Category: Immuno Oncology

FDA Approves KEYTRUDA® with Chemotherapy for HER2-Negative Gastric or GE Junction Adenocarcinoma

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SUMMARY: The FDA on November 16, 2023, approved Pembrolizumab (KEYTRUDA®) with Fluoropyrimidine and Platinum containing chemotherapy for the first-line treatment of adults with locally advanced unresectable or metastatic HER2-negative Gastric or GastroEsophageal Junction (GEJ) adenocarcinoma. The American Cancer Society estimates that in the US about 26,500 new Gastric cancer cases will be diagnosed in 2023 and about 11,130 people will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Several hereditary syndromes such as Hereditary Diffuse Gastric Cancer (HDGC), Lynch syndrome (Hereditary Nonpolyposis Colorectal Cancer) and Familial Adenomatous Polyposis (FAP) have been associated with a predisposition for Gastric cancer. Additionally, one of the strongest risk factor for Gastric adenocarcinoma is infection with Helicobacter pylori (H.pylori), which is a gram-negative, spiral-shaped microaerophilic bacterium.

Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with Gastric and GastroEsophageal junction Adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure. These patients frequently are treated with Platinum containing chemotherapy along with a Fluoropyrimidine and, if appropriate, HER2/neu-targeted therapy. This can however be associated with significant toxicities impacting patient’s quality of life. The efficacy of PD-1 inhibitors in combination with chemotherapy has been demonstrated in Gastric and GastroEsophageal cancer.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells.

The present FDA approval was based on KEYNOTE-859, which is a double-blind, placebo-controlled, randomized Phase III trial, conducted to evaluate the benefit of adding Pembrolizumab to Fluoropyrimidine and Platinum-containing doublet chemotherapy in patients with advanced HER2-negative Gastric or GastroEsophageal cancer. In this study, 1,579 patients with locally advanced or metastatic HER2-negative Gastric or GastroEsophageal adenocarcinoma, with known a PD-L1 Combined Positive Score (CPS), were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=790) or placebo (N=789), every 3 weeks for 35 cycles or less, given along with investigator’s choice of 5-FU plus Cisplatin or Capecitabine plus Oxaliplatin (CAPOX). Baseline characteristics were balanced between treatment groups and randomization was stratified by region, PD-L1 CPS (less than 1 versus 1 or more), and choice of chemotherapy. At baseline, 78% of patients had PD-L1 CPS 1 or more, while 35% had tumors with CPS 10 or more. The Primary end point was Overall Survival (OS) by blinded Independent Central Review. Secondary end points included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response (DOR) and Safety. The researchers provided the data from the interim analysis, at a median follow up of 31.0 months.

The median Overall Survival was 12.9 months with Pembrolizumab plus chemotherapy versus 11.5 months with chemotherapy alone (HR=0.78, P<0.0001). The median PFS was 6.9 months versus 5.6 months, respectively (HR=0.76, P<0.0001). The benefit with Pembrolizumab was consistent across subgroups, including those by PD-L1 CPS. The risk reduction was especially notable among patients with MicroSatellite Instability (MSI)-High status, who had a 66% relative reduction in the risk of death, and patients with PD-L1 CPS 10 or more, whose risk was reduced by 36%. The Objective Response Rate was 51.3% in the Pembrolizumab group and 42.0% in the control group (P=0.00009), and the median Duration of Response was 8.0 months versus 5.7 months, respectively. Immune-related toxicities, especially hypothyroidism, were more common with Pembrolizumab plus chemotherapy and no new safety signals were seen.

It was concluded that treatment with Pembrolizumab plus chemotherapy resulted in a statistically significant and clinically meaningful improvement in Overall Survival, Progression Free Survival and Objective Response Rate, among patients with locally advanced or metastatic, HER2-negative Gastric or GastroEsophageal adenocarcinoma of any PD-L1 expression level, thus providing a new treatment option for this patient group.

Pembrolizumab plus chemotherapy versus placebo plus chemotherapy for HER2-negative advanced gastric cancer (KEYNOTE-859): a multicentre, randomised, double-blind, phase 3 trial. Rha SY, Oh D-Y, Yanez P, et al. The Lancet Oncology 2023; 24:1181-1195.

FDA Approves Pembrolizumab with Chemotherapy for Biliary Tract Cancer

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SUMMARY: The FDA on October 31, 2023, approved Pembrolizumab (KEYTRUDA®) to be used with Gemcitabine and Cisplatin for locally advanced unresectable or metastatic Biliary Tract Cancer (BTC). Bile Tract cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer, and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract cancer and 174,000 patients will die of the disease each year globally. Biliary Tract cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival has been increasingly explored.

Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-966 is a multinational, randomized, double-blind, Phase III trial, conducted to determine whether adding the immune checkpoint inhibitor Pembrolizumab to first line standard chemotherapy, would impact survival outcomes in patients with metastatic or unresectable Biliary Tract cancers. In this study, 1069 patients (N=1069) with advanced and/or unresectable Biliary Tract cancers were randomly assigned to receive Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (N=533) or placebo (N=536). Both treatment groups received Gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks without preset maximum number of cycles, and Cisplatin 25 mg/m2 IV on days 1 and 8 every 3 weeks for up to 8 cycles. The median age was 63.5 years, majority of patients had metastatic disease (88%) and more than half had intrahepatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response and Safety. The median follow up was 25.6 months.

