Author: RR

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

RR

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.

Long Term Results in Prostate Cancer Patients after Short Term Androgen Suppression and Radiation Dose Escalation

RR

SUMMARY: Prostate cancer is the most common cancer in American men with the exclusion of skin cancer, and 1 in 8 men will be diagnosed with prostate cancer during their lifetime. It is estimated that in the United States, about 248,530 new cases of prostate cancer will be diagnosed in 2021 and 34,130 men will die of the disease.

The development and progression of prostate cancer is driven by androgens. Androgen Deprivation Therapy (ADT) or testosterone suppression has therefore been the cornerstone of treatment of advanced prostate cancer, and is the first treatment intervention. Treatment options for patients with intermediate and high risk prostate cancer include Radical Prostatectomy and External Beam Radiation Therapy (EBRT), and long term outcomes are similar with both treatment approaches. For those receiving EBRT, based on several clinical trials, a minimum radiation dose of 74 Gy is recommended for both intermediate and high risk prostate cancer patients. Numerous studies have demonstrated the benefit of combining Androgen Suppression (AS) with EBRT as initial treatment of localized prostate cancer. However, the optimal Androgen Suppression treatment duration has remained unclear. For patients with intermediate risk disease, 4-6 months of neoadjuvant/adjuvant Androgen Suppression is considered sufficient, whereas 2-3 years of Androgen Suppression is recommended for localized high risk disease.

EORTC 22991 was launched in 2001 to assess the benefit of 6 months of concomitant and adjuvant Androgen Suppression added to EBRT in men with intermediate and limited high risk localized prostate cancer. Eligible patients had histologically confirmed prostate adenocarcinoma (T1b-T2b), with PSA 10-20 ng/mL and/or Gleason sum equals 7, or patients with PSA less than 10 ng/mL, Gleason sum less than 7 and cT2b disease. Patients had no involvement of pelvic lymph nodes (N0) as assessed by CT or MRI or laparoscopic surgery, no clinical evidence of metastatic spread (M0), no previous pelvic irradiation or radical prostatectomy and no previous hormonal therapy. Either, a PSA of more than 20 ng/mL, a Gleason sum more than 7, or a disease stage more than cT2c, was classified high-risk disease, and these patients were ineligible. Patients (N=819) were randomly assigned to receive EBRT or EBRT plus Androgen Suppression, started on day 1 of EBRT. The treating Radiation Therapy (RT) facilities centers selected the EBRT dose (70Gy, 74Gy, or 78 Gy) as well as RT technique (3D-Conformal Radiation Therapy or IMRT). Androgen Suppression consisted of two subcutaneous injections of 3-monthly depot LHRH analog (Goserelin) given the first day of RT and then 3 months later. To avoid Flare phenomenon, patients received antiandrogen agent, Bicalutamide 50 mg orally daily for one month, starting 1 week before the first LHRH injection. Of the 481 patients with intermediate-risk disease, 342 patients had EBRT planned at 74 Gy and 139 patients had EBRT planned at 78 Gy. Of the 481 patients, 245 were randomly assigned to EBRT plus Androgen Suppression (173 patients at 74 Gy, 72 patients at 78 Gy) and 236 patients to EBRT only (169 patients at 74 Gy, 67 patients at 78 Gy). The Primary endpoint was Event Free Survival (EFS). Secondary end points included clinical Disease Free Survival (DFS), Overall Survival (OS) and Distant Metastasis Free Survival (DMFS).

The authors in 2016 reported that after a median follow up of 7.2 years, 6-month concomitant and adjuvant AS combined with EBRT improved 5-year EFS and clinical DFS of intermediate and limited high risk prostate cancer patients, compared with those treated with EBRT alone. The researchers in this publication reported the updated results. Limited high risk patients, and all patients treated with EBRT at 70 Gy were excluded from this present analysis, because this is considered suboptimal according to the current practice standards.

At a median follow up of 12.2 years, it was confirmed that the addition of 6 months of concomitant and adjuvant Androgen Suppression significantly improved EFS (HR=0.53; P<0.001), clinical DFS (HR=0.67; P=0.008) and locoregional control (HR=0.44; P=0.013), compared to EBRT alone. These benefits were seen across age groups (less than 70 yrs versus 70 yrs or more), and were independent of radiation dose (74Gy versus 78 Gy). The observed improvements in DMFS and OS however did not reach statistical significance and this was expected, as the trial was not powered to detect difference in these endpoints.

