Atezolizumab (Tecentriq)

Number: 0909

 

Policy

Note: REQUIRES PRECERTIFICATION. Precertification of atezolizumab is required of all Aetna participating providers and members in applicable plan designs.  For precertification of atezolizumab, call (866) 752-7021, or fax (866) 267-3277.

Aetna considers atezolizumab (Tecentriq) medically necessary for the following indications:

1. Urothelial Carcinoma - Bladder Cancer

   - for treatment as a single agent for bladder cancer when any of the following criteria are met: 
   
   

   1. The requested medication is used as first line therapy in cisplatin ineligible persons whose tumors express PD-L1 (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering greater than or equal to 5% of the tumor area) or in persons who are not eligible for any platinum containing chemotherapy regardless of PD-L1 expression for any of the following:
      
      
      1. Stage II or Stage IIIa disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy; or
      2. locally advanced or metastatic disease; or
      3. metastatic or local recurrence post-cystectomy; or
   2. The requested medication is used as subsequent systemic therapy following platinum containing chemotherapy for either of the following:
      
      
      1. locally advanced or metastatic disease; or
      2. metastatic or local recurrence post-cystectomy.

2. Urothelial Carcinoma - Primary Carcinoma of the Urethra

   - for treatment as a single agent for primary carcinoma of the urethra when any of the following criteria are met:
   
   

   1. The requested medication is used as first line therapy for recurrent, locally advanced or metastatic disease in cisplatin ineligible persons whose tumors express PD-L1 (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering greater than or equal to 5% of the tumor area) or in persons who are not eligible for any platinum containing chemotherapy regardless of PD-L1 expression; or
   2. The requested medication is used as subsequent therapy for recurrent, locally advanced or metastatic disease following platinum-containing chemotherapy.

3. Urothelial Carcinoma - Upper Genitourinary Tract Tumors or Urothelial Carcinoma of the Prostate

   - for treatment as a single agent for upper genitourinary tract tumors or urothelial carcinoma of the prostate when any of the following criteria are met:
   
   

   1. The requested medication is used as first line therapy locally advanced or metastatic disease in cisplatin ineligible persons whose tumors express PD-L1 (defined as PD-L1 stained tumor-infiltrating immune cells [IC] covering greater than or equal to 5% of the tumor area) or in persons who are not eligible for any platinum containing chemotherapy regardless of PD-L1 expression; or
   2. The requested medication is used as subsequent therapy for locally advanced or metastatic disease following platinum-containing chemotherapy.

4. Non-Small Cell Lung Cancer (NSCLC)

   - for treatment of NSCLC when any of the following criteria are met:
   
   

   1. The requested medication is used as treatment for recurrent, advanced or metastatic nonsquamous NSCLC in combination with carboplatin, paclitaxel and bevacizumab (if EGFR or ALK positive, will be used following EGFR or ALK therapy); or
   2. The requested medication is used as treatment for recurrent, advanced or metastatic nonsquamous NSCLC in combination with paclitaxel protein-bound and carboplatin (if EGFR or ALK positive, will be used following EGFR or ALK therapy); or
   3. The requested medication is used as continuation maintenance therapy as a single agent or in combination with bevacizumab for recurrent, advanced or metastatic nonsquamous NSCLC following atezolizumab/carboplatin/paclitaxel/bevacizumab therapy when tumor response or stable disease is achieved; or
   4. The requested medication is used as continuation maintenance therapy for recurrent, advanced or metastatic nonsquamous NSCLC following atezolizumab/carboplatin/paclitaxel protein-bound therapy when tumor response or stable disease is achieved; or
   5. The requested medication is used as subsequent therapy as a single agent for recurrent, advanced, or metastatic disease.

5. Breast Cancer

   - for treatment of unresectable locally advanced, recurrent, or metastatic breast cancer when all of the following criteria are met:
   
   

   1. The diagnosis of breast cancer is confirmed by the cancer cells testing negative for ALL of the following receptors: 
      
      
      1. human epidermal growth factor receptor 2 (HER-2); and
      2. estrogen; and
      3. progesterone; and
   2. Tumors must express programmed death ligand 1 (PD-L1) (i.e., PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering greater than or equal to 1 percent of the tumor area) (see  CPB 0715 - Pharmacogenetic and Pharmacodynamic Testing); and
   3. The requested medication will be used in combination with protein-bound paclitaxel (Abraxane).

6. Small Cell Lung Cancer (SCLC)

   - for treatment of small cell lung cancer when the following criteria is met:
   
   

1. The requested medication will be used as initial treatment in combination with etoposide and carboplatin (followed by single agent maintenance) for extensive-stage disease.

