Category: Immuno Oncology

FDA Approves TECENTRIQ® as Adjuvant Treatment for Non Small Cell Lung Cancer

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SUMMARY: The FDA on October 15, 2021, approved TECENTRIQ® (Atezolizumab) for adjuvant treatment, following resection and Platinum-based chemotherapy, in patients with Stage II to IIIA Non-Small Cell Lung Cancer (NSCLC) whose tumors have PD-L1 expression on 1% or more of tumor cells, as determined by an FDA-approved test. Lung cancer is the second most common cancer in both men and women and accounts for about 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

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.

TECENTRIQ® is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

IMpower 010 is a global, multicentre, open-label, randomized Phase III study evaluating the efficacy and safety of TECENTRIQ® compared with Best Supportive Care (BSC), in patients with Stage IB-IIIA NSCLC, following surgical resection and up to 4 cycles of adjuvant Cisplatin-based chemotherapy. In this study, 1005 patients were randomized 1:1 to receive TECENTRIQ® 1200 mg IV every 3 weeks for 16 cycles, or BSC. Both study groups were well balanced and eligible patients had an ECOG PS of 0-1. The Primary endpoint was Disease Free Survival (DFS) in the PD-L1-positive Stage II-IIIA patients, all randomized Stage II-IIIA patients and Intent to Treat (ITT) Stage IB-IIIA populations. Key Secondary endpoints included Overall Survival (OS) in the overall study population and ITT Stage IB-IIIA NSCLC patients. At data cutoff on January 21, 2021, median follow up was 32.2 months in the ITT population.

Treatment with TECENTRIQ® following surgery and chemotherapy reduced the risk of disease recurrence or death (DFS-Disease Free Survival) by 34% (HR=0.66; P=0.0039), in patients with Stage II-IIIA NSCLC, whose tumor PD-L1 expression was 1% or more, compared with BSC. In this patient population, median DFS was Not Reached for TECENTRIQ®, compared with 35.3 months for BSC. This benefit was even more so among Stage II-IIIA NSCLC patients with PD-L1 expression 50% or more. Adjuvant TECENTRIQ® following surgery and chemotherapy in this patient group reduced the risk of disease recurrence or death (DFS) by 57% (HR=0.43). In the larger population of all randomized Stage II-IIIA study patients, TECENTRIQ® reduced the risk of disease recurrence or death by 21% (HR=0.79, P=0.02). In this patient population, TECENTRIQ® increased DFS by a median of seven months, compared with BSC (42.3 months versus 35.3 months). The significance boundary was not crossed for DFS in the ITT patient population. Overall Survival data were immature and not formally tested. Safety data for TECENTRIQ® were consistent with its known safety profile and no new safety signals were identified.

It was concluded that this study met its Primary endpoint, and is the first Phase III study to demonstrate that treatment with TECENTRIQ® following surgery and chemotherapy can significantly delay disease recurrence in patients with early stage lung cancer, with a more pronounced benefit noted, in patients with tumor PD-LI expression of 1% or more.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Wakelee HA, Altorki NK, Zhou C, et al. J Clin Oncol. 2021;39:(suppl 15; abstr 8500). doi:10.1200/JCO.2021.39.15_suppl.8500

Durable Survival Benefit with First Line OPDIVO® plus YERVOY® and a Limited Course of Chemotherapy

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Immune checkpoints are cell surface inhibitory proteins/receptors that are expressed on activated T cells. They harness the immune system and prevent uncontrolled immune reactions by switching off the immune system T cells. Immune checkpoint proteins/receptors include CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152) and PD-1(Programmed cell Death 1). Checkpoint inhibitors unleash the T cells resulting in T cell proliferation, activation, and a therapeutic response. OPDIVO® is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the T cells. YERVOY® is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4. In the CheckMate-227, Part 1, Phase III trial, a combination of OPDIVO® plus YERVOY®, significantly improved Overall Survival (OS), Progression Free Survival (PFS), Objective Response Rates (ORR) and Duration of Response, compared to chemotherapy, independent of PD-L1 expression level. The authors in this study hypothesized that a limited course of chemotherapy combined with OPDIVO® plus YERVOY® could provide rapid disease control, while building on the durable Overall Survival benefit seen with dual PD-1 and CTLA-4 inhibition, as well as minimizing the toxicities associated with a full course of chemotherapy.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

CheckMate-9LA is a randomized, open-label, multi-center, Phase III trial which evaluated the benefit of a combination of OPDIVO® plus YERVOY®, and 2 cycles of Platinum-doublet chemotherapy (experimental arm) versus Platinum-doublet chemotherapy (control arm) for 4 cycles, followed by optional Pemetrexed maintenance therapy, as a first-line treatment in patients with metastatic or recurrent NSCLC, regardless of PD-L1 status and histology. In this study, 719 adults treatment naïve patients with histologically confirmed Stage IV/recurrent NSCLC, with ECOG Performance Status 0-1, and no known sensitizing EGFR/ALK alterations, were randomly assigned 1:1 to receive OPDIVO® 360 mg every 3 weeks plus YERVOY® 1 mg/kg every 6 weeks and 2 cycles of platinum-doublet chemotherapy (N=361), or 4 cycles of platinum-doublet chemotherapy alone (N=358). Chemotherapy was based on histology. Patients with non-squamous NSCLC in the chemo-only randomized group could receive optional Pemetrexed maintenance treatment. Patients were treated with immunotherapy until disease progression, unacceptable toxicity, or for 2 years. Patients were stratified by PD-L1 status (less than 1% versus 1% or more), sex, and histology (squamous versus non-squamous). Demographics in treatment groups were well balanced. Crossover between treatment groups was not permitted. However, at physician discretion, patients could receive subsequent immunotherapy upon discontinuation of study treatment in either group.