It was concluded that External Beam Radiation Therapy at 74 or 78 Gy, along with 6 months of concomitant and adjuvant Androgen Suppression, significantly improves Event Free Survival and Disease Free Survival in intermediate risk prostate carcinoma. The authors added that these are the most robust data yet, from a randomized trial with long term follow up, addressing this important question.

Short Androgen Suppression and Radiation Dose Escalation in Prostate Cancer: 12-Year Results of EORTC Trial 22991 in Patients With Localized Intermediate-Risk Disease. Bolla M, Neven A, Maingon P, et al. DOI: 10.1200/JCO.21.00855 Journal of Clinical Oncology. Published online July 26, 2021.

Duration of Adjuvant Aromatase Inhibitor Therapy in Postmenopausal Breast Cancer

RR

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.

Luminal breast cancer is the most prevalent molecular subtype in postmenopausal females, accounting for over 70%. Despite substantial improvements in adjuvant therapies, the risk of disease recurrence continues indefinitely, with more than half the recurrences occurring after the first 5 years following diagnosis. Following initial adjuvant endocrine therapy with Tamoxifen for 5 years, the addition of extended adjuvant therapy has resulted in 40% longer Disease Free Survival (DFS), when compared to placebo or no extended therapy. However the benefit of extending adjuvant Aromatase Inhibitor therapy for 5 years beyond the initial 5-year duration regimen is less well established. Further, the most effective duration of such extended adjuvant endocrine therapy remains unclear. Added to this dilemma are the side effects associated with Aromatase Inhibitor therapy including hot flushes, arthralgia, and bone pain, as well as treatment-induced osteoporosis, which can have a significant impact on patient’s quality of life. Researchers in the Secondary Adjuvant Long-Term Study with Arimidex [Anastrozole] (SALSA) prospectively investigated whether an additional 2 years or 5 years of Anastrozole therapy would result in better outcomes, following the initial 5 years of endocrine therapy, in postmenopausal women with Hormone Receptor-positive breast cancer.

The authors conducted a prospective, multicenter, randomized, Phase III trial, which included 3,470 eligible postmenopausal women with Stages I, II or III early stage breast cancer with no evidence of recurrence. Enrolled patients had invasive Hormone Receptor-positive breast cancer, and had received 5 years (plus or minus 12 months) of adjuvant endocrine therapy with Tamoxifen, Aromatase Inhibitors, or both sequentially, up until 12 months before randomization. Patients were randomly assigned 1:1 to receive Anastrozole 1 mg, orally daily, for either 2 additional years for a total of 7 years (N=1732) or 5 additional years for a total of 10 years (N=1738). The two treatment groups were well balanced. The median age at the time of randomization was 64 years, 72% of patients had tumors that were smaller than 2 cm, 66% had node-negative disease, and 19% had high-grade tumors. Stratification criteria included pathological tumor stage, pathological node stage, primary adjuvant endocrine therapy and adjuvant chemotherapy.

The primary analysis included all the patients who were still participating in the study (N=3208), including 1,603 in the 2-year group versus 1,605 in the 5-year group. In the primary analysis population of 3208 patients, 51% had received Tamoxifen alone for the initial 5 years, 7.3% had received an Aromatase Inhibitor alone, and 41.7% had received an Aromatase Inhibitor in combination with Tamoxifen. The Primary end point was Disease Free Survival (DFS). Secondary end points were Overall Survival (OS), contralateral breast cancer, second primary cancer, and clinical bone fracture. The median follow-up after randomization was 118 months.

The researchers observed no difference in DFS with 2 versus 5 additional years of adjuvant endocrine therapy with Anastrozole. The DFS 10 years since randomization was 73.6% in the 2-year group versus 73.9% in the 5-year group (HR=0.99; P=0.90). Contralateral breast cancer occurred in 2.2% versus 2.1% of patients (HR= 1.15), and local recurrence occurred in 3% versus 2.4% in the 2 year and 5 year groups, respectively. There was no difference noted for Overall Survival at 8 years between the two treatment groups (87.5% in the 2-year group and 87.3% in the 5-year group, HR for death from any cause=1.02). The risk of clinical bone fracture however was higher in the 5-year group than in the 2-year group (HR=1.35).