The median OS was 12.7 months in the Pembrolizumab group and 10.9 months in the placebo group (HR=0.83; P=0.0034). This represented a 17% reduction in the risk of death in the Pembrolizumab group compared to the placebo group. The 12-month OS rate was 52% with the Pembrolizumab regimen versus 44% for chemotherapy alone and the 24-month OS rates were 24.9% versus 18.1%, respectively. The OS results were generally consistent across subgroups.

There was no significant difference in PFS between the treatment groups but there was a trend toward improved PFS with Pembrolizumab. The median PFS was 6.5 months in the Pembrolizumab arm and 5.6 months in the placebo group (HR=0.87; P=0.23). The estimated 12-month PFS was 25% and 20% respectively.The Objective Response Rates were similar between the two treatment groups – 28.7% in the Pembrolizumab group and 28.5% in the placebo arm.The safety profile of Pembrolizumab was consistent with that observed in previously reported studies and Grade 3-4 adverse events were similar between treatment groups.

The authors concluded that KEYNOTE-966 is the largest randomized Phase III trial in advanced Biliary Tract cancers to date, with more patients enrolled from non-Asian countries. First line treatment with Pembrolizumab plus chemotherapy significantly improved Overall Survival, when compared with chemotherapy alone. The researchers added that one of the limitations of this study is that patients with intrahepatic bile duct cancers were overrepresented in the study population compared with the incidence of the disease in the general population, resulting in smaller sample sizes of patients with extrahepatic and gall bladder sites of origin.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Kelley RK, Ueno M, Yoo C, et al. The Lancet. 2023;401:1853-1865.

Late Breaking Abstract – ESMO Congress 2023: Perioperative OPDIVO® Plus Chemotherapy Improves Survival in Resectable Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 25% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based neoadjuvant or adjuvant chemotherapy to eradicate micrometastatic disease and decrease the risk of recurrence. However, conventional neoadjuvant or adjuvant chemotherapy provides only a 5% absolute improvement in Overall Survival (OS) at 5 years and 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

Nivolumab (OPDIVO®) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor which is highly expressed on activated T cells, and blocks its interaction with PD-L1 or PD-L2 on tumor cells, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. Combining cytotoxic chemotherapy with a PD 1 inhibitor therapy may augment the antitumor immune response through cell-death induced increased tumor antigenicity and reduction of Treg mediated immune suppression.

In the CheckMate 816 Phase III trial, neoadjuvant Nivolumab plus platinum-doublet chemotherapy in earlier stage resectable NSCLC resulted in a marked improvement in pathologic Complete Response rate, with a statistically significant improvement in the Event Free Survival among those receiving Nivolumab plus chemotherapy group, compared to those receiving chemotherapy alone.

CheckMate 77T, a multicenter, randomized, double-blind, Phase III trial, conducted to evaluate the efficacy of perioperative Nivolumab + chemotherapy in patients with resectable NSCLC. In this study, 461 patients (N=461) with untreated, resectable Stage IIA (more than 4 cm)-IIIB (N2) NSCLC were randomly assigned 1:1 to receive Nivolumab 360 mg IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery, and adjuvant Nivolumab 480 mg IV every 4 weeks for 1 year (N=229), or placebo IV every 3 weeks plus four cycles of histology-based platinum doublet chemotherapy followed by surgery and adjuvant placebo IV every 4 weeks for 1 year (N=232). Enrolled patients had no prior systemic anticancer treatment and no EGFR or ALK mutations. Patients were stratified according to histology, disease stage, and tumor PD-L1 expression (less than 1% versus 1% or more) and patients with brain metastasis were excluded. The median age was 66 years, and both treatment groups were well balanced. Approximately two-thirds had Stage III disease, more than 50% of patients had tumor PD-L1 expression of 1% or more, and about 40% of patients had PD-L1 expression less than 1%. Approximately 90% were current or former smokers and majority of patients (75%) received Carboplatin-based chemotherapy. Surgery was performed within 6 weeks following the last dose of neoadjuvant therapy and radiologic restaging. The Primary endpoint of this study was Event Free Survival (EFS) according to Blinded Independent Central Review. Secondary endpoints included Overall Survival, pathologic Complete Response, Major Pathologic Response (10% or less of viable tumor cells remaining at time of surgery), and Safety. The researchers presented the data from the first interim prespecified analysis of Event-Free Survival.

At a median follow-up of 25.4 months, approximately 78% in the Nivolumab/chemotherapy group and 77% in the placebo/chemotherapy group were able to undergo definitive surgery. Lobectomy was the most common type of surgery performed and about 90% of patients had a complete resection. Nivolumab plus chemotherapy significantly improved Event-Free Survival, compared to placebo plus chemotherapy (median Not Reached versus 18.4 months respectively; HR=0.58; P=00025). This represented a 42% improvement in Event-Free Survival among those treated with Nivolumab plus chemotherapy. The 12-month Event-Free Survival rate was 73% versus 59%, respectively and the 18-month Event-Free Survival rate was 70% versus 50%. The pathologic Complete Response rates as well as Major Pathologic Response rates were significantly higher with Nivolumab plus chemotherapy, compared to placebo plus chemotherapy (25.3% versus 4.7% and 35.4% versus 12.1% repectively). Surgery related adverse events were similar in both treatment groups at 12%.