The Primary end point was Overall Survival (OS). Secondary endpoints included Progression Free Survival (PFS), Objective Response Rate (ORR) and efficacy by PD-L1 subgroups. PFS2 was a pre-specified exploratory endpoint and was defined as time from randomization, to objectively documented progression after the next line of therapy, or to death from any cause, whichever occurred first. At a preplanned interim analysis after a minimum follow up 8.1 months, this trial met its primary and secondary endpoints, showing statistically significant improvements in OS, PFS, and Objective Response Rate (ORR), when compared to chemotherapy alone. This clinical benefit was noted across tumor PD-L1 expression levels and histologies.

The authors in this publication reported updated efficacy and safety outcomes, along with Progression-Free Survival (PFS) after next line of treatment (PFS2), Treatment-Related Adverse Events (TRAEs) by treatment cycle, and efficacy outcomes in patients who discontinued all treatment components in the experimental treatment group due to TRAEs, from the CheckMate 9LA Phase III trial. The minimum follow up for OS was 24.4 months. The majority of patients (93%) received two cycles of chemotherapy and 13% completed the maximum 2 years of immunotherapy treatment. The median number of doses was 9.0 for OPDIVO® and 4.0 for YERVOY®. In the control arm, 75% of patients received four cycles of chemotherapy and 67% patients who had non-squamous tumor histology receiving Pemetrexed maintenance. About 29% patients in the control arm had completed the full four cycles of chemotherapy without optional Pemetrexed maintenance therapy. The median duration of therapy was 6.1 months in the experimental arm and 2.5 months in the control arm.

With a median follow up of 30.7 months, OPDIVO® plus YERVOY® with a limited course of chemotherapy continued to prolong Overall Survival (OS), when compared to chemotherapy (Median OS 15.8 versus 11.0 months; HR=0.72). The 2-year OS rate was 38% versus 26%. This OS benefit was observed across most key subgroups including those with PD-L1 expression of less than 1%, more than 1%, as well as by histology. More importantly, patients with pretreated CNS metastases at baseline had a median OS of 19.9 months in the experimental group versus 7.9 months in the control group, respectively (HR=0.47).

PFS continued to be prolonged in the experimental group compared to the control group, with an Hazard Ratio of 0.67 and 2-year PFS rates of 20% versus 8%, respectively. The ORR was 38% in the experimental group and 25% in the control group (P=0.0003). 34% versus 12% of all responses respectively, were ongoing at 2 years. The median PFS2 in all randomized patients was 13.9 months in the experimental group and 8.7 months in the control group (HR=0.66). Again, PFS2 also favored the experimental arm over the control arm in subgroups by PD-L1 expression, and by histology.

No new safety signals were observed and majority of Grade 3/4 toxicities were mostly observed during the first two treatment cycles in the experimental group. In patients who discontinued all components of the experimental treatment (OPDIVO® plus YERVOY® with chemotherapy) due to toxicities (N=61), the median OS was 27.5 months and 56% of responders had an ongoing response, more than 1 year after discontinuation of therapy. After discontinuing the experimental regimen, patients remained treatment-free for a median of 11.9 months and had a 48% chance of being treatment-free at 1 year.

The researchers concluded that with a 2-year minimum follow-up, OPDIVO® plus YERVOY® with two cycles of chemotherapy provided durable efficacy benefits over conventional chemotherapy, with a manageable safety profile. They added that this treatment regimen remains an efficacious first line treatment of advanced Non Small Cell Lung Cancer.

First-line nivolumab plus ipilimumab with two cycles of chemotherapy versus chemotherapy alone (four cycles) in advanced non-small-cell lung cancer: CheckMate 9LA 2-year update. Reck M, Ciuleanu T-E, Cobo M, et al. https://doi.org/10.1016/j.esmoop.2021.100273

KEYTRUDA® in Combination with Chemotherapy Improves Overall Survival in Triple Negative Breast Cancer

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SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

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 rationale for combining chemotherapy with immunotherapy is that cytotoxic chemotherapy releases tumor-specific antigens, and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Single agent KEYTRUDA® in metastatic TNBC demonstrated durable antitumor activity in several studies, with Objective Response Rates (ORRs) ranging from 10-21% and improved clinical responses in patients with higher PD-L1 expression. When given along with chemotherapy as a neoadjuvant treatment for patients with high-risk, early-stage TNBC, KEYTRUDA® combination achieved Pathological Complete Response rate of 65%, regardless of PD-L1 expression. Based on this data, KEYTRUDA® in combination with chemotherapy was studied, for first line treatment of advanced TNBC.

KEYNOTE-355 is a randomized, double-blind, Phase III study, which evaluated the benefit of KEYTRUDA® in combination with one of the three different chemotherapy regimens, nab-Paclitaxel, Paclitaxel, or the non-taxane containing Gemzar/Carboplatin, versus placebo plus one of the three chemotherapy regimens, in patients with previously untreated or locally recurrent inoperable metastatic TNBC. In this study, 847 patients were randomized 2:1 to receive either KEYTRUDA® 200 mg IV on day 1 of each 21-day cycle along with either nab-Paclitaxel 100 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of each 28-day cycle, or Gemcitabine 1000 mg/m2 IV plus Carboplatin AUC 2, IV on days 1 and 8 of each 21-day cycle (N= 566) or placebo along with one of the three chemotherapy regimens (N= 281). This study was not designed to compare the efficacy of the different chemotherapy regimens. Treatment was continued until disease progression. Patients were stratified by chemotherapy, PD-L1 tumor expression (CPS of 1 or higher versus CPS of less than 1), and prior treatment with the same class of neoadjuvant/adjuvant chemotherapy (Yes versus No). The baseline characteristics of treatment groups were well-balanced. The co-Primary end points of the trial were Progression Free Survival (PFS) and Overall Survival (OS) in patients with PD-L1-positive tumors, and in all patients. Secondary end points were Objective Response Rate (ORR), Duration of Response, Disease Control Rate, and Safety.