It was concluded from this study that in postmenopausal women with Hormone Receptor positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending endocrine therapy with an Aromatase Inhibitor by an additional 5 years provided no benefit over a 2-year extension, but was associated with a greater risk of bone fracture.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer. Gnant M, Fitzal F, Rinnerthaler G, et al. N Engl J Med 2021; 385:395-405.

CALQUENCE® May Be Safer Than IMBRUVICA® in CLL Patients

RR

SUMMARY: The American Cancer Society estimates that for 2021, about 21,250 new cases of Chronic Lymphocytic Leukemia (CLL) will be diagnosed in the US and 4320 patients will die of the disease. CLL accounts for about one-quarter of the new cases of leukemia. The average age of patients diagnosed with CLL is around 70 years, and is rarely seen in people under age 40, and is extremely rare in children.

Bruton’s Tyrosine Kinase (BTK) is a member of the Tec family of kinases, downstream of the B-cell receptor and is predominantly expressed in B-cells. It is a mediator of B-cell receptor signaling in normal and transformed B-cells. Ibrutinib (IMBRUVICA®) is an oral, irreversible inhibitor of BTK and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Ibrutinib demonstrated survival benefits when compared to chemoimmunotherapy both in previously untreated (RESONATE-2), as well as relapsed (RESONATE) CLL patients. However, toxicities leading to Ibrutinib discontinuation occurred in a significant number of patients, and Atrial Fibrillation was noted in 11-16% of patients and hypertension rates were between 20-26%.BCR-Signal-Pathways-and-MOA-of-New-Agents

Acalabrutinib (CALQUENCE®) is a highly selective, next-generation, oral, covalent, irreversible Bruton Tyrosine Kinase (BTK) inhibitor with minimal activity against other kinases. Acalabrutinib has a shorter plasma half-life and inhibits cell proliferation and promotes programmed cell death (Apoptosis) by blocking B-cell activation and signaling. Acalabrutinib demonstrated superior Progression Free Survival (PFS) versus chemoimmunotherapy in patients with previously untreated (ELEVATE-TN), as well as Relapsed or Refractory (ASCEND) CLL. Acalabrutinib was better tolerated with lower rates of treatment discontinuation due to adverse events, and also demonstrated efficacy and tolerability in Ibrutinib-intolerant patients with CLL.

ELEVATE-RR is a prospective, randomized, multicenter, open-label, noninferiority, Phase III study, conducted to compare the efficacy and safety of Acalabrutinib with Ibrutinib, in patients with previously treated CLL, and to test the hypothesis that Acalabrutinib was noninferior to Ibrutinib in PFS, with improved tolerability. This trial included 533 previously treated patients with CLL who were randomly assigned 1:1 to receive Acalabrutinib 100 mg orally twice daily (N=268) or Ibrutinib 420 mg orally once daily (N=265). Treatment was continued until disease progression or unacceptable toxicity, and crossover between treatment groups was not permitted. Enrolled patients had centrally confirmed del(17)(p13.1) or del(11)(q22.3) and patients were stratified based on cytogenetics, ECOG Performance Status and number of prior therapies. Patients with significant cardiovascular disease, concomitant vitamin K antagonist treatment, prior BTK or BCL2 inhibitor treatment, or those requiring treatment with Proton-Pump Inhibitors were excluded. The Primary end point was Independent Review Committee-assessed noninferiority of Progression Free Survival (PFS). Secondary end points included incidences of any grade Atrial Fibrillation, Grade 3 or higher infections, Richter transformation and Overall Survival (OS)

After a median follow-up of 40.9 months, Acalabrutinib was determined to be noninferior to Ibrutinib with a median PFS of 38.4 months in both arms (HR=1.00), thus meeting the noninferiority criterion. Any-grade Atrial Fibrillation/Atrial Flutter incidence was significantly lower with Acalabrutinib compared to Ibrutinib (9.4% versus 16.0%; P=0.02). Bleeding events were less frequent with Acalabrutinib (38%) versus Ibrutinib (51.3%). The median Overall Survival was not reached in either treatment groups. Treatment was discontinued due to adverse events in 14.7% of Acalabrutinib-treated patients and 21.3% of Ibrutinib-treated patients.