The researchers concluded that CheckMate 77T met its primary endpoint and is the first Phase III perioperative study that builds on the current standard of care, neoadjuvant Nivolumab plus chemotherapy. Patient with early stage resectable NSCLC now have three different treatment options: 1) Neoadjuvant therapy followed by surgery 2) Surgery followed by adjuvant therapy, and 3) Now perioperative therapy, which includes neoadjuvant therapy, surgery, and adjuvant therapy. Circulating tumor DNA and other biomarkers may identify patients who are cured with chemoimmunotherapy and in whom adjuvant therapy can be avoided.

CheckMate 77T: Phase III study comparing neoadjuvant nivolumab (NIVO) plus chemotherapy (chemo) vs neoadjuvant placebo plus chemo followed by surgery and adjuvant NIVO or placebo for previously untreated, resectable stage II–IIIb NSCLC. Cascone T, Awad M, Spicer J, et al. ESMO Congress 2023. Abstract LBA1. Presented on October 21, 2023.

FDA Approves Nivolumab for Adjuvant Treatment of Stage IIB/C Melanoma

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SUMMARY: The FDA on October 13, 2023, approved Nivolumab (OPDIVO®) for the adjuvant treatment of completely resected Stage IIB/C melanoma in patients 12 years and older. The American Cancer Society’s estimates that for 2023, about 97,610 new cases of melanoma of the skin will be diagnosed in the United States and 7,990 people are expected to die of the disease. The rates of melanoma have been rising rapidly over the past few decades, but this has varied by age. Surgical resection with a curative intent is the standard of care for patients with early stage melanoma.

Patients with resected Stage IIB/C disease comprise a significant group of patients at significant risk of recurrence. Patients with Stage IIB disease have primary tumors that are more than 2 mm and 4 mm or less in thickness with ulceration (T3b) or more than 4 mm in thickness without ulceration (T4a). Patients with Stage IIC disease have primary tumors more than 4 mm in thickness with ulceration (T4b). Although Stage II melanoma is less advanced than Stage III, the 5-year risk of recurrence in patients with stage IIB or Stage IIC disease without adjuvant therapy is approximately 35% and 50% respectively. The 5-year Melanoma-Specific Survival (MSS) rates for patients with Stage IIB/IIC disease are similar to those for Stage IIIA, Stage IIIB and Stage IIIC disease.

Immune Checkpoint Inhibitors are the standard of care adjuvant treatment for high-risk, resected, Stage III melanoma. In the KEYNOTE-054 trial, the 5-year Relapse Free Survival (RFS) with adjuvant Pembrolizumab was 55.4% versus 38.3% with placebo, in patients with completely resected, Stage IIIA (more than 1 mm lymph node metastasis), IIIB or IIIC Melanoma. In the CHECKMATE-238 trial, the 4-year RFS rate was of 51.7% for Nivolumab versus 41.2% for ipilimumab among patients with resected Stage IIIB/C and IV melanoma.

CHECKMATE-76K is an ongoing, randomized, double-blind, Phase III study conducted to evaluate the efficacy of Nivolumab versus placebo as adjuvant treatment for patients with resected Stage IIB/C melanoma. In this study, 790 eligible patients were randomized (2:1) to Nivolumab 480 mg (N=526) or placebo (N=264) by IV infusion every 4 weeks for up to 1 year or until disease recurrence or unacceptable toxicity. Patient characteristics at baseline were well balanced between treatment groups and 50.5% had nodular melanoma, 39% had Stage IIC disease and patients were stratified by tumor category. The Primary endpoint was investigator-assessed Recurrence-Free Survival (RFS). Secondary endpoints included Distant Metastasis-Free Survival (DMFS) and Safety.

At a minimum follow up of 7.8 months, CheckMate 76K met its primary endpoint and Nivolumab significantly improved RFS versus placebo. Nivolumab demonstrated a 58% reduction in the risk of recurrence or death versus placebo in patients with resected stage IIB/C melanoma (HR = 0.42; P < 0.0001). The 12-month RFS was 89.0% for nivolumab and 79.4% for placebo. The benefit with nivolumab over placebo was observed across all pre-specified subgroups, including all disease Stages and T-category subgroups. Adjuvant Nivolumab demonstrated significant benefit in those with stage IIC disease, head and neck primaries or nodular disease, who are all considered to be at a higher absolute recurrence risk. Additionally, there was a clinically meaningful improvement in the Distant Metastasis-Free Survival with Nivolumab versus placebo (HR = 0.47). Further, a lower proportion of patients treated with nivolumab had multiple lesions detected at first recurrence versus those treated with placebo (3.4% versus 9.1%). Adverse events were similar to that observed in patients with resected stage III or stage IV disease and similar to the established anti-PD-1 monotherapy profile.

It was concluded that adjuvant Nivolumab significantly improved Relapse Free Survival as well as Distant Metastasis-Free Survival in patients with resected Stage IIB/C melanoma and this clinical benefit was observed across disease subgroups, including all T categories.