The authors had previously reported that KEYTRUDA® in combination with chemotherapy, significantly improved PFS in patients with CPS (Combined Positive Score) of 10 or greater. The median PFS was 9.7 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for placebo plus chemotherapy (HR=0.65, P=0.0012). This represented a 35% reduction in the risk of disease progression. Among patients with CPS of 1 or greater, the median PFS was 7.6 months for KEYTRUDA® plus chemotherapy, compared with 5.6 months for the placebo plus chemotherapy arm (HR= 0.74; P=0.0014). This however based on prespecified statistical criteria, was not considered statistically significant. Among the entire Intention-To-Treat (ITT) population, the median PFS was 7.5 months in the KEYTRUDA® plus chemotherapy group, compared with 5.6 months for chemotherapy plus placebo group (HR=0.82).

The researchers have now reported the Overall Survival results after a median follow up of 44.1 months. The OS in the subgroup of patients with PD-L1 CPS of 10 or more was significantly better with first line KEYTRUDA® plus chemotherapy versus placebo plus chemotherapy (23.0 months versus 16.1 months, respectively; HR=0.73; P=0.0093). This represented a 27% reduction in the risk of death with the KEYTRUDA® combination. Among this subgroup, factors significantly associated with superior outcomes included age 65 yrs and older, use of Paclitaxel as the on-study chemotherapy, no prior adjuvant therapy, de novo metastasis, Disease Free Interval of 12 months or more, and less than 3 metastatic sites. However, this OS benefit was not noted in the subgroup of patients with PD-L1 CPS scores of 1 or less. In this subgroup, the median OS was 17.6 months in the KEYTRUDA® group and 16 months in the placebo group (HR=0.86; P=Not Significant). The same was true among the Intention-To-Treat (ITT) population, including all randomized patients regardless of PD-L1 tumor status. In this patient group, the median OS was 17.2 months in the KEYTRUDA® group and 15.5 months in the placebo group, and this was not statistically significant (HR=0.89).

The authors concluded that these updated results support KEYTRUDA® in combination with chemotherapy as a new standard-of-care treatment regimen for patients with locally recurrent unresectable or metastatic Triple Negative Breast Cancer, whose tumors express PD-L1, with CPS of 10 or more.

KEYNOTE-355: Final results from a randomized, double-blind phase 3 study of first-line pembrolizumab + chemotherapy vs placebo + chemotherapy for metastatic TNBC. Cortes J, Cescon DW, Rugo HS. et al. European Society for Medical Oncology (ESMO) Annual Meeting 2021: Abstract LBA16. Presented on September 19, 2021.

KRAS Variant Status and Outcomes with Immune Checkpoint Inhibitor-Based Therapy in Advanced Non Small Cell Lung Cancer

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SUMMARY: The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.

Patients with advanced NSCLC without a driver mutation and with Programmed cell Death Ligand 1 (PD-L1) expression of 50% or greater, are often treated first line with Immune Checkpoint Inhibition (ICI) monotherapy or ICI in combination with chemotherapy. The choice between these two treatment regimens is usually based on tumor burden and patient comorbidities, as there are presently no biomarkers available to predict the risk and benefit of these treatment interventions. The KEYNOTE-042 study demonstrated that single agent Pembrolizumab given as first line therapy demonstrated Overall Survival (OS) benefit over chemotherapy, in patients with previously untreated advanced NSCLC, with PD-L1 expression of 1% or greater. In an exploratory analysis, this benefit was seen regardless of KRAS status, but was more pronounced in patients with KRAS variants than those without KRAS variants.

The KRAS (kirsten rat sarcoma viral oncogene homologue) proto-oncogene encodes a protein that is a member of the small GTPase super family. The KRAS gene provides instructions for making the KRAS protein, which is a part of a signaling pathway known as the RAS/MAPK pathway. When mutated, KRAS oncogene has the potential to change normal cells cancerous. KRAS is the most frequently mutated oncogene in human cancers and are often associated with resistance to targeted therapies and poor outcomes. The KRAS-G12C mutation occurs in approximately 12-15% of NSCLC and in 3-5% of Colorectal cancers and other solid cancers. KRAS G12C is one of the most prevalent driver mutations in NSCLC and accounts for a greater number of patients than those with ALK, ROS1, RET, and TRK 1/2/3 mutations combined. KRAS G12C cancers are genomically more heterogeneous and occur more frequently in current or former smokers, and are likely to be more complex genomically than EGFR mutant or ALK rearranged cancers.

The authors conducted this study to evaluate the association of KRAS status with outcomes following ICI monotherapy versus chemoimmunotherapy in patients with PD-L1 of 50% or greater. The researchers used the Flatiron Health database, comprising 280 cancer clinics across the US and analyzed 1127 patients with advanced non-squamous NSCLC with PD-L1 expression of 50% or greater, known KRAS variant status, and no alteration in EGFR, ALK, or ROS1, who were treated with first line ICI monotherapy or chemoimmunotherapy between January 2016 and May 2020. Of the patients analyzed, 50.8% had KRAS variant status and 49.2% had KRAS wild type status. Patients with KRAS variant status were more likely to be female (58.7% versus 47.1%; P =0.002) and had smoking history (96.4% versus 87.7%; P < .001). Other patient demographics and patient characteristics, including age, race, ethnicity, Performance Status, and stage at diagnosis, were well balanced among the groups analyzed. Patient groups were stratified by treatment type and KRAS status (variant or wild type), and Overall Survival (OS) was compared between the treatment groups. Adjusted Hazard ratios for death associated with KRAS status and treatment regimen was estimated, using Cox proportional hazards models.