The authors concluded that this is the first direct comparison of Ibrutinib with Acalabrutinib in CLL and Acalabrutinib demonstrated noninferior PFS and provides improved safety, with fewer Atrial Fibrillation events and discontinuations because of adverse events, when compared to Ibrutinib.

Acalabrutinib Versus Ibrutinib in Previously Treated Chronic Lymphocytic Leukemia: Results of the First Randomized Phase III Trial. Byrd JC, Hillmen P, Ghia P, et al. DOI: 10.1200/JCO.21.01210 Journal of Clinical Oncology. Published online July 26, 2021.

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

RR

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.

No Difference in Overall Survival between R-CHOP and R-EPOCH in Advanced MYC-Rearranged, Double Hit, or Triple Hit DLBCL

RR

SUMMARY: The American Cancer Society estimates that in 2021, about 81,560 people will be diagnosed with Non Hodgkin Lymphoma (NHL) in the United States and about 20,720 individuals will die of this disease. Diffuse Large B-Cell Lymphoma (DLBCL) is the most common of the aggressive Non-Hodgkin lymphoma’s in the United States, and the incidence has steadily increased 3-4% each year. More than half of patients are 65 or older at the time of diagnosis and the incidence is likely to increase with the aging of the American population. The etiology of Diffuse Large B-Cell Lymphoma is unknown. Contributing risk factors include immunosuppression (AIDS, transplantation setting, autoimmune diseases), UltraViolet radiation, pesticides, hair dyes, and diet.

DLBCL is a neoplasm of large B cells and the most common chromosome abnormality involves alterations of the BCL-6 gene at the 3q27 locus, which is critical for germinal center formation. Two major molecular subtypes of DLBCL arising from different genetic mechanisms have been identified, using gene expression profiling: Germinal Center B-Cell-like (GCB) and Activated B-Cell-like (ABC). Patients in the GCB subgroup have a higher five year survival rate, independent of clinical IPI (International Prognostic Index) risk score, whereas patients in the ABC subgroup have a significantly worse outcome. Regardless, R-CHOP regimen (RITUXAN®-Rituximab, Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone), given every 21 days, for 6 cycles, delivered with curative intent, is the current standard of care for patients of all ages, with newly diagnosed DLBCL, regardless of molecular subtype.

MYC is a proto-oncogene and transcription factor and is rearranged in up to 15% of patients with DLBCL. MYC activation is an important adverse prognostic feature and results in aggressive cellular proliferation associated with DNA replication and transcription, protein synthesis, and altered cellular metabolism. BCL2 is a potent anti-apoptotic factor and dual rearrangement of MYC with BCL2 and less commonly, BCL6, occurs in 5% to 7% of cases of DLBCL. Further, both MYC and BCL2 proteins can be overexpressed, either with or without the underlying respective chromosomal rearrangements, in about 30% of patients with DLBCL.

The combination of MYC activation and anti-apoptosis (BCL2) results in a clinically aggressive phenotype called Double-Hit Lymphoma (DHL), which is associated with poor long-term survival after standard chemoimmunotherapy. Similar poor outcomes have been noted in patients with MYC activation along with BCL2, and BCL6 rearrangement, known as Triple Hit Lymphoma (THL).

The long term survival for patients with DHL or THL treated with R-CHOP is less than 20%. Patients are therefore often treated with more intensive regimens such as R-EPOCH (Rituximab, Etoposide, Prednisone, Vincristine, Cyclophosphamide, and Doxorubicin), although prospective data supporting the use of one regimen over another are limited.

The present study was conducted to compare Overall Survival of patients with advanced stage MYC-rearranged DLBCL and DHL/THL who were treated with R-CHOP versus R-EPOCH. The researchers analyzed de-identified data from a nationwide Flatiron Health Electronic Health Record database on patients diagnosed with DLBCL at 280 cancer clinics in the U.S. between January 2011, and June 2020. Among 6,809 total DLBCL patients, 443 (6.5%) were found to have MYC-rearranged DLBCL. Among these, 218 patients had advanced Stage (III/IV) disease at diagnosis, 64 patients had MYC-rearranged DLBCL only, and 117 and 37 had DHL or THL, respectively. Among those patients with DHL/THL, 43 patients (median age 73 years) were treated with R-CHOP and 111 patients (median age 67 years) received R-EPOCH. Among those with MYC-rearranged DLBCL only, 36 received R-CHOP (median age 70 years), and 28 received R-EPOCH (median age 61 years).