Adjuvant nivolumab in resected stage IIB/C melanoma: primary results from the randomized, phase 3 CheckMate 76K trial. Kirkwood, J.M., Del Vecchio, M., Weber, J. et al. Nat Med (2023). https://doi.org/10.1038/s41591-023-02583-2

KEYTRUDA® in Combination with HER2 Blockade Improves PFS in Gastric and GE Junction Cancer

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SUMMARY: Gastroesophageal cancers consist of a group of heterogeneous tumors, including gastric cancer, gastroesophageal junction cancer, and esophageal cancer. The majority of gastric and gastroesophageal junction cancers are adenocarcinomas, while the two main histological subtypes of esophageal cancer are esophageal adenocarcinoma and esophageal squamous cell carcinoma. The American Cancer Society estimates that in the US about 26,500 new gastric cancer cases and 21,560 new esophageal cancers will be diagnosed in 2023 and about 11,130 and 16,120 people respectively, will die of the disease. It is one of the leading causes of cancer-related deaths in the world. Patients with localized disease (Stage II and Stage III) are often treated with multimodality therapy and 40% of the patients may survive for 5 years or more. However, majority of the patients with gastric and gastroesophageal junction adenocarcinoma have advanced disease at the time of initial presentation and have limited therapeutic options with little or no chance for cure.

The Human Epidermal growth factor Receptor (HER) or erbB family of receptors, consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of advanced gastric and gastroesophageal (GE) junction cancers, overexpress or have amplification of the HER2 oncogene. These patients often receive first line treatment with a combination of chemotherapy plus anti-HER2 antibody, Trastuzumab, as there is Overall Survival (OS) benefit with this combination regimen. Pembrolizumab (KEYTRUDA®) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor expressed on activated T cells, and blocks its interaction with ligands PD-L1 and PD-L2. It thereby reverses the PD-1 pathway-mediated inhibition of the immune response and unleashes the tumor-specific effector T cells. In two Phase II studies, Pembrolizumab in combination with Trastuzumab and chemotherapy showed promising efficacy with manageable toxicities. The FDA in 2021 granted accelerated approval to Pembrolizumab in combination with Trastuzumab, Fluoropyrimidine and Platinum-containing chemotherapy for the first-line treatment of patients with locally advanced unresectable or metastatic HER2 positive gastric or gastroesophageal junction adenocarcinoma, based on Overall Response Rates (ORR).

KEYNOTE-811 is an ongoing, global, multicenter, randomized Phase III trial which evaluated the benefit of adding Pembrolizumab to Trastuzumab and chemotherapy in patients with locally advanced unresectable or metastatic HER2-positive gastric or gastroesophageal junction adenocarcinoma. In this study, 698 treatment naïve eligible patients (N=698) were randomly assigned 1:1 to receive Pembrolizumab 200 mg IV (N=350) or placebo (N=348) every 3 weeks plus Trastuzumab and investigator’s choice of Fluorouracil/Cisplatin or Capecitabine/Oxaliplatin. Trastuzumab was given at 6 mg/kg IV once every 3 weeks after a loading dose of 8 mg/kg IV. Chemotherapy consisted of 5-FU 800 mg/m2 IV on days 1 to 5 of each 3-week cycle and Cisplatin 80 mg/m2 IV once every 3 weeks, or Capecitabine 1,000 mg/m2 orally twice daily on days 1 to 14 of each 3-week cycle and Oxaliplatin 130 mg/m2 IV once every 3 weeks. Treatment was continued for up to 35 cycles or until disease progression or unacceptable toxicity. Approximately 81% were male and patients were stratified by PD-L1 status, and chemotherapy received. Over 80% of patients had a PD-L1 Combined Positive Score of 1 or more. The dual Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS). Secondary end points included Objective Response Rate (ORR), Duration of Response, and Safety. The researchers reported the results at the third interim analysis, after a median follow up of 38.5 months.

At the third interim analysis, the results continued to show superiority with the addition of Pembrolizumab to Trastuzumab and chemotherapy. The median PFS with Pembrolizumab versus placebo was 10 months versus 8.1 months, respectively (HR = 0.73; P=0.0002). This represented a 27% reduction in risk for progression with Pembrolizumab versus placebo. The median OS showed numerical improvement and was 20.0 months versus 16.8 months (HR=0.84), but did not meet prespecified criteria for significance. Follow up for Overall Survival is continuing, and results will be updated at the final analysis. Patients whose tumors had PD-L1 Combined Positive Score of 1 or more benefitted the most, and there was little to no benefit among patients whose tumors had PD-L1 Combined Positive Scores less than 1. The researchers had previously reported an ORR of 74% in the the Pembrolizumab group and 52% in the placebo group, yielding a 22% improvement for the Pembrolizumab group (P=0.00006). Disease Control Rates were 96.2% versus 89.3% respectively. Grade 3 or more treatment-related adverse events were higher among patients assigned to Pembrolizumab versus placebo group (58% versus 51%). The most common treatment-related adverse events of any grade were diarrhea, nausea and anemia.

The authors concluded that Pembrolizumab when combined with first line Trastuzumab and chemotherapy significantly improved Progression Free Survival when compared to placebo, in metastatic HER2-positive gastroesophageal cancer. This benefit was specifically noted among patients with tumors with a PD-L1 Combined Positive Score of 1 or more. Follow up for Overall Survival is ongoing and will be updated at the final analysis.