It was noted that among patients treated with ICI monotherapy, KRAS variant status was associated with superior median survival compared with KRAS wild type (21.1 months versus 13.6 months; HR=0.77; P=0.03), and this was statistically significant. However, among patients treated with chemoimmunotherapy, there was no significant median survival difference between patients with KRAS variant and KRAS wild type status (20.0 months versus 19.3 months; HR=0.99; P=0.93).

Among patients with KRAS variant status, the median OS did not differ between those treated with ICI monotherapy and chemoimmunotherapy (21.1 months versus 20.0 months; P =0.78), whereas among patients with KRAS wild type status, those treated with ICI monotherapy had numerically worse median survival than those treated with chemoimmunotherapy, although this difference was not statistically significant (13.6 months versus 19.3 months; HR=1.19; P =0.06).

In conclusion, this data suggests that chemoimmunotherapy might be favored over ICI monotherapy for patients with KRAS wild type tumors associated with high PD-L1 expression. The authors caution that in this analysis KRAS variant subtype and co-mutation status including TP53 and STK11 was unknown, and further investigation is needed to selection appropriate therapies for patients with PD-L1 High NSCLC.

Association Between KRAS Variant Status and Outcomes With First-line Immune Checkpoint Inhibitor–Based Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. Sun L, Hsu M, Cohen RB, et al. JAMA Oncol. 2021;7:937-939.

FDA Approves KEYTRUDA® for High Risk Early Stage Triple Negative Breast Cancer

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SUMMARY: The FDA on July 26, 2021, approved KEYTRUDA® (Pembrolizumab) for high risk, early stage, Triple Negative Breast Cancer (TNBC), in combination with chemotherapy, as neoadjuvant treatment, and then continued as a single agent as adjuvant treatment following surgery. The FDA also granted regular approval to KEYTRUDA® in combination with chemotherapy for patients with locally recurrent unresectable or metastatic TNBC whose tumors express PD-L1 (Combined Positive Score – CPS 10 or more), as determined by an FDA approved test. FDA granted accelerated approval to KEYTRUDA® for this indication in November 2020.

Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Triple Negative Breast Cancer (TNBC) is a heterogeneous, molecularly diverse group of breast cancers and are ER (Estrogen Receptor), PR (Progesterone Receptor) and HER2 (Human Epidermal Growth Factor Receptor-2) negative. TNBC accounts for 15-20% of invasive breast cancers, with a higher incidence noted in young patients. It is usually aggressive, and tumors tend to be high grade and patients with TNBC are at a higher risk of both local and distant recurrence. Those with metastatic disease have one of the worst prognoses of all cancers with a median Overall Survival of 13 months. The majority of patients with TNBC who develop metastatic disease do so within the first 3 years after diagnosis, whereas those without recurrence during this period of time have survival rates similar to those with ER-positive breast cancers.

The lack of known recurrent oncogenic drivers in patients with metastatic TNBC, presents a major therapeutic challenge. Nonetheless, patients with TNBC often receive chemotherapy in the neoadjuvant, adjuvant or metastatic settings and approximately 30-40% of patients achieve a pathological Complete Response (pCR) in the neoadjuvant setting. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pCR following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. For all these reasons, pCR is considered a valid endpoint for clinical testing of neoadjuvant therapy in patients with early stage TNBC. It appears that there are subsets of patients with TNBC who may be inherently insensitive to cytotoxic chemotherapy. Three treatment approaches appear to be promising and they include immune therapies, PARP inhibition and inhibition of PI3K pathway. Previously published studies have shown that presence of tumor-infiltrating lymphocytes was associated with clinical benefit, when treated with chemotherapy and immunotherapy, in patients with TNBC, and improved clinical benefit was observed in patients with immune-enriched molecular subtypes of metastatic TNBC.

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. Cytotoxic chemotherapy releases tumor-specific antigens and immune checkpoint inhibitors such as KEYTRUDA® when given along with chemotherapy can enhance endogenous anticancer immunity. Preliminary results from Phase I and II trials have shown that in patients with TNBC, KEYTRUDA® given along with chemotherapy in a neoadjuvant setting resulted in a high rate of pCR.

The present FDA approvals were based on KEYNOTE-522, which is an international, randomized, multicenter, double-blind, placebo controlled Phase III trial, conducted to evaluate the safety and efficacy of neoadjuvant KEYTRUDA® plus chemotherapy followed by adjuvant KEYTRUDA® or placebo, in patients with early stage TNBC. In this study, 1,174 patients were randomly assigned in a 2:1 ratio to receive neoadjuvant KEYTRUDA® 200 mg IV every 3 weeks (N=784) or placebo (N=390). All patients received 4 cycles of Carboplatin plus Paclitaxel, followed by 4 cycles of Doxorubicin or Epirubicin plus Cyclophosphamide, in the neoadjuvant setting. Following definitive surgery, adjuvant KEYTRUDA® or placebo was continued every 3 weeks for 9 cycles or until disease recurrence or unacceptable toxicity. Enrolled TNBC patients were newly diagnosed, early stage, high risk, treatment naïve, and included both node-negative and node-positive patients with nonmetastatic disease (Tumor Stage T1c, Nodal Stage N1-N2 or Tumor Stage T2-T4, Nodal Stage N0-N2, per AJCC criteria). Patients were enrolled regardless of tumor PD-L1 expression. Treatment groups were well balanced and patients were stratified according to nodal status, tumor size, and Carboplatin schedule (weekly versus every 3 weeks). The two Primary endpoints were pathological Complete Response (pCR) at the time of definitive surgery and Event Free Survival (EFS).