Aetna considers continuation of atezolizumab (Tecentriq) medically necessary for members meeting initial selection criteria for the indications listed above, and who have not experienced disease progression or an unacceptable toxicity from therapy.

Aetna considers atezolizumab experimental and investigational for all other indications including the following (not an all-inclusive list) due to insufficient evidence in the peer-reviewed literature:

• Acute myeloid leukemia
• Appendiceal adenocarcinoma
• Asymptomatic myeloma
• Bone plasmacytoma
• Cervical cancer
• Cholangiocarcinoma
• Chronic lymphocytic leukemia
• Chronic myelomonocytic leukemia
• Fallopian tube carcinoma
• Gastrointestinal cancers (e.g., colorectal, esophageal, gastric, and gastro-esophageal junction cancers)
• Glioblastoma
• Hodgkin lymphoma
• Melanoma
• Mesothelioma
• Multiple myeloma
• Myelodysplastic syndrome
• Non-Hodgkin’s lymphoma
• Ovarian carcinoma
• Pancreatic adenocarcinoma
• Peritoneal carcinoma
• Polycythemia vera
• Primary myelofibrosis
• Prostate cancer
• Renal cell carcinoma
• Sarcoma (e.g., alveolar soft part sarcoma, myxoid/round cell liposarcoma and synovial sarcoma)
• Small lymphocytic lymphoma
• Smoldering multiple myeloma
• Thyroid carcinoma
• Uterine cancer
• Uveal melanoma.

Aetna considers atezolizumab experimental and investigational if disease progresses while on prior anti-PD-1 therapy (e.g., nivolumab (Opdivo), avelumab (Bavencio), pembrolizumab (Keytruda), and durvalumab (Imfinzi)).

Dosing Recommendations

Atezolizumab (Tecentriq) is available as 840 mg/14 mL (60 mg/mL) and 1200 mg/20mL (60 mg/mL) solution in a single-dose vial to be administered as an intravenous (IV) infusion over 60 minutes until disease progression or unacceptable toxicity. If the first infusion is tolerated, subsequent infusions may be delivered over 30 minutes.

• Urothelial carcinoma: as a single-agent, 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 ng every 4 weeks. 
  
  
• Non-small cell lung cancer (NSCLC): 
   
  
  • As a single agent - 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. 
  • With platinum-based chemotherapy - administer Tecentriq 1200 mg every 3 weeks. Administer Tecentriq prior to chemotherapy and bevacizumab when given on the same day. Refer to the Prescribing Information for the chemotherapy agents or bevacizumab administered in combination with Tecentriq for recommended dosing information. Following completion of 4-6 cycles of chemotherapy, and if bevacizumab is discontinued, the recommended dosage of Tecentriq is 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks. 
    
    
• Triple-negative breast cancer (TNBC): 840 mg, followed by 100 mg/m² paclitaxel protein-bound (Abraxane). For each 28-day cycle, Tecentriq is administered on days 1 and 15, and paclitaxel protein-bound is administered on days 1, 8, and 15. Tecentriq and paclitaxel protein-bound may be discontinued for toxicity independently of each other.
  
  
• Small cell lung cancer:
  
  
  • FDA: Recommended dosage when administering with carboplatin and etoposide is Tecentriq 1200 mg every 3 weeks prior to chemotherapy. Following completion of 4 cycles of carboplatin and etoposide, administer Tecentriq as: 840 mg every 2 weeks, 1200 mg every 3 weeks, or 1680 mg every 4 weeks.
  • NCCN: carboplatin AUC 5 day 1 and etoposide 100 mg/m² days 1, 2, 3 and atezolizumab 1200 mg day 1 every 21 days for 4 cycles followed by maintenance atezolizumab 1200 mg. Maximum 4-6 cycles. Not recommended for relapsed disease in persons on maintenance atezolizumab at time of relapse. For persons who relapse after greater than 6 months of atezolizumab maintenance therapy, NCCN recommends re-treatment with carboplatin plus etoposide alone.

Source: FDA (Genentech, 2019); NCCN guidelines “Small cell lung cancer” (version 2.2020).

Background

Atezolizumab is a programmed death-ligand blocking antibody approved by the U.S. Food and Drug Administration (FDA) under an accelerated approval. The accelerated approval was based on duration of response and tumor response rate. Tecentriq was first approved for locally advanced or metastatic urothelial carcinoma who: have disease progression during or following platinum-containing chemotherapy; or have disease progression within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy. The FDA approval notes that continued approval for this indication may be contingent upon verification and description of clinical benefit in confirmatory trials.