The investigators found no difference in the 4-year Overall Survival rates between the R-CHOP and R-EPOCH treatment arms in different patient groups. Among the MYC-rearranged DLBCL cohort, the 4-year Overall Survival rates were 32.8% with R-CHOP versus 30.4% with R-EPOCH regimens. In the DHL/THL group of patients, the 4-year Overall Survival rates were 54.5% with R-CHOP versus 49.6% with R-EPOCH. Among DHL/THL patient group, 89% of deaths occurred within 2 years of diagnosis, and among MYC- rearranged DLBCL, 78% of deaths occurred in the first 2 years. ECOG Performance Status score of 2 or more and elevated LDH were independently associated with worse mortality for these patients, by multivariate analysis.

It was concluded from this analysis that Overall Survival outcomes were similar between patients with MYC-rearranged Diffuse Large B-Cell Lymphoma and Double-Hit lymphoma/Triple-Hit Lymphoma (THL) who were treated with R-CHOP versus R-EPOCH. The authors suggested that further studies are needed to better risk stratify patients with DLBCL, for optimizing outcomes.

No difference in overall survival between R-CHOP and R-EPOCH among patients with advanced stage MYC-rearranged, double hit, or triple hit diffuse large B-cell lymphoma. Magnusson T, Narkhede M, Mehta A, et al. Abstract #S224. Presented at the EHA2021 Virtual Congress, June 9-17, 2021.

De-escalated Neoadjuvant Dual Anti-HER2 Blockade and Survival Outcomes in Early Breast Cancer

RR

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.

The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.

Trastuzumab is a humanized monoclonal antibody targeting HER2. It binds to the extracellular subdomain IV of the receptor and disrupts ligand independent HER2 downstream cell signaling pathways. Pertuzumab is a recombinant, humanized, monoclonal antibody that binds to the HER2 subdomain II and blocks ligand dependent HER2 heterodimerization with other HER receptors. Thus Trastuzumab along with Pertuzumab provide a more comprehensive blockade of HER2 driven signaling pathways. Dual HER2 blockade with Trastuzumab and Pertuzumab, given along with chemotherapy (with or without endocrine therapy), as first line treatment, in HER2 positive metastatic breast cancer patients, was shown to significantly improve Progression Free Survival (PFS) as well as Overall Survival (OS). The superior benefit with dual HER2 blockade has been attributed to differing mechanisms of action and synergistic interaction between HER2 targeted therapies.

Pathological Complete Response (pCR) after neoadjuvant therapy has strong prognostic significance in HER2+ breast cancer and pCR rates in HER2+/HR− tumors exceed those in HER2+/HR+ tumors, and this in turn correlates with superior Event Free Survival. The FDA approved anti-HER2 dual blockade with Pertuzumab and Trastuzumab, given along with chemotherapy for the neoadjuvant treatment of patients with HER2-positive, locally advanced, inflammatory, or early stage breast cancer, based on the NeoSphere trial, and for metastatic disease based on positive survival results in the CLEOPATRA trial. The role of chemotherapy free anti-HER2 dual blockade however has remained unclear.

ADAPT (Adjuvant Dynamic marker-Adjusted Personalized Therapy) is one of the first new generation neoadjuvant trials addressing individualization of neoadjuvant therapy in early breast cancer and was initiated to establish early predictive surrogate markers such as Ki-67 for therapy response following a short course of induction treatment, in order to maximally individualize therapy and avoid unnecessary toxicity by ineffective treatment. West German Study Group (WSG)-ADAPT trials were designed separately for HER2+/HR− and HER2+/HR+ breast cancer sub groups as they are biologically distinct, with HER2+/HR− subgroup being more aggressive but also more chemosensitive, as evidenced by response to neoadjuvant therapy and subsequent survival rates.