At the first interim analysis, at a median follow up of 15.5 months, the pCR among the first 602 patients who underwent randomization was 64.8% in the KEYTRUDA® plus chemotherapy group, compared with 51.2% in the placebo plus chemotherapy group (HR=0.63; P<0.001). At the median follow-up of 39 months, EFS data were made available, and this showed that KEYTRUDA® demonstrated a statistically significant EFS benefit compared with chemotherapy alone. The number of patients who experienced an EFS event was 16% and 24%, respectively (HR=0.63; P=0.00031). Among patients who were in the PD-L1 positive, defined as those with a CPS of 1 or higher, there was a 33% reduced risk of EFS events with KEYTRUDA® compared with the placebo group (HR=0.67). In the PD-L1 negative group, patients receiving the KEYTRUDA® combination had a reduced risk for EFS events by 52% compared with the placebo-chemotherapy group (HR=0.48). Across all treatment phases, Grade 3 or higher treatment-related toxicities were 78.0% in the KEYTRUDA® plus chemotherapy group and 73.0% in the placebo plus chemotherapy group

It can be concluded from this study that among patients with early stage Triple Negative Breast Cancer, the addition of KEYTRUDA® to neoadjuvant chemotherapy significantly increased the pathological Complete Response rate, compared to those who received placebo plus neoadjuvant chemotherapy, with a statistically significant Event Free Survival benefit. This KEYTRUDA® combination therapy is a meaningful milestone for breast cancer patients, and is the first immunotherapy regimen to be approved in high risk, early stage Triple Negative Breast Cancer.

https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-pembrolizumab-high-risk-early-stage-triple-negative-breast-cancer.

Long Term Survival Benefit in Advanced Melanoma with OPDIVO® plus YERVOY®

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SUMMARY: The American Cancer Society’s estimates that for 2021, about 106,110 new cases of melanoma will be diagnosed in the United States and 7,180 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.

A better understanding of Immune checkpoints has opened the doors for the discovery of novel immune targets. Immune checkpoints are cell surface inhibitory proteins/receptors that harness the immune system and prevent uncontrolled immune reactions. Survival of cancer cells in the human body may be related to their ability to escape immune surveillance, by inhibiting T lymphocyte activation. Under normal circumstances, inhibition of an intense immune response and switching off the T cells of the immune system is accomplished by Immune checkpoints or gate keepers. With the recognition of Immune checkpoint proteins and their role in suppressing antitumor immunity, antibodies have been developed that target the membrane bound inhibitory Immune checkpoint proteins/receptors such as CTLA-4 (Cytotoxic T-Lymphocyte Antigen 4, also known as CD152), PD-1(Programmed cell Death 1), etc. By blocking the Immune checkpoint proteins, T cells are unleashed, resulting in T cell proliferation, activation and a therapeutic response.Unleashing-T-Cell-Function-with-Immune-Checkpoint-Inhibitors

YERVOY® (Ipilimumab) is a fully human immunoglobulin G1 monoclonal antibody that blocks Immune checkpoint protein/receptor CTLA-4, and was the first systemic therapy in randomized Phase III trials, to show prolonged Overall Survival (OS) in patients with advanced melanoma. YERVOY® in a pooled analysis of data from 12 studies showed a 3-year Overall Survival of 26% among treatment naive patients, and survival up to 10 years in approximately 20% of all patients, with advanced melanoma. The two PD-1 inhibitors of interest are OPDIVO® (Nivolumab) and KEYTRUDA® (Pembrolizumab), which are fully human, Immunoglobulin G4, anti-PD-1 targeted monoclonal antibodies that bind to the PD-1 receptor, and block its interaction with ligands PD-L1 and PD-L2, following which the tumor-specific effector T cells are unleashed. They are thus able to undo PD-1 pathway-mediated inhibition of the immune response. When compared with YERVOY® in patients with advanced melanoma, PD-1 inhibitors, both OPDIVO® and KEYTRUDA® have demonstrated superior Overall Survival (OS), Progression Free Survival (PFS), and Objective Response Rate (ORR), with a better safety profile. OPDIVO® in combination with YERVOY® in a Phase I study resulted in an Overall Survival of 68% at 3 years among patients with advanced melanoma, regardless of prior therapies.

CheckMate 067 is a double-blind Phase III study in which patients with previously untreated advanced melanoma were randomly assigned in a 1:1:1 ratio to receive one of the three regimens: OPDIVO® 1 mg/kg every 3 weeks plus YERVOY® 3 mg/kg every 3 weeks for four doses, followed by OPDIVO® 3 mg/kg every 2 weeks (N=314); OPDIVO® 3 mg/kg every 2 weeks plus placebo (N=316); or YERVOY® 3 mg/kg every 3 weeks for four doses plus placebo (N=315). Randomization was stratified according to BRAF mutation status, metastasis stage, and Programmed cell Death Ligand 1 (PD-L1) status. Treatment was continued until disease progression or unacceptable toxicities. The two Primary end points were PFS and OS in the OPDIVO® plus YERVOY® group, and in the OPDIVO® group versus the YERVOY® group.

As previously reported, there was a durable and sustained clinical benefit at 5 years, with superior PFS and OS among patients treated with OPDIVO® plus YERVOY® combination therapy or with OPDIVO® alone, compared with single agent YERVOY®. The authors in this publication reported the efficacy and safety outcomes in this untreated, unresectable Stage III or IV patients with advanced melanoma, after an extended follow up of 6.5 years.