Atezolizumab belongs to a class of immunotherapy drugs known as checkpoint inhibitors, which prevent the protein PD-L1 found on some tumor cells from binding to the protein, PD-, on immune cells (Genentech, 2016). The binding of these “checkpoint” proteins suppresses the immune response, thereby allowing immune cells to attack tumors. The FDA also approved a test, called Ventana PD-L1 (sp142) to measure PD-L1 expression on patients' tumor-infiltrating immune cells.  However, the test is not required for patients to receive atezolizumab, and patients whose tumors are classified as negative for PD-L1 might still respond to the therapy.

Rosenberg et al (2016) conducted a multicenter, single-arm, two-cohort, phase 2 trial in 486 patients aged 18 or older presenting with inoperable locally advanced or metastatic urothelial carcinoma. Inclusion criteria included a requirement that disease be inoperable locally advanced or metastatic urothelial carcinoma whose disease had progressed after previous platinum-based chemotherapy, adequate hematological and end-organ function, no autoimmune disease or active infections, Eastern Cooperative Oncology Group performance status of 0 or 1, and measurable disease defined by response Evaluation Criteria in Solid Tumors version 1.1 (RECIST).  Results of this study indicated that treatment with atezolizumab resulted in a significantly improved RECIST objective response rate for each prespecified immune cell group (p = 0.0001 - 0.0004) as well as in all patient combined analysis (p = 0.0058).  The Cancer Genoma Atlas (TCGA) subtypes and mutation load were found to be independently predictive for response to atezolizumab.  The investigators concluded that atezolizumab was found to have durable activity and good tolerability in the study population, with increased levels of PD-L1 expression on immune cells.  The authors stated that, although this is a Phase II clinical trial, this study is well designed with robust statistical power and highly significant findings in support of the use of atezolizumab for this indication.

The recommended dose of atezolizumab for urothelial carcinoma is 1200 mg which should be administered as an intravenous infusion over 60 minutes every 3 weeks until disease progression or unacceptable toxicity. The product labeling notes that if the first infusion is tolerated, all subsequent infusions may be delivered over 30 minutes.  Atezolizumab may not be administered as an intravenous push or bolus (Genentech, 2016).

The U.S. Food and Drug Administration (FDA) granted an accelerated approval to atezolizumab to be used as a first-line treatment for cisplatin-ineligible patients with locally advanced or metastatic urothelial carcinoma (Genentech, 2017).  

The treatment-naive IMvigor210 cohort enrolled 123 patients with cisplatin-ineligible locally advanced or metastatic urothelial carcinoma at 47 locations in North America and Europe between June 9, 2014, and March 30, 2015 (Genentech, 2017). Patients received 1200 mg of atezolizumab IV every three weeks until progression. The primary endpoint was ORR, with secondary outcomes measures including progression-free survival (PFS) and overall survival (OS). Among the 123 patients, 119 received at least one dose of atezolizumab. There was an association between tumor mutation load and response. The median progression-free survival and overall survival were 2.7 months and 15.9 months, respectively. The median duration of response had not yet reached at the time of the FDA approval for this indication. Among patients with PD-L1 expression 5 percent or more (32 patients), the ORR was 28.1 percent, including a CR rate of 6.3 percent. In patients with PD-L1 expression less than 5 percent, the corresponding rates were 21.8 percent and 6.9 percent, respectively. 

The most common grade 3/4 adverse events (AEs) included fatigue (8 percent), urinary tract infection (5 percent), anemia (7 percent), diarrhea (5 percent), increased creatinine (5 percent), increased alanine transaminase (ALT) (4 percent), hyponatremia (15 percent), decreased appetite (3 percent) and back/neck pain (3 percent) (Genentech, 2017). 

The FDA approved atezolizumab for the treatment of people with metastatic non-small cell lung cancer (NSCLC) who have disease progression during or following platinum-containing chemotherapy and have progressed on an appropriate FDA-approved targeted therapy if their tumor has EGFR or ALK gene abnormalities.

The approval was based on results from the randomized Phase III OAK and Phase II POPLAR studies. OAK was a multicenter, open-label, randomized, controlled Phase III study that evaluated the efficacy and safety of atezolizumab compared with docetaxel in 1,225 subjects with locally advanced or metastatic NSCLC whose disease had progressed following previous treatment with platinum-containing chemotherapy, with the primary analysis consisting of the first 850 randomized patients. The study enrolled subjects regardless of their PD-L1 status and included both squamous and non-squamous disease types. Patients with both squamous and non-squamous disease were randomized (1:1) to receive either atezolizumab administered intravenously at 1200 mg every 3 weeks or docetaxel administered intravenously at 75 mg/m 2 every 3 weeks. The co-primary endpoints were overall survival (OS) in all randomized patients (intention-to-treat [ITT] population) and in a PD-L1-selected subgroup in the primary analysis population. OAK showed that persons assigned to atezolizumab lived a median of 13.8 months, 4.2 months longer than those treated with docetaxel chemotherapy (median overall survival [OS]: 13.8 vs. 9.6 months; HR = 0.74, 95 % confidence interval [CI]: 0.63, 0.87).