The WSG-ADAPT HER2+/HR- trial is a multicenter, prospective Phase II/III trial which assessed whether patients with strong early response to dual HER2 blockade alone might achieve pathological Complete Response (pCR), comparable to that of patients receiving dual HER2 blockade and chemotherapy. In this study, 134 patients (N=134) with cT1-cT4c, cN0-3 HER2+/HR- early breast cancer were randomly assigned 5:2 to either receive Trastuzumab and Pertuzumab alone in arm A or with added Paclitaxel in arm B. In Arm A, patients (N = 92) received a loading dose of Trastuzumab 8 mg/kg IV and then 6 mg/kg three weekly along with Pertuzumab 840 mg loading dose and then 420 mg 3 weekly, for a total of 12 weeks. In Arm B (N=42), in addition to Trastuzumab and Pertuzumab as administered in Arm A, Paclitaxel 80 mg/m2 IV was given every week for 12 weeks. Eligible patients had tumors that were ER and PR negative (less than 1%) and HER2-positive (IHC 2+ and FISH positive or IHC 3+ positive). After neoadjuvant treatment, surgery or histological confirmation of non-pCR by core needle biopsy within 3 weeks was mandatory. Pathological Complete Response (pCR) at surgery was defined as no invasive tumor residuals in breast and lymph nodes.

The Primary endpoint was pCR and omission of further chemotherapy was allowed in patients with pCR, and Secondary endpoints included 5 year distant Disease Free Survival (DFS) and Overall Survival (OS). An important objective of this study was to identify an early-responder population with regard to pCR after Trastuzumab and Pertuzumab alone treatment, which is strongly associated with long-term prognosis particularly in HER2+/HR− breast cancer, and assess whether this population might be spared neoadjuvant chemotherapy. Early response was defined as proliferation decrease 30% or more of Ki-67 (compared to baseline) or low cellularity (less than 500 invasive tumor cells) in the 3-week biopsy. The trial was stopped early due to the observed pCR superiority in the dual HER2 blockade plus chemotherapy group. The authors previously reported that the pCR rate in the dual HER2 blockade plus chemotherapy group was 90.5%, compared with 36.3% in the dual HER2 blockade alone. The authors have now reported the first survival data.

After a median follow-up of 5 years, there were no significant differences in DFS, distant DFS and OS between the 2 study groups. The invasive DFS rate was 98% with dual HER2 blockade and chemotherapy and 87% with dual HER2 blockade alone (HR=0.32; P=0.144). Distant DFS was 98% and 92%, respectively (HR=0.34; P=0.313) and Overall Survival was 98% and 94% (HR=0.41; P=0.422). The achievement of a pathologic Complete Response following 12 weeks of treatment was strongly associated with improved invasive DFS at 5 years, irrespective of study group (98.5% versus 82%; HR=0.14; P=0.011). The researchers also examined the benefit of neoadjuvant chemotherapy-free dual HER2 blockade alone and noted that no pCR was observed in patients with low HER2 expression (IHC 1+ or 2+ and FISH positive) and/or basal-like subtype as detected by PAM50 assay. In the total study population, low HER2 expression and/or no early response was strongly associated with worse distant DFS (P=0.029) and invasive DFS (P=0.068).

The authors concluded that excellent pCR and Survival can be accomplished in patients treated by de-escalated 12-week neoadjuvant weekly Paclitaxel and dual HER2 blockade, irrespective of additional chemotherapy use. They added that early pCR after only 12 weeks of neoadjuvant Paclitaxel plus dual HER2 blockade was strongly associated with improved outcome, and may thus serve as a predictive clinical marker for further treatment de-escalation.

De-escalated neoadjuvant pertuzumab+trastuzumab with or without paclitaxel weekly in HR-/HER2+ early breast cancer: ADAPT-HR-/HER2+ biomarker and survival results. Harbeck N, Gluz O, Christgen M, et al. J Clin Oncol 39, 2021 (suppl 15; abstr 503)

KEYTRUDA® Versus ADCETRIS® in Relapsed or Refractory Classical Hodgkin Lymphoma

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SUMMARY: The American Cancer Society estimates that in the United States for 2021, about 8,830 new cases of Hodgkin Lymphoma will be diagnosed and about 960 patients will die of the disease. Hodgkin lymphoma is most common in early adulthood and the average age of people when they are diagnosed is 39 years, although the risk of Hodgkin lymphoma rises again in late adulthood after age 55.