The median Overall Survival for patients treated with OPDIVO® plus YERVOY® combination therapy was 72.1 months, for those treated with single agent OPDIVO® was 36.9 months, compared with 19.9 months with single agent YERVOY®. At the time of analysis at 6.5 years, 49% of patients treated with OPDIVO® plus YERVOY® were alive, compared to 42% of those treated with OPDIVO® alone and 23% of those treated with single agent YERVOY®. The PFS at 6.5 years was 34% for the OPDIVO® plus YERVOY® group, 29% for the OPDIVO® alone group, and 7% for the YERVOY® group.

It was concluded that the results from the 6.5 year analysis showed durable improved outcomes with OPDIVO® plus YERVOY®, and OPDIVO® alone, when compared to single agent YERVOY®, among patients with advanced melanoma. Further, there was an improvement in OS and PFS with OPDIVO® plus YERVOY®, over OPDIVO® alone. The authors added that this analysis represents the longest follow up from a Phase III melanoma trial in the modern checkpoint inhibitor combination therapy and targeted therapy era.

CheckMate 067: 6.5-year outcomes in patients (pts) with advanced melanoma. Wolchok JD, Chiarion-Sileni V, Gonzalez R, et al. J Clin Oncol 39, 2021 (suppl 15; abstr 9506)

Adjuvant TECENTRIQ® Improves Disease Free Survival in 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 14% of all new cancers and 27% of all cancer deaths. The American Cancer Society estimates that for 2021, about 235,760 new cases of lung cancer will be diagnosed and 131,880 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.
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.

TECENTRIQ® (Atezolizumab) is an anti PD-L1 monoclonal antibody, designed to directly bind to PD-L1 expressed on tumor cells and tumor-infiltrating immune cells, thereby blocking its interactions with PD-1 and B7.1 receptors expressed on activated T cells. PD-L1 inhibition may prevent T-cell deactivation and further enable the activation of T cells.

IMpower 010 is a global, multicentre, open-label, randomized Phase III study evaluating the efficacy and safety of TECENTRIQ® compared with Best Supportive Care (BSC), in patients with Stage IB-IIIA NSCLC, following surgical resection and up to 4 cycles of adjuvant Cisplatin-based chemotherapy. In this study, 1005 patients were randomized 1:1 to receive TECENTRIQ® 1200 mg IV every 3 weeks for 16 cycles, or BSC. Both study groups were well balanced and eligible patients had an ECOG PS of 0-1. The Primary endpoint was Disease Free Survival (DFS) in the PD-L1-positive Stage II-IIIA patients, all randomized Stage II-IIIA patients and Intent to Treat (ITT) Stage IB-IIIA populations. Key Secondary endpoints included Overall Survival (OS) in the overall study population and ITT Stage IB-IIIA NSCLC patients. At data cutoff on January 21, 2021, median follow up was 32.2 months in the ITT population.

Treatment with TECENTRIQ® following surgery and chemotherapy reduced the risk of disease recurrence or death (DFS) by 34% (HR=0.66; P=0.0039), in patients with Stage II-IIIA NSCLC, whose tumor PD-L1 expression was 1% or more, compared with BSC. In this patient population, median DFS was Not Reached for TECENTRIQ®, compared with 35.3 months for BSC.

In the larger population of all randomized Stage II-IIIA study patients, TECENTRIQ® reduced the risk of disease recurrence or death by 21% (HR=0.79, P=0.02). In this patient population, TECENTRIQ® increased DFS by a median of seven months, compared with BSC (42.3 months versus 35.3 months).

The significance boundary was not crossed for DFS in the ITT patient population. Overall Survival data were immature and not formally tested. Safety data for TECENTRIQ® were consistent with its known safety profile and no new safety signals were identified.

It was concluded that this study met its Primary endpoint, and is the first Phase III study to demonstrate that treatment with TECENTRIQ® following surgery and chemotherapy can significantly delay disease recurrence in patients with early stage lung cancer, with a more pronounced benefit noted, in patients with tumor PD-LI expression of 1% or more.

IMpower010: Primary results of a phase III global study of atezolizumab versus best supportive care after adjuvant chemotherapy in resected stage IB-IIIA non-small cell lung cancer (NSCLC). Wakelee HA, Altorki NK, Zhou C, et al. J Clin Oncol. 2021;39:(suppl 15; abstr 8500). doi:10.1200/JCO.2021.39.15_suppl.8500

FDA Approves KEYTRUDA® plus Trastuzumab and Chemotherapy for HER2 Positive Gastric or Gastroesophageal Junction Cancer

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SUMMARY: The FDA on May 5, 2021 granted accelerated approval to KEYTRUDA® (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 (GEJ) adenocarcinoma. The American Cancer Society estimates that in the US, about 26,560 new cases of Gastric cancer will be diagnosed in 2021 and about 11,180 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.

Majority of the patients with Gastric and GastroEsophageal (GE) 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.
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, KEYTRUDA® in combination with Trastuzumab and chemotherapy showed promising efficacy with manageable toxicities.

The present FDA approval was based on KEYNOTE-811 trial, an ongoing global, multicenter, randomized, double blind, placebo controlled, Phase III study, which assessed whether adding KEYTRUDA® to Standard of Care chemotherapy improved efficacy, compared to Standard of Care alone, among patients with HER2+ metastatic Gastric/GEJ cancer. A total of 692 patients were enrolled and patients were randomized (1:1) to receive KEYTRUDA® 200 mg IV or placebo IV every 3 weeks, in combination with Trastuzumab and investigator’s choice of Fluorouracil plus Cisplatin (FP), or Capecitabine plus Oxaliplatin (CAPOX). Treatment is being given for up to 2 years or until intolerable toxicity or progressive disease. Patients were enrolled irrespective of PD-L1 status, and HER2-positive status was defined as ImmunoHistoChemistry (IHC) 3+ or IHC 2+ and FISH positivity. The dual Primary end points are Progression Free Survival (PFS) by Blinded, Independent Central Review (BICR) and Overall Survival (OS). Secondary end points are Overall Response Rate (ORR) and Duration of Response (DOR) assessed by BICR, and Safety.