The POPLAR study was a multicenter, open-label, randomized Phase II trial that evaluated the efficacy and safety of atezolizumab compared with chemotherapy (docetaxel) in 287 subjects with previously treated recurrent locally advanced or metastatic NSCLC. The primary endpoint was OS; secondary endpoints included progression-free survival (PFS), objective response rate (ORR) and safety. From an updated analysis with a median follow-up of 22 months, the median overall survival with atezolizumab was 12.6 months, 2.9 months longer than those treated with docetaxel chemotherapy (median OS: 12.6 vs. 9.7 months; HR = 0.69, 95 % CI: 0.52, 0.92). There were no significant differences between atezolizumab and docetaxel groups with respect to ORR (15% in both groups), complete response (0.7% vs. 0%), and partial response (15% in both groups). Median duration of response in the atezolizumab group was 18.6 months (95% CI: 11.6, not estimable) versus 7.2 months (95 % CI: 5.6, 12.5) in the docetaxel group.  

Most common side effects (greater than or equal to 20%) in patients with metastatic non-small cell lung cancer were fatigue, decreased appetite, dyspnea, cough, nausea, musculoskeletal pain, and constipation. Nine patients (6.3%) who were treated with atezolizumab experienced either pulmonary embolism (2), pneumonia (2), pneumothorax, ulcer hemorrhage, cachexia secondary to dysphagia, myocardial infarction, or large intestinal perforation which led to death. Atezolizumab was discontinued for adverse reactions in 4 percent (6) of the 142 patients.

Breast Cancer

Emens (2017) noted that immunotherapy is revolutionizing the management of multiple solid tumors, and early data have revealed the clinical activity of the programmed death 1 (PD-1) or its ligand (PD-L1) antagonists in small numbers of metastatic breast cancer patients.  Clinical activity appeared more likely if the tumor is triple negative, PD-L1+, and/or harbors higher levels of TILs.  Responses to atezolizumab and pembrolizumab appeared to be durable in metastatic triple negative breast cancer (TNBC), suggesting these agents may transform the lives of responding patients.  Current clinical efforts are focused on developing immunotherapy combinations that convert non-responders to responders, deepen those responses that do occur, and surmount acquired resistance to immunotherapy.  Identifying biomarkers that can predict the potential for response to single-agent immunotherapy, identify the best immunotherapy combinations for a particular patient, and guide salvage immunotherapy in patients with progressive disease are high priorities for clinical development.  Smart clinical trials testing rational immunotherapy combinations that include robust biomarker evaluations will accelerate clinical progress, moving researchers closer to effective immunotherapy for almost all breast cancer patients.

On March 8, 2019, the Food and Drug Administration (FDA) granted accelerated approval for atezolizumab to be used in combination with paclitaxel protein-bound for adult patient with unresectable locally advanced or metastatic triple-negative breast cancer (TNBC) whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] of any intensity covering ≥ 1% of the tumor area), as determined by an FDA-approved test. In addition, the FDA approved the VENTANA PD-L1 (SP142) Assay as a companion diagnostic device for selecting TNBC patients for atezolizumab. This indication was approved under FDA accelerated approval based on progression-free survival in the IMpassion130 trial (NCT02425891) (FDA, 2019).

Schmid et al. (2018) state that atezolizumab (Tecentriq) plus nab-paclitaxel (paclitaxel protein-bound, Abraxane) prolonged progression-free survival among patients with metastatic triple-negative breast cancer (TNBC) in both the intention-to-treat (ITT) population and the PD-L1-positive subgroup. The authors conducted a multicenter, international, double-blinded, placebo-controlled phase 3 trial (IMpassion130) which randomized (1:1) 902 patients with untreated metastatic TNBC to receive either atezolizumab (840 mg) intravenous (IV) or placebo infusions on days 1 and 15 of every 28-day cycle, plus paclitaxel protein-bound (100 mg/m2) IV on days 1, 8, and 15 of every 28-day cycle. Patients continued the intervention until disease progression, or an unacceptable level of toxic effects occurred. Patients were stratified by presence of liver metastases, prior taxane treatment, and by PD-L1 expression status in tumor infiltrating immune cells (PD-L1 stained tumor-infiltrating immune cells [IC] <1% of tumor area vs. ≥ 1% of the tumor area) by the VENTANA PD-L1 (SP142) Assay. The two primary end points were progression-free survival (PFS) (in the intention-to-treat (ITT) population and PD-L1-positive subgroup) and overall survival (tested in the ITT population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). Of the 902 patients in the intent to treat population (ITT), 41% (369 patients) were classified as PD-L1 expression ≥ 1%. Patients were excluded if they had a history of autoimmune disease, administration of a live attenuated vaccine within 4 weeks prior to randomization, administration of systemic immunostimulatory agents within 4 weeks or systemic immunosuppressive medications within 2 weeks prior to randomization; or untreated or corticosteroid-dependent brain metastases. The first primary end point outcomes in the ITT analysis reflected a median PFS of 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (p=0.002).  Among patients with PD-L1-positive tumors, the median PFS was 7.5 months and 5.0 months, respectively (p<0.001). The outcomes of the second primary end point in the ITT analysis reflected the median overall survival of 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (p=0.08). Among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively. No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. In conclusion, in patients with metastatic TNBC whose tumors express PD-L1, study outcomes for progression-free survival were in favor of the atezolizumab plus paclitaxel protein-bound arm; however, overall survival data were immature with 43% deaths in the intent to treat (ITT) population.