Pembrolizumab plus trastuzumab and chemotherapy for HER2-positive gastric or gastro-oesophageal junction adenocarcinoma: interim analyses from the phase 3 KEYNOTE-811 randomised placebo-controlled trial. Janjigian YY, Kawazoe A, Bai Y, et al. Published:October 20, 2023. DOI:https://doi.org/10.1016/S0140-6736(23)02033-0

FDA Approves Perioperative KEYTRUDA® for Resectable Early Stage Non Small Cell Lung Cancer

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SUMMARY: The FDA on October 16, 2023, approved KEYTRUDA® (Pembrolizumab) with platinum-containing chemotherapy as neoadjuvant treatment, and with continuation of single-agent KEYTRUDA® as post-surgical adjuvant treatment for resectable (tumors 4 cm or more or node positive) Non-Small Cell Lung Cancer (NSCLC). Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression. KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

The present FDA approval was based on the KEYNOTE-671 trial, which is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival (OS). Secondary end points included major pathological response, pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. The Event-Free Survival (EFS) at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group. The median EFS was not reached in the Pembrolizumab group and was 17.0 months in the placebo group (HR=0.58; P<0.001). The EFS benefit with Pembrolizumab was consistent across all subgroups examined. The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02) at this first interim analysis.

A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Adjuvant KEYTRUDA® in Resected NSCLC Irrespective of PD-L1 Expression

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-091/EORTC-1416-LCG/ETOP-8-15 – PEARLS trial is a multicenter, randomized, triple-blind, placebo-controlled Phase III trial, which compared the efficacy of KEYTRUDA® with placebo, among patients with resected NSCLC. In this study, 1,177 patients with completely resected Stage IB (T2a ≥4 cm), II, or IIIA NSCLC with negative margins, and with tumor tissue available for PD-L1 testing were included. Systematic complete or lobe-specific mediastinal lymph node dissection was recommended. In the least, the subcarinal and 1 lobe-specific lymph node must have been examined. Eligible patients had not received neoadjuvant radiotherapy or chemotherapy, had ECOG PS of 0-1, and adjuvant chemotherapy for up to four cycles was optional. Adjuvant chemotherapy could be considered for those with Stage IB disease and was strongly recommended for those with Stage II and IIIA disease. Patients were randomized (1:1) to receive KEYTRUDA® 200 mg or placebo IV every three weeks and treatment was continued until disease recurrence, unacceptable toxicity, or up to 1 year. Both treatment groups were well balanced. The median patient age was 65 years, majority of patients (68%) were male, approximately 65% of patients had nonsquamous histology, 56% of patients had Stage II disease and 86% of patients had received adjuvant platinum-based chemotherapy following complete resection. Stratification factors included disease stage, receipt of adjuvant chemotherapy, PD-L1 Tumor Proportion Score and geographic region of the world. The median duration of exposure to KEYTRUDA® was 11.7 months and 68% of patients in the KEYTRUDA® group were exposed to KEYTRUDA® for at least 6 months. The dual Primary endpoints were Disease-Free Survival (DFS) in the overall population and in the population with PD-L1 Tumor Proportion Score (TPS) of 50% or greater. An additional efficacy outcome was Overall Survival (OS). The median follow up for this interim analysis was 35.6 months.

The trial met its Primary endpoint, demonstrating a statistically significant improvement in DFS in the overall population. In the overall population, median DFS was 53.6 months in the KEYTRUDA® group versus 42.0 months in the placebo group (HR=0.76; P=0.0014), reducing the risk of disease recurrence or death by 24% versus placebo, regardless of PD-L1 expression. In the PD-L1 TPS of 50% or greater population, median DFS was not reached in either the KEYTRUDA® group or the placebo group. Overall survival Data were not mature.

It was concluded that these data support the benefit of KEYTRUDA® as a new adjuvant immunotherapy treatment option, for early-stage Non Small Cell Lung Cancer following complete resection, and if indicated, adjuvant chemotherapy, regardless of PD-L1 expression.

Pembrolizumab versus placebo as adjuvant therapy for completely resected stage IB-IIIA non-small-cell lung cancer (PEARLS/KEYNOTE-091):an interim analysis of a randomised, triple-blind, phase 3 trial. O’Brien M, Paz-Ares L, Marreaud S, et al. Lancet Oncol. 2022;10:1274-1286.

Late Breaking Abstract- ASCO 2023: BCMA-directed CAR T-cell therapy Cilta-cel in Lenalidomide Refractory Multiple Myeloma

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SUMMARY: Multiple Myeloma is a clonal disorder of plasma cells in the bone marrow and the American Cancer Society estimates that in the United States, 35,730new cases will be diagnosed in 2023 and 12,590 patients are expected to die of the disease. Multiple Myeloma is a disease of the elderly, with a median age at diagnosis of 69 years and characterized by intrinsic clonal heterogeneity. Almost all patients eventually will relapse, and patients with a high-risk cytogenetic profile, extramedullary disease or refractory disease have the worst outcomes. The introduction of Proteasome Inhibitors, Immunomodulatory agents and CD38 targeted therapies has resulted in higher Response Rates, as well as longer Progression Free Survival (PFS) and Overall Survival (OS), with the median survival for patients with myeloma approaching 10 years or more. Nonetheless, multiple myeloma in 2023 remains an incurable disease. Multiple myeloma patients triple refractory to Immunomodulatory drugs (IMiD), Proteasome Inhibitors (PIs), and anti-CD38 monoclonal antibodies have a poor prognosis with a median progression-free survival (PFS) of 3-4 months and a median Overall Survival (OS) of 8-9 months.

With the introduction of new combinations of antimyeloma agents in earlier lines of therapy, patients with Relapsed or Refractory myeloma often have disease that is refractory to multiple drugs. There is an urgent unmet medical need for agents with novel mechanisms of action that are safe and effective, for patients with aggressive and resistant disease.