The first interim analysis included 264 patients with a median follow up of 12 months. At the time of this interim analysis, 133 patients were randomized to KEYTRUDA® plus Standard of Care and 131 patients to Placebo plus Standard of care. Approximately 88% and 85% of the patients in the KEYTRUDA® and Placebo groups respectively, had a PD-L1 Combined Positive Score of 1 or more.
The confirmed ORR was 74.4% for KEYTRUDA® plus Standard of Care versus 51.9% for Placebo plus Standard of care (P=0.00006). The Complete Response rate was 11.3% versus 3.1% and Disease Control Rate was 96.2% versus 89.3% respectively. The median Duration of Response was 10.6 months for patients treated with KEYTRUDA® and 9.5 months for those in the placebo group. Adverse Events were similar between the two treatment groups and immune-mediated pneumonitis and colitis were more common as expected, in the KEYTRUDA® group.

It was concluded that the addition of KEYTRUDA® to Trastuzumab and chemotherapy, as first line therapy for HER2+ metastatic Gastric/GE Junction cancer, resulted in a substantial, statistically significant increase in Overall Response Rate, compared to Trastuzumab and chemotherapy alone. The authors added that these initial data are practice-changing and support KEYTRUDA® plus Trastuzumab and chemotherapy as a potential new treatment option for this patient group.

Pembrolizumab plus trastuzumab and chemotherapy for HER2+ metastatic gastric or gastroesophageal junction (G/GEJ) cancer: Initial findings of the global phase 3 KEYNOTE-811 study. Janjigian YY, Kawazoe A, Yanez PE, et al. DOI: 10.1200/JCO.2021.39.15_suppl.4013 Journal of Clinical Oncology 39, no. 15_suppl (May 20, 2021) 4013-4013.

Late Breaking Abstract – ASCO 2021: Adjuvant KEYTRUDA® Improves Disease Free Survival in Renal Cell Carcinoma

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SUMMARY: The American Cancer Society estimates that 76,080 new cases of kidney cancers will be diagnosed in the United States in 2021 and about 13,780 people will die from the disease. Renal Cell Carcinoma (RCC) is by far the most common type of kidney cancer and is about twice as common in men as in women. Modifiable risk factors include smoking, obesity, workplace exposure to certain substances and high blood pressure. The five year survival of patients with advanced RCC is less than 10% and there is a significant unmet need for improved therapies for this disease.

The prognosis for patients with Renal Cell Carcinoma (RCC) is dependent on the stage of disease and risk factors. Two validated models, the University of California Los Angeles Integrated Staging System (UISS) and the Stage, Size, Grade, and Necrosis (SSIGN) score were developed, to assess the risk for relapse. UISS is based on ECOG Performance Status, Fuhrman nuclear grading and TNM pathological stage, whereas the SSIGN score takes Stage, Size, Grade and Necrosis into consideration. Approximately 16% of patients with RCC present with Locoregional disease, and up to 40% of these patients relapse with metastatic disease, following nephrectomy. The 5-year survival for locoregional (stage III) disease is 53%, and 8% for metastatic disease. The standard management of high risk patients following nephrectomy has been surveillance, as there has been limited data demonstrating the benefit of adjuvant therapy in reducing the risk of relapse. Adjuvant therapy with immune check point inhibitors therapy is a potentially attractive treatment strategy for this patient group.

KEYNOTE-564 is a multicenter, double-blind, Phase III trial in which the benefit of adjuvant therapy with KEYTRUDA® was compared with placebo, following nephrectomy, in patients with clear cell RCC. In this study, 994 patients were randomized 1:1 to receive either KEYTRUDA® or placebo at least 12 weeks after surgery. Enrolled patients had histologically confirmed clear cell RCC, with Intermediate-High risk (pT2, Grade 4 or Sarcomatoid, N0 M0; or pT3, any Grade, N0 M0), High risk (pT4, any Grade, N0 M0; or pT any Stage, any Grade, N+ M0), or M1 with No Evidence of Disease after primary tumor and soft tissue metastases were completely resected, 1 year or less from nephrectomy. Treatment consisted of KEYTRUDA® 200 mg IV every 3 weeks (N=496) or placebo (N=498), every 3 weeks, for approximately 1 year. Both treatment groups were well balanced. The Primary end point of the trial was Disease Free Survival (DFS) assessment in all randomized patients and Secondary end points included Overall Survival (OS) and Safety. The median follow up at the time of data cut-off was 24.1 months.

At first prespecified interim analysis, the Primary endpoint of DFS was met. The median DFS was not reached for both treatment groups. KEYTRUDA® reduced the risk of recurrence or death by 32% compared with placebo, and this difference was statistically significant (HR=0.68; P=0.0010). The estimated DFS rate at 24 months was 77.3% with KEYTRUDA® versus 68.1% with placebo and this DFS benefit was consistent across subgroups. The estimated OS rate at 24 months was 96.6% with KEYTRUDA® versus 93.5% with placebo. Survival data are premature and additional follow up is planned for OS.

It was concluded that KEYTRUDA® demonstrated a statistically significant and clinically meaningful improvement in Disease Free Survival compared to placebo, in patients with Renal Cell Carcinoma, with a high risk of recurrence. The authors added that this is the first positive Phase III study with a checkpoint inhibitor, in adjuvant Renal Cell Carcinoma, and these practice changing results support KEYTRUDA® as a potential new standard of care for this patient group.

