The FDA on October 4, 2018 approved HEMLIBRA® injection for prophylaxis to prevent or reduce the frequency of bleeding episodes in adult and pediatric patients (ages newborn and older) with Hemophilia A (congenital Factor VIII deficiency) with or without Factor VIII (FVIII) inhibitors. HEMLIBRA® is a product of Genentech, Inc.
Author: RR
LIBTAYO® (Cemiplimab-rwlc)
The FDA on September 28, 2018 approved LIBTAYO® for patients with metastatic Cutaneous Squamous Cell Carcinoma (CSCC) or locally advanced CSCC, who are not candidates for curative surgery or curative radiation. LIBTAYO® is a product of Regeneron Pharmaceuticals Inc.
HER2 Testing in Breast Cancer American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update
HER2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update
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 266,120 new cases of invasive breast cancer will be diagnosed in 2018 and about 40,920 women will die of the disease. 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. HERCEPTIN® (Trastuzumab) is a humanized monoclonal antibody targeting HER2, and adjuvant and neoadjuvant chemotherapy given along with HERCEPTIN® reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage as well as advanced metastatic breast cancer. Since the approval of HERCEPTIN®, several other HER2-targeted therapies have become available. Accurate determination of HER2 status of the tumor is therefore essential for patients with invasive breast cancer, to ensure that those most likely to benefit are offered a HER2-targeted therapy and those who are unlikely to benefit can avoid toxicities as well as financial burden associated with those drugs.
Laboratory testing for HER2 status in patients with breast cancer in the US is performed according to guidelines developed by an Expert panel of members of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP). The ASCO/CAP guidelines were first published in 2007 and were updated in 2013. The Expert panel in 2018 developed and issued a focused update of the clinical practice guideline on HER2 testing in breast cancer. This new information made available since the previous update in 2013 addresses uncommon clinical scenarios and improves clarity, particularly for infrequent HER2 test results that are of uncertain biologic or clinical significance. There are currently two approved methods for determining HER2 status in breast cancer: ImmunoHistoChemistry (IHC) and In Situ Hybridization (ISH). This new guideline enables the Health Care Provider, how to best evaluate some of the less common patterns in HER2 results emerging from ISH.
Guideline Questions
1) What is the most appropriate definition for ImmunoHistoChemistry (IHC) 2+ (IHC equivocal)?
2) Must Human Epidermal growth factor Receptor 2 (HER2) testing be repeated on a surgical specimen if the initially tested core biopsy is negative?
3) What is the optimal algorithm for less common patterns observed when performing dual-probe In Situ Hybridization (ISH) HER2 testing in breast cancer?
Updated Recommendations
1) Immunohistochemistry (IHC) 2+ is defined as invasive breast cancer with weak to moderate complete membrane staining observed in more than 10% of tumor cells.
2) If the initial HER2 test result in a core needle biopsy specimen of a primary breast cancer is negative, a new HER2 test may (not “must”) be ordered on the excision specimen based on some criteria (such as tumor grade 3).
3)The HER2 testing algorithm now includes more rigorous interpretation criteria of the less common patterns that can be seen in about 5% of all cases when HER2 status in breast cancer is evaluated using a dual-probe ISH assay. These scenarios are described as ISH group 2 (HER2/Chromosome Enumeration Probe 17 [CEP17] ratio of 2.0 or more; average HER2 copy number less than 4.0 signals per cell), ISH group 3 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 6.0 or more signals per cell), and ISH group 4 (HER2/CEP17 ratio less than 2.0; average HER2 copy number 4.0 or more and less than 6.0 signals per cell). These cases, described as ISH groups 2-4, should now be assessed using a diagnostic approach that includes a concomitant review of the IHC (ImmunoHistoChemistry) test, which will help the pathologist make a final determination of the tumor specimen as HER2 positive or negative.
4)The Expert Panel also preferentially recommends the use of dual-probe instead of single-probe ISH assays, but it recognizes that several single-probe ISH assays have regulatory approval in many parts of the world.
Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Focused Update. Wolff AC, Hammond EH, Allison KH, et al. J Clin Oncol 2018; 36:2105-2122.
Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors
Dual Inhibition Improves Outcomes for Patients with BRAF-Mutated Colorectal Tumors
SUMMARY: ColoRectal Cancer (CRC) is the third most common cancer diagnosed in both men and women in the United States. The American Cancer Society estimates that approximately 135,430 new cases of ColoRectal Cancer will be diagnosed in the United States in 2017 and over 50,260 patients are expected to die of the disease. The DNA MisMatchRepair (MMR) system is responsible for molecular surveillance and works as an editing tool that identifies errors within the microsatellite regions of DNA and removes them. Defective MMR system leads to MSI (Micro Satellite Instability) and hypermutation, triggering an enhanced antitumor immune response. MSI (Micro Satellite Instability) is therefore a hallmark of defective/deficient DNA MisMatchRepair (MMR) system and occurs in 15% of all colorectal cancers. Defective MisMatchRepair can be a sporadic or heritable event. Approximately 65% of the MSI tumors are sporadic and MSI-High tumors tend to have better outcomes. Patients with stage IV colorectal cancer are now routinely analyzed for extended RAS and BRAF mutations. KRAS mutations are predictive of resistance to Epidermal Growth Factor Receptor (EGFR) targeted therapy. Approximately 5-10% of all metastatic CRC tumors present with BRAF V600 mutations and BRAF V600 is recognized as a marker of poor prognosis in this patient group. These patients tend to have aggressive disease with a higher rate of peritoneal metastasis and do not respond well to standard treatment intervention. Approximately 25% of the BRAF-mutated population in the metastatic setting has MSI-High tumors, but MSI-High status does not confer protection to this patient group.
The Mitogen-Activated Protein Kinase pathway (MAPK pathway) is an important signaling pathway which enables the cell to respond to external stimuli. This pathway plays a dual role, regulating cytokine production and participating in cytokine dependent signaling cascade. The MAPK pathway of interest is the RAS-RAF-MEK-ERK pathway. The RAF family of kinases includes ARAF, BRAF and CRAF signaling molecules.BRAF is a very important intermediary of the RAS-RAF-MEK-ERK pathway. The BRAF V600 mutations results in constitutive activation of the MAP kinase pathway. Inhibiting BRAF can transiently reduce MAP kinase signaling. However, this can result in feedback upregulation of EGFR signaling pathway, which can then reactivate the MAP kinase pathway. This aberrant signaling can be blocked by dual inhibition of both BRAF and EGFR.
ZELBORAF® (Vemurafenib), is a selective oral inhibitor of mutated BRAF whereas ERBITUX® (Cetuximab) is a monoclonal antibody targeting Epidermal Growth Factor Receptor (EGFR). Preclinical studies have shown that adding CAMPTOSAR® (Irinotecan) to ZELBORAF® and ERBITUX®, in patients with refractory BRAF V600E metastatic CRC, led to a durable responses and this combination was safe and tolerable. However, both single agent ZELBORAF® and ERBITUX® were shown to have limited activity in this patient group.
Based on this scientific rationale, a phase II trial was conducted (SWOG 1406), in which 106 metastatic ColoRectal Cancer patients, with mutations in BRAF V600 and extended RAS wild-type, were enrolled. Patients were randomized to receive CAMPTOSAR® 180 mg/m2 IV every 14 days and ERBITUX® 500 mg/m2 IV every 14 days, with or without ZELBORAF® 960 mg orally twice daily. The median age was 62 years and about 50% of patients had received 1 prior regimen for metastatic or locally advanced unresectable metastatic CRC, and 39% had received prior treatment with CAMPTOSAR® . Prior therapy with anti-EGFR agent or RAF or MEK inhibitors was not allowed. Crossover from the control arm to the experimental group was allowed, after documented disease progression. The primary endpoint was Progression Free Survival.
