotherapy doesn’t add significant toxicity. This regimen is now a new standard of care for gastroesophageal cancers.

KEYNOTE-811: Pembrolizumab Plus Trastuzumab and Chemotherapy for HER2+ Advanced Gastroesophageal Cancer

Manish A. Shah, MD:
The last study that I’d like to talk about is the practice-changing phase III KEYNOTE-811 trial, which is evaluating the addition of pembrolizumab to first-line standard-of-care treatment in HER2-positive gastric cancers.[Janjigian 2021] Since the ToGA trial in 2010, trastuzumab has been available to treat HER2-positive gastric cancer.[Bang 2010] More recently, the antibody–drug conjugate T-DXd has been approved in the second- and third-line settings for patients with locally advanced or metastatic HER2-positive gastric cancer who have received prior trastuzumab.[Trastuzumab Deruxtecan PI]

KEYNOTE-811 is an ongoing randomized study of trastuzumab 6 mg/kg every 3 weeks plus chemotherapy (either 5-fluorouracil/cisplatin or oxaliplatin and capecitabine) with either placebo or pembrolizumab for patients with HER2-positive advanced gastric cancer or gastroesophageal adenocarcinoma and no prior treatment for advanced disease.[Janjigian 2021] The primary endpoints are OS and PFS, with secondary endpoints including ORR, DoR, and safety. At ASCO 2021, results were presented from an interim analysis of efficacy in 264 patients and safety in 433 patients who had received at least 1 dose of study drug.

KEYNOTE-811 Interim Analysis: Baseline Characteristics

Manish A. Shah, MD:
The baseline characteristics were well balanced between arms. The majority of patients (~80%) had disease with intestinal or indeterminate histology. More than 85% of patients had a PD-L1 CPS of 1 or higher, and approximately 80% had HER2 IHC 3+ staining.

KEYNOTE-811 Interim Analysis: Target Lesion Change From Baseline

Manish A. Shah, MD:
The ORR with the pembrolizumab combination was 74.4% vs 51.9% in the placebo arm, a highly significant 22.7% improvement (P = .00006). The DCR was 96% with the addition of pembrolizumab, which is remarkable. The median DoR (to date) is also quite long, at 10.6 months with pembrolizumab vs 9.5 months with placebo.

KEYNOTE-811 Interim Analysis: Target Lesion Change From Baseline

Manish A. Shah, MD:
These waterfall plots demonstrate that the addition of pembrolizumab really does improve the chance of responding to treatment. A total of 97% of pembrolizumab-treated patients had some decrease in lesion size (vs 90% on the placebo arm), and 32% had a decrease of at least 80% (vs 15% on the placebo arm).

KEYNOTE-811 Interim Analysis: Clinical Implications

Manish A. Shah, MD:
Based on this improved response rate, the FDA granted accelerated approval to pembrolizumab in combination with trastuzumab and fluoropyrimidine- and platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2-positive gastric or GEJ adenocarcinoma.[Pembrolizumab PI] This is really terrific and exciting for patients with gastroesophageal cancer.

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