Chimeric Antigen Receptor (CAR) T-cell therapy has been associated with long-term disease control in some hematologic malignancies and showed promising activity in a Phase 1 study involving patients with Relapsed or Refractory myeloma. B-cell Maturation Antigen (BCMA) is a member of the Tumor Necrosis Factor superfamily of proteins. It is a transmembrane signaling protein primarily expressed by malignant and normal plasma cells and some mature B cells. BCMA is involved in JNK and NF-kB signaling pathways that induce B-cell development and autoimmune responses. BCMA has been implicated in autoimmune disorders, as well as B-lymphocyte malignancies, Leukemia, Lymphomas, and Multiple Myeloma.

Anti-BCMA CAR T-Cell Therapy is a type of immunotherapy and consists of T cells collected from the patient’s blood in a leukapheresis procedure. These T cells are then stimulated by treating with interleukin 2 (IL-2) and anti-CD3 antibodies in vitro, so that they will actively proliferate and expand to large numbers. These T cells are then genetically engineered to produce special receptors on their surface called Chimeric Antigen Receptors (CAR), by transducing with a gene encoding the engineered CAR, via a retroviral vector such as lentiviral vector. These reprogrammed cytotoxic T cells with the Chimeric Antigen Receptors on their surface are now able to recognize a specific antigen such as BCMA on tumor cells. These genetically engineered and reprogrammed CAR T-cells are grown in the lab and are then infused into the patient. These cells in turn proliferate in the patient’s body and the engineered receptor on the cell surface help recognize and kill cancer cells that expresses that specific antigen such as BCMA. The patient undergoes lymphodepletion chemotherapy with Fludarabine and Cytoxan prior to the introduction of the engineered CAR T-cells. By depleting the number of circulating leukocytes, cytokine production is upregulated and reduces competition for resources, which in turn promotes the expansion of the engineered CAR T-cells.

Ciltacabtagene autoleucel (Cilta-cel), a B-cell maturation antigen (BCMA)-directed CAR T-cell therapy, is effective in heavily pretreated patients with Relapsed or Refractory multiple myeloma and was approved by the FDA in February 2022 for the treatment of adult patients with Relapsed or Refractory multiple myeloma after four or more prior lines of therapy, including a Proteasome Inhibitor (PI), an Immunomodulatory agent (IMiD), and an anti-CD38 monoclonal antibody. The researchers in this study investigated the efficacy of cilta-cel in earlier treatment lines among patients with Lenalidomide-refractory disease.

CARTITUDE-4 is an open-label, multicenter, randomized Phase III trial conducted to compare cilta-cel with the physician’s choice of either of two highly effective standard-of-care therapies, in patients with lenalidomide-refractory multiple myeloma after one to three lines of therapy. In this study a total of 419 eligible patients (N=419) were randomly assigned in a 1:1 ratio to receive either one of the standard-of-care physicians choice of PVd-Pomalidomide, Bortezomib, and Dexamethasone, DPd-Daratumumab, Pomalidomide, and Dexamethasone (N=211) or a single infusion of cilta-cel administered after the physician’s choice of bridging therapy with PVd or DPd (N=208). In the standard-of-care group, DPd was administered in 28-day cycles and PVd in 21-day cycles until disease progression. Patients in the cilta-cel group underwent apheresis, followed by at least one bridging therapy cycle, with the number of cycles based on patient clinical status and cilta-cel manufacturing time, and lymphodepletion with Cyclophosphamide 300 mg/m2 IV and Fludarabine 30 mg/m2 IV daily for 3 days. Patients then received a single cilta-cel infusion at a target dose of 0.75X106 CAR-positive T cells/kg of body weight 5-7 days after the initiation of lymphodepletion. The median age was 61 yrs, median time from diagnosis was 3.2 years, about 60% of patients had high risk cytogenetic abnormalities and all patients had received 1-3 previous lines of treatment. In the cilta-cel group, 14.4% had triple-class drug resistance and 24.0% had resistance to anti-CD38 antibody. The Primary outcome was Progression Free Survival and Secondary outcomes sequentially tested included Complete Response (CR) or better, Overall Response Rate (ORR), Minimal Residual Disease (MRD) negativity, and Overall Survival (OS).

Treatment with cilta-cel resulted in a significantly lower risk of disease progression or death than standard-of-care (HR=0.26; P<0.001). The median PFS was not reached in the cilta-cel group and was 11.8 months in the standard-of-care group. Progression-free survival at 12 months was 75.9% in the cilta-cel group and 48.6% in the standard-of-care group. The ORR was 84.6% in the cilta-cel group and 67.3% in the standard-of-care group (P<0.001), the CR rate or better was 73.1% versus 21.8% (P<0.001), and MRD negativity was 60.6% versus 15.6% (P<0.001), respectively. Among the patients who had a response, an estimated 84.7% in the cilta-cel group as compared with 63.0% in the standard-of-care group continued to have a response for at least 12 months.

The most common Grade 3 or 4 adverse events in both groups were hematologic and most high-grade cytopenias in patients who received cilta-cel recovered to Grade 2 or less by day 60. Serious adverse events were reported in 44% of patients in the cilta-cel group and in 39% of patients in the standard-of-care group. Lower rates of cytopenias, Cytokine Release Syndrome, and CAR-T–related neurotoxicity were seen in this study compared to previous cilta-cel studies suggesting that cilta-cel may have a better side-effect profile when used earlier in treatment.