The most common adverse reactions (greater than or equal to 20% of patients) with atezolizumab with paclitaxel protein-bound were alopecia, peripheral neuropathies, fatigue, nausea, diarrhea, anemia, constipation, cough, headache, neutropenia, vomiting, and decreased appetite (FDA, 2019).

Gastrointestinal Cancers (e.g. Colorectal, Esophageal and Gastric Cancers)

Basile and co-workers (2017) stated that in the past few years, significant advances in molecular biology have provided new therapeutic options for colorectal cancer (CRC).  The development of new drugs that target the immune response to cancer cells appeared very promising and has already been established for other tumor types.  In particular, the use of immune checkpoint inhibitors appeared to be an encouraging immunotherapeutic strategy.  These investigators provided an update of the current evidence related to this topic, though most immunotherapies are still in early-phase clinical trials for CRC.  To understand the key role of immunotherapy in CRC, these researchers discussed the delicate balance between immune-stimulating and immune-suppressive networks that occur in the tumor microenvironment.  Modulation of the immune system through checkpoint inhibition is an emerging approach in CRC therapy.  Nevertheless, selection criteria that could enable the identification of patients who may benefit from these agents are necessary.  Furthermore, potential prognostic and predictive immune biomarkers based on immune and molecular classifications have been proposed.  The authors concluded that additional studies are needed to develop biomarkers, effective therapeutic strategies and novel combinations to overcome immune escape resistance and enhance effector response; atezolizumab was one of the keywords of this article.

Bilgin and colleagues (2017) stated that VEGF, HER2 and EGFR targeted agents are currently used in gastric, esophageal and colorectal cancers.  However, treatment outcomes are still poor in most gastro-intestinal (GI) cancers.  Immune checkpoints are one of the most promising immunotherapy approaches.  These investigators discussed the safety and effectiveness of anti-PD-1/PD-L1 therapies in GI cancers, including gastric, esophageal and colorectal cancer in published or reported studies.  They performed a literature search from PubMed and ASCO Annual Meeting abstracts by using the following search keywords: "nivolumab", "pembrolizumab", "avelumab", "GI cancers" "anti-PD1 therapy" and "anti-PD-L1 therapy".  The last search was on November 2, 2016.  The most important limitation of this review was that most of the data on anti-PD-1/PD-L1 therapies in GI cancers relied on phase-I and phase-II clinical trials.  Currently, there are 2 anti-PD-1 (nivolumab and pembrolizumab) and 1 anti-PDL1 (atezolizumab) agents approved by FDA.  After the treatment efficacy of immune checkpoint blockade was shown in melanoma, renal cell cancer (RCC) and non-squamous lung cancer, trials that evaluated immune checkpoint blockade in GI cancers are ongoing.  Early results of trials have been promising and encouraging for patients with advanced stage gastro-esophageal cancer.  According to early results of published trials, response to anti-PD1/PD-L1 agents appeared to be associated with tumor PD-L1 levels.  According to 2 published phase-II clinical trials, the clinical benefits of immune checkpoint blockade with both nivolumab and pembrolizumab were limited in patients with microsatellite instability (MSI)-positive advanced CRC.  However, several phase II/III clinical trials are still ongoing.  The authors concluded that both pembrolizumab and nivolumab showed promising efficacy with acceptable safety data in published trials in GI cancers, especially in refractory MSI positive metastatic CRC.