The median Progression Free Survival was 4.4 months with the triplet, versus 2.0 months with CAMPTOSAR® plus ERBITUX® (HR=0.42; P =0.0002). The response rate was 16% versus 4%, and the Disease Control Rate was 67% versus 22% (P =0.001), with a higher Duration of Response with the addition of ZELBORAF® to CAMPTOSAR® and ERBITUX® (Triplet). Approximately 50% of the patients in the control group crossed over to the experimental group at the time of disease progression. Overall Survival data and efficacy at cross-over, data, remain immature. Patients in the experimental group (Triplet group) experienced more grade 3/4 toxicities such as neutropenia, anemia and nausea, and this increase was attributed to increased duration of exposure to therapy.
The authors concluded that the addition of ZELBORAF® to the combination of CAMPTOSAR® and ERBITUX® resulted in a 58% reduction in the risk of disease progression and a higher Disease Control Rate, suggesting that simultaneous EGFR and BRAF inhibition (Dual Inhibition) is effective in BRAF V600 mutated ColoRectal Cancer. Subgroup analysis will examine the role of CAMPTOSAR® pre-treatment and the outcomes of patients based on tumor MicroSatellite Instability. Randomized trial of irinotecan and cetuximab with or without vemurafenib in BRAF-mutant metastatic colorectal cancer (SWOG 1406). Kopetz S, McDonough SL, Morris VK, et al. J Clin Oncol 35, 2017 (suppl 4S; abstract 520)
VIZIMPRO® (Dacomitinib)
The FDA on September 27, 2018 approved VIZIMPRO® for the first-line treatment of patients with metastatic Non-Small Cell Lung Cancer (NSCLC) with Epidermal Growth Factor Receptor (EGFR) exon 19 deletion or exon 21 L858R substitution mutations, as detected by an FDA-approved test. VIZIMPRO® is aproduct of Pfizer Pharmaceutical Company.
COPIKTRA® (Duvelisib)
The FDA on September 24, 2018 granted regular approval to COPIKTRA® for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Llymphoma (SLL) after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies. COPIKTRA® is a product of Verastem, Inc.
COPIKTRA® (Duvelisib)
The FDA on September 24, 2018 granted regular approval to COPIKTRA® for adult patients with Relapsed or Refractory Chronic Lymphocytic Leukemia (CLL) or Small Lymphocytic Llymphoma (SLL) after at least two prior therapies. In addition, COPIKTRA® received accelerated approval for adult patients with Relapsed or Refractory Follicular Lymphoma (FL) after at least two prior systemic therapies. COPIKTRA® is a product of Verastem, Inc.
Hyperprogressive Disease after Immunotherapy in Advanced Non-Small Cell Lung Cancer
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 2018 about 234,030 new cases of lung cancer will be diagnosed and over 154,050 patients will die of the disease. Lung cancer is the leading cause of cancer-related mortality in the United States. Immunotherapy with PD-1 (Programmed cell Death 1) and PD-L1 (Programmed cell Death Ligand 1) inhibitors have demonstrated a clear survival benefit both as a single agent or in combination, compared with standard chemotherapy, in both treatment-naive and previously treated patients for advanced Non Small Cell Lung Cancer (NSCLC). Immuno-Oncology therapies unleash the T cells by blocking the Immune checkpoint proteins, thereby resulting in T cell proliferation, activation and a therapeutic response.
Recent reports of an acceleration of tumor growth during immunotherapy, defined as HyperProgressive Disease (HPD), has been observed in 9% of advanced malignancies and in 29% of patients with Head and Neck cancer treated with PD-1/PD-L1 inhibitors. It has been postulated that high level of interferon gamma (IFN-gamma) usually released by PD-1 blockade may have detrimental effects on immunity. Alternatively PD-1/PD-L1 blockade may upregulate Interleukin 6, Interleukin 17, and neutrophil axis, generating a potent aberrant inflammation, responsible for immune escape and accelerated growth.
HyperProgressive Disease should be differentiated from Pseudoprogression. The later is defined as progressive disease, followed by Complete Response and/or Partial Response or Stable Disease longer than 6 months. The Tumor Growth Rate (TGR) estimates the increase in tumor volume over time based on two Computed Tomography (CT) scan measurements. TGR can be used to quantitatively assess tumor dynamics and kinetics during treatment and can be specifically applied to identify the subset of patients experiencing HPD.