Hodgkin Lymphoma is classified into two main groups – Classical Hodgkin Lymphomas and Nodular Lymphocyte Predominant type, by the World Health Organization. The Classical Hodgkin Lymphomas include Nodular sclerosing, Mixed cellularity, Lymphocyte rich, Lymphocyte depleted subtypes and accounts for approximately 10% of all malignant lymphomas. Nodular sclerosis Hodgkin Lymphoma histology, accounts for approximately 80% of Hodgkin lymphoma cases in older children and adolescents in the United States. Classical Hodgkin Lymphoma is a malignancy of primarily B lymphocytes and is characterized by the presence of large mononucleated Hodgkin (H) and giant multinucleated Reed-Sternberg (RS) cells, collectively known as Hodgkin and Reed-Sternberg cells (HRS).The HRS cells in turn recruit an abundance of ineffective inflammatory cells and infiltrates of immune cells.WHO-Classification-of-Hodgkin-Lymphoma

Preclinical studies suggest that HRS cells evade immune detection by exploiting the pathways associated with immune checkpoint, Programmed Death-1 (PD-1) and its ligands PD-L. Classical Hodgkin Lymphoma is an excellent example of how the tumor microenvironment influences cancer cells to proliferate and survive. The most common genetic abnormality in Nodular sclerosis subtype of Hodgkin lymphoma is the selective amplification of genes on the short arm of chromosome 9 (9p24.1) which includes JAK-2, with resulting increased expression of PD-1 ligands such as PDL1 and PDL2 on HRS cells, as well as increased JAK-STAT activity, essential for the proliferation and survival of Hodgkin Reed-Sternberg (HRS) cells. Infection with Epstein–Barr virus (EBV) similarly can increase the expression of PDL1 and PDL2 in EBV-positive Hodgkin lymphomas. It would therefore seem logical to block or inhibit immune check point PD-1 rather than both its ligands, PDL1 and PDL2.

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. 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, thereby undoing PD-1 pathway-mediated inhibition of the immune response and unleashing the tumor-specific effector T cells. ADCETRIS® (Brentuximab vedotin) is an Antibody-Drug Conjugate (ADC) that targets CD30, which is a surface antigen, expressed on Reed-Sternberg cells, in patients with Classical Hodgkin Lymphoma. This ADC consists of an anti-CD30 monoclonal antibody linked to MonoMethyl Auristatin E (MMAE), an antimicrotubule agent. Upon binding to the CD30 molecule on the cancer cells, MMAE is released into the cancer cell, resulting in cell death.

Patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL) are often treated with salvage chemotherapy and Autologous Stem Cell Transplant (ASCT). There are however no standard interventions for patients ineligible for ASCT due to chemo-refractory disease, comorbidity, or advanced stage. PD-1 inhibitor such as KEYTRUDA® as well as ADCETRIS® has shown antitumor activity in R/R cHL.

KEYNOTE-204 is a randomized, international, open-label, Phase III study in which KEYTRUDA® was compared with ADCETRIS® among patients with Relapsed or Refractory Classical Hodgkin Lymphoma (R/R cHL). In this study, 304 patients were randomized 1:1, and 300 patients were treated with either KEYTRUDA® 200 mg IV every 3 weeks (N=148) or ADCETRIS® 1.8 mg/kg IV every 3 weeks (N=152). Enrolled patients were post-Autologous Stem Cell Transplant (ASCT) or ineligible for ASCT, had measurable disease, and had an ECOG Performance Status of 0 or 1. Both ADCETRIS®-naive and ADCETRIS®-exposed patients were eligible. Patients were stratified by prior ASCT and status after first-line therapy (primary refractory versus relapsed less than 12 months versus relapsed 12 months or more after end of first-line therapy). The Primary endpoints were Progression Free Survival (PFS) per Blinded Independent Central Review (BICR) and Overall Survival (OS). Secondary endpoints included PFS per investigator review, Objective Response Rate (ORR), and Safety. The authors presented results from the second interim analysis, after a median follow up was 25.7 months.