Melanoma

Grimaldi and associates (2017) stated that the mitogen-activated protein kinase (MAPK) cascade is an intracellular signaling pathway involved in the regulation of cellular proliferation and the survival of tumor cells.  Several different mutations, involving BRAF or NRAS, exert an oncogenic effect by activating the MAPK pathway, resulting in an increase in cellular proliferation.  These mutations have become targets for new therapeutic strategies in melanoma and other cancers.  Selective MEK inhibitors have the ability to inhibit growth and induce cell death in BRAF- and NRAS-mutant melanoma cell lines.  MEK inhibitor therapy in combination with a BRAF inhibitor is more effective and less toxic than treatment with a BRAF inhibitor alone, and has become the standard of care for patients with BRAF-mutated melanoma.  Trametinib was the 1st MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma not previously treated with BRAF inhibitors, and is also approved in combination with the BRAF inhibitor dabrafenib.  Furthermore, cobimetinib is another MEK inhibitor approved for the treatment of BRAF-mutated metastatic melanoma in combination with a BRAF inhibitor, vemurafenib.  The MEK inhibitor binimetinib in combination with the BRAF inhibitor encorafenib is in clinical development.  The addition of an anti-PD-1/PD-L1 agent (e.g., pembrolizumab, durvalumab or atezolizumab) to combined BRAF and MEK inhibition has shown considerable promise, with several trials ongoing in metastatic melanoma.  Binimetinib has also shown efficacy in NRAS-mutated melanoma patients.  The authors stated that future possibilities for MEK inhibitors in advanced melanoma, as well as other solid tumors, include their use in combination with other targeted therapies (e.g. anti-CDK4/6 inhibitors) and/or various immune-modulating antibodies.

Metastatic Non-squamous Non-small Cell Lung Cancer (NSCLC)

On December 4, 2019, the U.S. FDA approved Tecentriq (atezolizumab) in combination with chemotherapy (Abraxane [paclitaxel protein-bound; nab-paclitaxel] and carboplatin) for the initial (first-line) treatment of adults with metastatic non-squamous non-small cell lung cancer (NSCLC) with no EGFR or ALK genomic tumour aberrations. FDA approval is based on the safety and efficacy from a multicenter, international, randomized, open-label, Phase 3, IMpower130 study in which chemotherapy-naïve patients with metastatic non-squamous NSCLC  received atezolizumab 1200 mg and carboplatin AUC 6 mg/mL/min intravenously on Day 1 and paclitaxel protein-bound 100 mg/m² intravenously on Day 1, 8, and 15 of each 21-day cycle for a maximum of 4 or 6 cycles, followed by atezolizumab 1200 mg intravenously every 3 weeks until disease progression or unacceptability toxicity. Patients could have received prior EGFR or ALK kinase inhibitor, if appropriate. Among patients receiving atezolizumab (Tecentriq), 55% were exposed for 6 months or longer and 3.5% were exposed for greater than one year. The outcomes of the study showed that atezolizumab plus chemotherapy demonstrated a significant overal survival (OS) compared to chemotherapy alone (median [OS]=18.6 versus 13.9 months; p=0.0384) in the intention-to-treat wild-type (ITT-WT) population, as well as, significantly improved progression-free survival (PFS) compared with chemotherapy alone (median PFS=7.2 versus 6.5 months; p=0.0024) in the ITT-WT population. PFS and OS benefit was observed in all PD-L1 subgroups, and consistently across all subgroups, except in patients with liver metastases and EGFR/ALK genomic alterations. (Capuzzo et al, 2018; Genentech, 2019; Roche, 2019).

Safety for the atezolizumab plus chemotherapy combination appeared consistent with the known safety profiles of the individual medicines, and no new safety signals were identified with the combination. Grade 3-4 treatment-related adverse events were reported in 73.2% of people receiving atezolizumab plus chemotherapy compared with 60.3% of those receiving chemotherapy alone (Roche, 2019).

Prostate Cancer

Vaishampayan (2017) highlighted some developments as well as ongoing challenges of managing advanced prostate cancer.  Significant strides are being made in managing metastatic prostate cancer.  With the evolution of multiple new therapies, now the optimal use of these therapies and their proper sequencing is being addressed.  Research is ongoing for mapping out pathways of resistance to therapies and for discovering new targets.  Genomic alterations and abnormalities in circulating tumor DNA are being detected and will hopefully lead toward biomarker-based therapies.  The next era in oncology belongs to immune therapy.  However, in prostate cancer the immune checkpoint inhibitors have shown modest responses and a phase-III clinical trial of radiation therapy ± ipilimumab revealed no benefit.  Efforts are ongoing with combination trials of enzalutamide and atezolizumab or pembrolizumab; inhibitors of the enzyme poly ADP ribose polymerase (PARP) are gradually being established for therapeutic purposes, with olaparib achieving breakthrough status for prostate cancer patients with BRCA1 and 2 and ATM mutations.  The authors concluded that the future will bring an era of personalized medicine in advanced prostate cancer as well as optimization and more strategic sequencing of existing therapies.