Pembrolizumab versus placebo as post-nephrectomy adjuvant therapy for patients with renal cell carcinoma: Randomized, double-blind, phase III KEYNOTE-564 study. Choueiri TK, Tomczak P, Park SH, et al. J Clin Oncol 2021; 39: (suppl 15; abstr LBA5) DOI: 10.1200/JCO.2021.39.15_suppl.LBA5

Adjuvant Treatment with OPDIVO® in Muscle-Invasive Urothelial Carcinoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2021, about 83,730 new cases of bladder cancer will be diagnosed and approximately 17,200 patients will die of the disease. Bladder cancer is the fourth most common cancer in men, but it is less common in women. A third of the patients initially present with locally invasive or metastatic disease. Even though radical cystectomy is considered the standard of care for patients with localized Muscle Invasive Bladder Cancer (MIBC), two large randomized trials and two meta-analysis have shown greater survival benefit with neoadjuvant Cisplatin-based combination chemotherapy for patients with MIBC, compared to surgery alone. However, not all patients with MIBC benefit from neoadjuvant Cisplatin based therapy, with only 25-50% attaining a pathologic response. More than 50% of patients with MIBC or regional lymph node involvement will develop metastatic disease following radical cystectomy. There is presently no clear consensus with regards to the routine use of adjuvant Cisplatin-based chemotherapy. Further, not all patients are eligible for adjuvant or neoadjuvant Cisplatin-based chemotherapy.

OPDIVO® (Nivolumab) is a fully human, immunoglobulin G4 monoclonal antibody that binds to the PD-1 receptor and blocks its interaction with PD-L1 and PD-L2. Blocking the Immune checkpoint proteins unleashes the T cells, resulting in T cell proliferation, activation and a therapeutic response. OPDIVO® has been shown to have antitumor activity in patients with metastatic urothelial carcinoma who had previously received platinum treatment, and is presently approved by the FDA for this patient group.

CheckMate 274 is a multicenter, double-blind, randomized, Phase III trial conducted to evaluate the efficacy and safety of adjuvant OPDIVO®, as compared with placebo, in patients with muscle-invasive urothelial carcinoma following radical surgery (with or without previous neoadjuvant Cisplatin-based combination chemotherapy). A total of 709 patients with muscle-invasive urothelial carcinoma who had undergone radical surgery were randomly assigned in a 1:1 ratio to receive either OPDIVO® 240 mg as a 30-minute IV infusion (N=353) or placebo (N=356), every 2 weeks for up to 1 year. To be eligible, patients must have had radical surgery (R0, with negative surgical margins), with or without neoadjuvant Cisplatin-based chemotherapy. Patients must have had pathological evidence of urothelial carcinoma (originating in the bladder, ureter or renal pelvis) with a high risk of recurrence defined as follows: pathological stage of pT3, pT4a, or pN+ and patients not eligible for or declined adjuvant Cisplatin-based combination chemotherapy, patients who had not received neoadjuvant Cisplatin-based chemotherapy, and pathological stage of ypT2 to ypT4a or ypN+ for patients who received neoadjuvant Cisplatin. Both treatment groups were well balanced and approximately 40% of patients in both treatment groups had PD-L1 expression of 1% or more and 43% of patients had received previous neoadjuvant cisplatin therapy. The two Primary endpoints were Disease Free Survival (DFS) among all the patients, and among patients with a tumor Programmed Death-Ligand 1 (PD-L1) expression level of 1% or more. Secondary endpoints included Survival free from recurrence outside the urothelial tract, Overall Survival and Safety. The median follow up was 20.9 months among patients who received OPDIVO® and 19.5 months among those who received placebo.

The median DFS was 20.8 months in the OPDIVO® group and 10.8 months in the placebo group in the intention-to-treat population, which was nearly double that with placebo. The percentage of patients who were alive and disease-free at 6 months was 74.9% with OPDIVO® and 60.3% with placebo, in the intention-to-treat population (HR for disease recurrence or death=0.70; P<0.001). Among patients with a PD-L1 expression level of 1% or more, the percentage who were alive and disease-free at 6 months was 74.5% with OPDIVO® and 55.7% with placebo, in the Intention-to-Treat Population (HR=0.55; P<0.001). The subgroup analysis showed that there was a higher probability of DFS with OPDIVO® than with placebo, and this benefit was observed regardless of nodal status, PD-L1 status, or use or nonuse of previous neoadjuvant Cisplatin-based chemotherapy.

The median survival free from recurrence outside the urothelial tract, in the intention-to-treat population, was 22.9 months among patients who received OPDIVO® and 13.7 months with placebo. The percentage of patients who were alive and free from recurrence outside the urothelial tract at 6 months was 77% with OPDIVO® and 62.7% with placebo (HR for recurrence outside the urothelial tract or death=0.72). Among those with a PD-L1 expression level of 1% or more, the percentage who were alive and free from recurrence outside the urothelial tract at 6 months was 75.3% and 56.7%, respectively (HR=0.55). Grade 3 or higher toxicities were noted in 17.9% of patients in the OPDIVO® group and 7.2% of patients in the placebo group.

It was concluded that among patients with high risk muscle-invasive urothelial carcinoma who had undergone radical surgery with curative intent, adjuvant treatment with OPDIVO® significantly improved Disease Free Survival, compared to placebo, in both intention-to-treat population and among patients with a PD-L1 expression level of 1% or more.

Adjuvant Nivolumab versus Placebo in Muscle-Invasive Urothelial Carcinoma. Bajorin DF, Witjes JA, Gschwend JE, et al. N Engl J Med 2021;384:2102-2114.