The median PFS was 13.2 months in the KEYTRUDA® group compared with 8.3 months in the ADCETRIS® group (HR=0.65, P=0.0027), suggesting an increase in PFS of 4.9 months with KEYTRUDA®. This benefit with KEYTRUDA® was observed in all subgroups tested, including those ineligible for ASCT (HR=0.61), those with primary refractory disease (HR=0.52), those who were ADCETRIS® naïve (HR=0.67), as well as those who received prior treatment with ADCETRIS® (HR=0.34). The ORR was 65.6% versus 54.2% and this was considered non significant (P=0.023). The median Duration of Response was 20.7 months versus 13.8 months, in the KEYTRUDA® and ADCETRIS® groups respectively, with 62% versus 50% of responses lasting for at least 12 months. Treatment Related Adverse Events were similar in both treatment groups and Grade 3-5 toxicities occurred in 19.6% of patients treated with KEYTRUDA® and 25% of patients treated with ADCETRIS®.

It was concluded that among patients with Relapsed/Refractory Classical Hodgkin Lymphoma, KEYTRUDA® was superior to ADCETRIS®, with a statistically significant and clinically meaningful improvement in PFS across all subgroups tested, and with safety consistent with previous reports. The authors added that KEYTRUDA® should be considered the preferred treatment option and the new standard of care in this patient population. Further, KEYTRUDA® can be tolerated for extended periods as it is not associated with neurotoxicity.

Pembrolizumab versus brentuximab vedotin in relapsed or refractory classical Hodgkin lymphoma (KEYNOTE-204): an interim analysis of a multicentre, randomised, open-label, phase 3 study. Kuruvilla J, Ramchandren R, Santoro A, et al. Lancet Oncol. 2021;22:512-524.

Circulating Tumor DNA as a Biomarker in Advanced Colorectal Cancer

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SUMMARY: Colorectal Cancer (CRC) is the third leading cause of cancer-related deaths in men and women in the United States. The American Cancer Society estimates that approximately 149,500 new cases of CRC will be diagnosed in the United States in 2021 and about 52,980 patients will die of the disease. The lifetime risk of developing CRC is about 1 in 23.

Cell-free DNA (cfDNA) refers to DNA molecules that circulate in the bloodstream after cell apoptosis or necrosis. A specific portion of cfDNA that originates from tumor cells is referred to as circulating tumor DNA (ctDNA), which can be detected in the cell-free component of peripheral blood samples in almost all patients with advanced solid tumors, including advanced colorectal cancer. ctDNA is a valuable biomarker and allows early detection of relapse.Liquid-Biopsy

Patients with metastatic colorectal cancer are often treated with chemotherapy and sometimes surgical intervention. Treatment decisions are based on clinical and pathological characteristics such as tumor size and number of metastatic lesions, which is an arbitrary method of treatment stratification. ctDNA can be a potential biomarker of tumor biology and disease trajectory, and can be an important clinical decision tool. The present study was conducted to systematically review ctDNA in Stage IV colorectal cancer, and assess its potential role as a prospective biomarker, to guide treatment decisions.

This meta-analysis included 2823 patients from 28 studies. ctDNA was detectable in 80-90% of patients with metastatic CRC prior to treatment. This analysis found a strong correlation between detectable ctDNA after treatment with surgery or chemotherapy and Overall Survival (HR=2.2; P<0.00001), as well as Progression Free Survival (HR= 3.15; P<0.00001). Further, ctDNA as an early biomarker was able to consistently predict long term prognosis in patients with unresectable disease, with changes after one cycle of systemic therapy demonstrating prognostic value. In patients with surgically resectable disease treated with curative intent, detection of ctDNA offered a lead time of 10 months, over radiological recurrence.

The authors concluded from this analysis that ctDNA is detectable in the majority of resectable and unresectable patients with metastatic colorectal cancer, and the presence of ctDNA is clearly associated with shorter Overall Survival. ctDNA may serve as an early biomarker and dynamic assessment of ctDNA may predict treatment efficacy.

Circulating tumour DNA as a biomarker in resectable and irresectable stage IV colorectal cancer; a systematic review and meta-analysis. Jones RP, Pugh SA, Graham J, et al. Eur J Cancer. 2021 Feb;144:368-381. doi: 10.1016/j.ejca.2020.11.025. Epub 2021 Jan 7.

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)