Renal Cell Carcinoma

Atkins and associates (2017) noted that there has been dramatic expansion of the treatment armamentarium for patients with advanced RCC (aRCC), including drugs targeting vascular endothelial growth factor (VEGF) and mammalian target of rapamycin (mTOR) pathways.  Despite these advances, patient outcomes remain suboptimal, underscoring the need for therapeutic interventions with novel mechanisms of action.  The advent of immunotherapy with checkpoint inhibitors has led to significant changes in the treatment landscape for several solid malignancies.  Specifically, drugs targeting the PD-1 and cytotoxic T-lymphocyte associated antigen (CTLA-4) pathways have demonstrated considerable clinical efficacy and gained regulatory approval as single-agent or combination therapy for the treatment of patients with metastatic melanoma, NSCLC, aRCC, advanced head and neck squamous cell carcinoma (HNSCC) , urothelial cancer and Hodgkin lymphoma.  In aRCC, the PD-1 inhibitor nivolumab was approved in both the U.S. and Europe for the treatment of patients who have received prior therapy, based on improved OS compared with the mTOR inhibitor everolimus.  Other checkpoint inhibitors, including the CTLA-4 inhibitor ipilimumab in combination with several agents, and the PD-L1 inhibitor atezolizumab, are in various stages of clinical development in patients with aRCC.

Small Cell Lung Cancer

Seeber and colleagues (2017) stated that systemic therapy options for small cell lung cancer (SCLC) patients with extensive disease remain poor.  After an initial response on 1st-line therapy, virtually all SCLC patients develop disease progression.  For those who showed an initial response only few therapeutic options with low response rates are currently available.  Until now, many experimental and targeted agents have failed to yield convincing clinical benefits, and new therapeutic options are clearly needed for these patients.  The authors noted that in this year's oncological congresses, several new therapy strategies, including checkpoint inhibition, showed promising results in ongoing trials.  Furthermore, a potential benefit of new agents targeting DLL3, Aurora A kinase and PARP-inhibitor was reported.  These researchers summarized new developments and highlighted the most important and promising data in the treatment of patients with relapsed SCLC; atezolizumab was one of the keywords of this article.

Horn et al (2018) stated that enhancing tumor-specific T-cell immunity by inhibiting programmed death ligand 1 (PD-L1)-programmed death 1 (PD-1) signaling has shown promise in the treatment of extensive-stage small-cell lung cancer.  Combining checkpoint inhibition with cytotoxic chemotherapy may have a synergistic effect and improve efficacy.  These researchers conducted a double-blind, placebo-controlled, phase-III clinical trial to evaluate atezolizumab plus carboplatin and etoposide in patients with extensive-stage small-cell lung cancer who had not previously received treatment.  Patients were randomly assigned in a 1:1 ratio to receive carboplatin and etoposide with either atezolizumab or placebo for four 21-day cycles (induction phase), followed by a maintenance phase during which they received either atezolizumab or placebo (according to the previous random assignment) until they had unacceptable toxic effects, disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, or no additional clinical benefit.  The 2 primary endpoints were investigator-assessed progression-free survival (PFS) and overall survival (OS) in the intention-to-treat (ITT) population.  A total of 201 patients were randomly assigned to the atezolizumab group, and 202 patients to the placebo group.  At a median follow-up of 13.9 months, the median OS was 12.3 months in the atezolizumab group and 10.3 months in the placebo group (hazard ratio [HR] for death, 0.70; 95 % confidence interval [CI]: 0.54 to 0.91; p = 0.007).  The median PFS was 5.2 months and 4.3 months, respectively (HR for disease progression or death, 0.77; 95 % CI: 0.62 to 0.96; p = 0.02).  The safety profile of atezolizumab plus carboplatin and etoposide was consistent with the previously reported safety profile of the individual agents, with no new findings observed.  The authors concluded that the addition of atezolizumab to chemotherapy in the 1st-line treatment of extensive-stage small-cell lung cancer resulted in significantly longer OS and PFS than chemotherapy alone.