This study was conducted to investigate whether HPD is observed in patients with advanced NSCLC treated with PD-1/PD-L1 inhibitors compared with single-agent chemotherapy and whether there is an association between treatment and HPD. This multicenter, retrospective study included 406 consecutive eligible patients with confirmed Stage III or IV NSCLC treated with PD-1/PD-L1 inhibitors such as OPDIVO® (Nivolumab), KEYTRUDA® (Pembrolizumab), TECENTRIQ® (Atezolizumab), or IMFINZI® (Durvalumab) as monotherapy in second or later line treatment, at eight French institutions between November 2012 and April 2017. The control cohort included equivalent data collected on 59 eligible patients with advanced NSCLC, who had failed a Platinum-based regimen and received single-agent chemotherapy (Taxanes, Pemetrexed, Vinorelbine , or Gemcitabine) in 4 French institutions from August 2011, to June 2016. The median age was 50 years, over 70% of the patients had nonsquamous histology and approximately 20% of the patients had PD-L1 positive status (1% or more by IHC) confirmed. The median followup was 12.1 months. Measurable disease (defined by Response Evaluation Criteria in Solid Tumors – RECIST version 1.1) on at least two CT scans before treatment and one CT scan during treatment, was required. HyperProgressive Disease (HPD) was defined as disease progression on the first CT scan during treatment with an absolute increase in Tumor Growth Rate exceeding 50%. The Primary end point was assessment of the HyperProgressive Disease rate in patients treated with Immunotherapy or chemotherapy.
Among those treated with PD-1/PD-L1 inhibitors, HyperProgressive Disease was noted in 13.8% of patients. HPD was significantly associated with more than two metastatic sites prior to treatment with PD-1/PD-L1 inhibitors, compared with those without HPD (62.5% versus 42.6%; P=0.006). However, baseline tumor burden and number of previous lines of therapy did not make a significant difference. Patients experiencing HPD within the first 6 weeks of beginning PD-1/PD-L1 inhibitor therapy had significantly lower median Overall Survival compared with those with progressive disease without HyperProgression at the first evaluation (3.4 months versus 6.2 months; HR=2.18; P=0.003). Pseudoprogression was observed in 4.7% patients.
Among patients treated with single-agent chemotherapy, only 5.1% were classified as having HyperProgressive Disease and the median Overall Survival was 4.5 months in those with HPD and 3.9 months in other patients with progressive disease without HyperProgression at the first evaluation (P=0.60).
The authors concluded that HyperProgressive Disease is more common with PD-1/PD-L1 inhibitors compared with chemotherapy, among previously treated patients with advanced NSCLC, and is also associated with high number of metastatic sites at baseline and poor survival. They added that the present study is the largest analysis exploring HPD to date and is the first conducted, in a dedicated NSCLC population, with a control cohort of chemotherapy-treated patients Hyperprogressive Disease in Patients With Advanced Non–Small Cell Lung Cancer Treated With PD-1/PD-L1 Inhibitors or With Single-Agent Chemotherapy. Ferrara R, Mezquita L, Texier M, et al. JAMA Oncol. Published online September 6, 2018. doi:10.1001/jamaoncol.2018.3676
XARELTO® in Cancer Patients Associated with Fewer Episodes of VTE Compared with FRAGMIN® but Increase in Nonmajor Bleeding
SUMMARY: The Center for Disease Control and Prevention (CDC) estimates that approximately 1-2 per 1000 individuals develop Deep Vein Thrombosis (DVT)/Pulmonary Embolism (PE) each year in the United States, resulting in 60,000-100,000 deaths. Venous ThromboEmbolism (VTE) is the third leading cause of cardiovascular mortality, after myocardial infarction and stroke.