It was concluded that a single cilta-cel infusion resulted in a lower risk of disease progression or death, as well as rapid and deep responses, compared to standard therapies in Lenalidomide-refractory patients with multiple myeloma who had received one to three previous therapies.

Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma. San-Miguel J, Dhakal B, Yong K, et al. N Engl J Med 2023;389:335-347.

Perioperative Pembrolizumab for Early Stage Non Small Cell Lung Cancer

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SUMMARY: Lung cancer is the second most common cancer in both men and women and accounts for about 13% of all new cancers and 21% of all cancer deaths. The American Cancer Society estimates that for 2023, about 238,340 new cases of lung cancer will be diagnosed and 127,070 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Non-Small Cell Lung Cancer (NSCLC) accounts for approximately 85% of all lung cancers. Of the three main subtypes of NSCLC, 30% are Squamous Cell Carcinomas (SCC), 40% are Adenocarcinomas and 10% are Large Cell Carcinomas. With changes in the cigarette composition and decline in tobacco consumption over the past several decades, Adenocarcinoma now is the most frequent histologic subtype of lung cancer.

The 5-year survival rate for patients diagnosed with lung cancer in the US is about 25%, which is a significant improvement over the past 5 years, in part due to earlier detection from lung cancer screening, reduction in smoking, advances in diagnostic and surgical procedures, as well as the introduction of new therapies. However, the 5-year survival rate remains significantly lower among communities of color at 20%. Early detection and screening remain an important unmet need, as 44% of lung cancer cases are not found until they are advanced. In the US, only 5.8% of those individuals at high risk were screened in 2021.

Surgical resection is the primary treatment for approximately 30% of patients with NSCLC who present with early Stage (I–IIIA) disease. These patients are often treated with platinum-based adjuvant chemotherapy to decrease the risk of recurrence. Nonetheless, 45-75% of these patients develop recurrent disease. There is therefore an unmet need for this patient population.

Immunotherapy with Immune Checkpoint Inhibitors (ICIs) has revolutionized cancer care and has become one of the most effective treatment options, by improving Overall Response Rate and prolongation of survival, across multiple tumor types. These agents target Programmed cell Death protein-1 (PD-1), Programmed cell Death Ligand-1 (PD-L1), Cytotoxic T-Lymphocyte-Associated protein-4 (CTLA-4), and many other important regulators of the immune system. Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. Biomarkers predicting responses to ICIs include Tumor Mutational Burden (TMB), Mismatch Repair (MMR) status, and Programmed cell Death Ligand 1 (PD‐L1) expression.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2.

KEYNOTE-671 trial is a randomized, double-blind, placebo-controlled, Phase III trial, conducted to evaluate whether a perioperative approach of combined neoadjuvant Pembrolizumab plus Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, would improve efficacy as compared with neoadjuvant Cisplatin-based chemotherapy and resection alone, in patients with resectable Stage II or III NSCLC. This study included patients with pathologically confirmed, resectable Stage II, IIIA, or IIIB (N2 disease-with involvement of 1 or more ipsilateral mediastinal lymph nodes or subcarinal lymph node) NSCLC. Eligible patients were randomly assigned in a 1:1 ratio to receive neoadjuvant Pembrolizumab 200 mg IV (N=397) or placebo (N=400) once every 3 weeks, each of which was given with Cisplatin-based chemotherapy for 4 cycles, followed by surgery and adjuvant Pembrolizumab 200 mg IV or placebo once every 3 weeks for up to 13 cycles. The median age was 64 years, 70% had Stage III disease, about 44% had N2 nodal stage, 57% has nonsquamous histology and 43% had squamous histology, about 36% had less than 1% PD-L1 Tumor Proportion Score (TPS), whereas 30% of patients had tumors with a TPS of 1-49% and 33% had TPS of 50% or more. The dual Primary end points were Event-Free Survival (the time from randomization to the first occurrence of local progression that precluded the planned surgery, unresectable tumor, progression or recurrence, or death), and Overall Survival. Secondary end points included major pathological response, Pathological Complete Response, and Safety.

The researchers reported the efficacy and safety data from the prespecified first interim analysis. The median follow-up was 25.2 months. Event-Free Survival at 24 months was 62.4% in the Pembrolizumab group and 40.6% in the placebo group (HR=0.58; P<0.001). The estimated 24-month Overall Survival was 80.9% in the Pembrolizumab group and 77.6% in the placebo group and this was not statistically significant (P=0.02). A major pathological response occurred in 30.2% of the patients in the Pembrolizumab group and in 11.0% of those in the placebo group (P<0.0001) and a pathological Complete Response occurred in 18.1% and 4.0%, respectively (P<0.0001). An exploratory analysis showed that the Event-Free Survival benefit was noted in the Pembrolizumab group regardless of whether participants had a major pathological response or a pathological Complete Response. The benefit with Pembrolizumab therapy appeared to be similar across both squamous and nonsquamous histologies. Approximately 45% of the patients in the Pembrolizumab group and 37% in the placebo group had treatment-related adverse events of Grade 3 or higher.