Approximately 20% of cancer patients develop VTE and there is a two-fold increase in the risk of recurrent thrombosis in patients with cancer, compared with those without cancer. The current recommendations are treatment with parenteral Low Molecular Weight Heparin (LMWH) preparations for at least 6 months or probably longer, as long as the cancer is active. This however can be inconvenient and expensive, leading to premature discontinuation of treatment. LMWH accelerates the inhibition by Antithrombin of activated Factor X, in the conversion of Prothrombin to Thrombin. Direct Oral AntiCoagulants (DOACs) have been proven to be noninferior to COUMADIN® (Warfarin), a Vitamin K antagonist, for the treatment of acute VTE, and are associated with less frequent and less severe bleeding and fewer drug interactions. However, the efficacy and safety of DOACs for the treatment of cancer-associated VTE have not been established. The Direct Oral AntiCoagulants (DOACs) include PRADAXA® (Dabigatran), which is a direct Thrombin inhibitor and XARELTO® (Rivaroxaban), ELIQUIS® (Apixaban), SAVAYSA® (Endoxaban), BEVYXXA® (Betrixaban) which are Factor Xa inhibitors. Compared to COUMADIN® , the New Oral Anticoagulants have a rapid onset of action, wider therapeutic window, shorter half-lives (7-14 hours in healthy individuals), no laboratory monitoring and fixed dosing schedule. In the EINSTEIN trial which compared XARELTO® with LMWH followed by COUMADIN® in patients with acute symptomatic DVT or PE, only 5.5% of patients had active cancer at baseline.
This study was conducted to assess VTE recurrence rates in patients with active cancer, treated with either XARELTO® or FRAGMIN® (Dalteparin) and whether XARELTO® would offer an alternative treatment for cancer patients with VTE. SELECT-D (Selected Cancer Patients at Risk of Recurrence of Venous Thromboembolism) is a randomized, open-label, multicenter pilot trial in which patients with active cancer, who had symptomatic Pulmonary Embolism (PE), incidental PE, or symptomatic lower-extremity proximal Deep Vein Thrombosis (DVT) were enrolled to receive either XARELTO® or FRAGMIN®. Active cancer was defined as a diagnosis of cancer (other than Basal-cell or Squamous-cell skin carcinoma) in the previous 6 months, any treatment for cancer within the previous 6 months, recurrent or metastatic cancer, or cancer not in Complete Remission (hematologic malignancy). In this study, 58% of the patients had metastatic disease, approximately 25% of patients had Colorectal cancer and 83% were receiving chemotherapy at the time of their VTE. A total of 406 patients were randomly assigned in a 1:1 ratio to receive either FRAGMIN® 200 IU/kg SC once daily for the first 30 days and then 150 IU/kg SC daily for an additional 5 months or XARELTO® 15 mg orally twice daily for 3 weeks, then 20 mg once daily for a total of 6 months. Patients were assessed at 3-month intervals until month 12 and then at 6-month intervals until month 24. The primary outcome was VTE recurrence over 6 months, using compression ultrasound (CUS). Secondary outcomes were major bleeding and Clinically Relevant NonMajor Bleeding (CRNMB).
The cumulative VTE recurrence rate at 6 months was 11% for patients receiving FRAGMIN® and 4% for patients receiving XARELTO® (HR=0.43). The 6-month cumulative rate of major bleeding was 4% for FRAGMIN® and 6% for XARELTO® (HR= 1.83). Corresponding cumulative rate of CRNMB at 6 months was 4% and 13% respectively. Most major bleeding events were GI, and there were no CNS bleeds. Patients with esophageal or gastroesophageal cancer experienced more major bleeds with XARELTO® than with FRAGMIN® (36% versus 11%). Overall Survival at 6 months was 70% with FRAGMIN® and 75% with XARELTO®.