It was concluded that among patients with resectable Stage II, IIIA, or IIIB (N2 stage) NSCLC, the addition of Pembrolizumab to neoadjuvant Cisplatin-based chemotherapy, followed by surgical resection and adjuvant Pembrolizumab therapy, led to a significant improvement in Event-Free Survival, major pathological response, and Pathological Complete Response, as compared with neoadjuvant chemotherapy alone followed by surgery. It should be noted that this trial was not designed to assess the relative contribution of adjuvant Pembrolizumab.

Perioperative Pembrolizumab for Early-Stage Non–Small-Cell Lung Cancer. Wakelee H, Liberman M, Kato T, et al., for the KEYNOTE-671 Investigators. N Engl J Med 2023;389:491-503.

Pembrolizumab Plus Chemotherapy Improves Overall Survival in Advanced Biliary Tract Cancer

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SUMMARY: Bile Tract cancer (Cholangiocarcinoma) is a rare and highly aggressive heterogenous cancer, and is the second most common type of primary liver cancer after Hepatocellular carcinoma. It comprises about 30% of all primary liver tumors and includes both intrahepatic and extrahepatic bile duct cancers. It is estimated that approximately 211,000 patients are diagnosed with Biliary Tract cancer and 174,000 patients will die of the disease each year globally. Biliary Tract cancer is most frequently diagnosed in patients between 50 to 70 years old, and 75% of patients are diagnosed at an advanced stage. Klatskin tumor is a type of Cholangiocarcinoma that begins in the hilum, at the junction of the left and right bile ducts. It is the most common type of Cholangiocarcinoma, accounting for more than half of all cases. About 8,000 people in the US are diagnosed with Cholangiocarcinoma each year and approximately 20% of the cases are suitable for surgical resection. Patients diagnosed with Biliary Tract cancer have a very poor prognosis, and the 5-year survival among those with advanced stage disease is less than 10%, with limited progress made over the past two decades. There is therefore an urgent unmet need for new effective therapies.

Patients with advanced Biliary Tract cancers often receive chemotherapy in the first and second line settings, with limited benefit. Gemcitabine and Cisplatin combination is currently the first line standard-of-care treatment. With the recognition of immunogenic features displayed by Biliary Tract cancers, the role of immune checkpoint inhibitors for improving disease control and prolonging survival has been increasingly explored.

KEYTRUDA® (Pembrolizumab) is a fully humanized, Immunoglobulin G4, anti-PD-1, monoclonal antibody, that binds to the PD-1 receptor and blocks its interaction with ligands PD-L1 and PD-L2. By doing so, it unleashes the tumor-specific effector T cells, and is thereby able to undo PD-1 pathway-mediated inhibition of the immune response.

KEYNOTE-966 is a multinational, randomized, double-blind, Phase III trial, conducted to determine whether adding the immune checkpoint inhibitor Pembrolizumab to first line standard chemotherapy, would impact survival outcomes in patients with metastatic or unresectable Biliary Tract cancers. In this study, 1069 patients (N=1069) with advanced and/or unresectable Biliary Tract cancers were randomly assigned to receive Pembrolizumab 200 mg IV every 3 weeks for up to 35 cycles (N=533) or placebo (N=536). Both treatment groups received Gemcitabine 1000 mg/m2 IV on days 1 and 8 every 3 weeks without preset maximum number of cycles, and Cisplatin 25 mg/m2 IV on days 1 and 8 every 3 weeks for up to 8 cycles. The median age was 63.5 years, majority of patients had metastatic disease (88%) and more than half had intrahepatic disease. The Primary endpoint was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR), Duration of Response and Safety. The median follow up was 25.6 months.

The median OS was 12.7 months in the Pembrolizumab group and 10.9 months in the placebo group (HR=0.83; P=0.0034). This represented a 17% reduction in the risk of death in the Pembrolizumab group compared to the placebo group. The 12-month OS rate was 52% with the Pembrolizumab regimen versus 44% for chemotherapy alone and the 24-month OS rates were 24.9% versus 18.1%, respectively. The OS results were generally consistent across subgroups.

There was no significant difference in PFS between the treatment groups but there was a trend toward improved PFS with Pembrolizumab. The median PFS was 6.5 months in the Pembrolizumab arm and 5.6 months in the placebo group (HR=0.87; P=0.23). The estimated 12-month PFS was 25% and 20% respectively.The Objective Response Rates were similar between the two treatment groups – 28.7% in the Pembrolizumab group and 28.5% in the placebo arm.The safety profile of Pembrolizumab was consistent with that observed in previously reported studies and Grade 3-4 adverse events were similar between treatment groups.

The authors concluded that KEYNOTE-966 is the largest randomized Phase III trial in advanced Biliary Tract cancers to date, with more patients enrolled from non-Asian countries. First line treatment with Pembrolizumab plus chemotherapy significantly improved Overall Survival, when compared with chemotherapy alone. The researchers added that one of the limitations of this study is that patients with intrahepatic bile duct cancers were overrepresented in the study population compared with the incidence of the disease in the general population, resulting in smaller sample sizes of patients with extrahepatic and gall bladder sites of origin.

Pembrolizumab in combination with gemcitabine and cisplatin compared with gemcitabine and cisplatin alone for patients with advanced biliary tract cancer (KEYNOTE-966): A randomised, double-blind, placebo-controlled, phase 3 trial. Kelley RK, Ueno M, Yoo C, et al. Lancet. Published online April 16, 2023. https://doi.org/10.1016/S0140-6736(23)00727-4.