It was concluded that XARELTO® was associated with relatively low VTE recurrencein patients with cancer but with higher Clinically Relevant NonMajor Bleeding, compared with LMWH, FRAGMIN®. Comparison of an Oral Factor Xa Inhibitor With Low Molecular Weight Heparin in Patients With Cancer With Venous Thromboembolism: Results of a Randomized Trial (SELECT-D). Young AM, Marshall A, Thirlwall J, et al. Journal of Clinical Oncology 2018;36:2017-2023
FDA Approves KEYTRUDA® for Cervical Cancer
SUMMARY: The FDA on June 12, 2018, approved KEYTRUDA® (Pembrolizumab) for patients with recurrent or metastatic Cervical cancer with disease progression on or after chemotherapy, whose tumors express PD-L1 (Combined Positive Score-CPS, of 1 or more) as determined by an FDA-approved test. The American Cancer Society estimates that for Cervical cancer in the US for 2018, about 13,240 new cases of invasive Cervical cancer will be diagnosed and about 4,170 women will die of the disease. Cervical pre-cancers are diagnosed far more often than invasive Cervical cancer. Cervical cancer is most frequently diagnosed in women between the ages of 35 and 44 and in the US. Hispanic women are most likely to get Cervical cancer, followed by African-Americans, Asians and Pacific Islanders, and whites.
Approximately 5% of new diagnoses of Cervical cancer accounts for stage IV disease. However, metastatic disease develops in 15-60% of women, usually within the first two years of completing primary treatment. A select group of women with locally recurrent or limited metastatic disease may be potentially cured with surgical resection or radiotherapy. This however may not be feasible in the majority of cases. Patients with recurrent and metastatic Cervical cancer have a poor prognosis, with limited systemic treatment options. There is currently no consensus on the standard of care for second-line systemic treatment of recurrent or metastatic Cervical cancer, and as such represents a significant unmet clinical need.
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 FDA approval was based on KEYNOTE-158 study, which is a multicenter, non-randomized, open-label, multi-cohort phase II basket study trial, investigating the antitumor activity of KEYTRUDA® in 11 different advanced cancer types, who had progressed on standard-of-care therapy. Basket Trial by definition allows the testing of one drug on a single mutation in a variety of tumor types, at the same time, thereby potentially increasing the number of patients who are eligible to receive certain drugs. KEYTRUDA® was investigated in 98 patients with recurrent or metastatic Cervical cancer, enrolled in a single cohort of the KEYNOTE- 158 trial.
Key eligibility criteria for this cohort included patients with histologically or cytologically confirmed advanced Cervical cancer who had progressed on or intolerant to one or more lines of standard therapy and had tumor sample available for biomarker analysis. Patients were treated with KEYTRUDA® 200 mg IV every 3 weeks until documented disease progression or unacceptable toxicity..PD-L1 positivity, defined as a Combined Positive Score (CPS) of 1 or more, was evaluated retrospectively by ImmunoHistoChemistry (IHC) using the PD-L1 IHC 22C3 pharmDx Kit. Median age was 46 years and 77 patients (79%) of enrolled patients had PD-L1 positive tumors. Primary endpoint was Objective Response Rate (ORR) assessed by independent central review. Secondary endpoints included Duration of Response (DOR), Progression Free Survival (PFS), Overall Survival (OS) and safety.
With a median follow up time of 11.7 months, the ORR in the 77 PD-L1 positive patients was 14.3% including 2.6% Complete Responses and 11.7% Partial Responses. The estimated median response duration was not reached, 91% had response duration of 6 months or more, and no responses were observed in patients whose tumors did not have PD-L1 expression (CPS less than 1). The most common adverse reactions in at least 10% of patients were fatigue, fever, nausea, vomiting, diarrhea/colitis, abdominal pain, constipation, hypothyroidism, and dyspnea. KEYTRUDA® was discontinued due to adverse reactions in 8% of patients.
It was concluded that KEYTRUDA® is the first anti-PD-1 therapy approved for the treatment of advanced Cervical cancer, providing an important new second-line option for certain patients with this disease, with durable antitumor activity and manageable toxicity profile. Pembrolizumab treatment of advanced cervical cancer: Updated results from the phase 2 KEYNOTE-158 study. Chung HC, Schellens JH, Delord J, et al. J Clin Oncol 36, 2018 (suppl; abstr 5522)