Uveal Melanoma

Algazi and associates (2016) noted that the safety and effectiveness of PD-1 blockade in patients with uveal melanoma has not been well characterized.  In a multi-center, comparative study, 58 patients with stage IV uveal melanoma received PD-1 or PD-L1 antibodies between 2009 and 2015 at 9 academic centers.  Patients who were evaluable for response were eligible for the analysis.  Imaging was performed every 12 weeks and at the investigators' discretion.  Safety and clinical efficacy outcomes, including the best overall response, PFS, and OS, were retrospectively determined.  Of 56 eligible patients, 48 (86 %) had received prior therapy, and 35 (63 %) had received treatment with ipilimumab; 3 patients had an objective response to ipilimumab, and 8 had stable disease (SD) as their best response; 38 patients (68 %) received pembrolizumab, 16 (29 %) received nivolumab, and 2 (4 %) received atezolizumab.  Objective tumor responses were observed in 2 patients for an overall response rate of 3.6 % (95 % CI: 1.8 % to 22.5 %); SD (greater than or equal to 6 months) was observed in 5 patients (9 %).  The median PFS was 2.6 months (95 % CI: 2.4 to 2.8 months), and the median OS was 7.6 months (95 % CI: 0.7 to 14.6 months).  There was no association between prior treatment with ipilimumab or liver-directed therapy and PFS or OS.  Treatment was well-tolerated, and only 1 patient discontinued treatment because of toxicity.  The authors concluded that PD-1 and PD-L1 antibodies rarely conferred durable remissions in patients with metastatic uveal melanoma. 

Experimental Indications

There is insufficient evidence in peer-reviewed published literature to support the use of atezolizumab for the treatment of various malignancies including acute myeloid leukemia, appendiceal adenocarcinoma, asymptomatic myeloma, bone plasmacytoma, cervical cancer, cholangiocarcinoma, chronic lymphocytic leukemia, chronic myelomonocytic leukemia, colorectal cancer, fallopian tube carcinoma, gastric cancer, gastro-esophageal junction cancer, glioblastoma, Hodgkin lymphoma, melanoma, mesothelioma, multiple myeloma, myelodysplastic syndrome, non-Hodgkin’s lymphoma, ovarian carcinoma, pancreatic adenocarcinoma, peritoneal carcinoma, polycythemia vera, primary myelofibrosis, prostate cancer, renal cell carcinoma, sarcoma (e.g., alveolar soft part sarcoma, myxoid/round cell liposarcoma and synovial sarcoma), small lymphocytic lymphoma, smoldering multiple myeloma, thyroid carcinoma, uterine cancer, and uveal melanoma.

National Comprehensive Cancer Network

The National Comprehensive Cancer Network (NCCN) practice guidelines on “Breast cancer” (version 1.2019) recommends atezolizumab in combination with albumin-bound paclitaxel as preferred therapy for PD-L1 positive triple negative recurrent or stage IV (M1) disease (Category 2A). In the workup for recurrent or stage IV TNBC, NCCN states to assess PD-L1 biomarker status on tumor-infiltrating immune cells to identify patients most likely to benefit from atezolizumab plus albumin-bound paclitaxel.

NCCN Drugs and Biologics Compendium (NCCN, 2020) provides the following recommends for atezolizumab (Tecentriq):

Bladder Cancer

• Upper GU Tract Tumor
  
  Therapy for metastatic disease as a single agent for first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression, or second-line systemic therapy post-platinum (alternative preferred regimen) [2A].
  
  
• Primary Carcinoma of the Urethra
  
  
  • Primary treatment as a single agent for clinical stage T3-4, cN1-2 disease or cN1-2 palpable inguinal lymph nodes as first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression [2A].
  • Used as a single agent for recurrent or metastatic disease as [2B for recurrence of clinical stage T3-4 disease or palpable inguinal lymph nodes; 2A for all others]
    
    
    • first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression
    • second-line systemic therapy post-platinum (alternative preferred)
      
      
• Bladder Cancer
  
  
  • Used as second-line systemic therapy post-platinum as a single agent (alternative preferred) for [2A]
    
    
    • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with downstaging systemic therapy or concurrent chemoradiotherapy
    • stage IVA (cT4b, any N, M0) disease if tumor is present following reassessment of tumor status after primary treatment with systemic therapy or concurrent chemoradiotherapy
    • stage IVA (any T, any N, M1a) disease if stable disease or progression following reassessment of tumor status after primary treatment with first-line systemic therapy
    • stage IVB (any T, any N, M1b) disease
    • muscle invasive local recurrence or persistent disease in a preserved bladder
    • metastatic or local recurrence post cystectomy
      
      
  • Used as first-line systemic therapy as a single agent (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression for [2A]
    
    
    • stage II (cT2, N0) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy
    • stage IIIA (cT3, N0; cT4a, N0; cT1-T4a, N1) disease if tumor is present following reassessment of tumor status 2-3 months after primary treatment with concurrent chemoradiotherapy
    • for non-cystectomy candidates with stage IIIA (cT3, N0; cT4a, N0; cT1-4a, N1) disease if tumor is present upon reassessment of tumor status 2-3 months after primary treatment
    • stage IIIB (cT1-T4a, N2,3) disease as downstaging systemic therapy
    • stage IIIB (cT1-T4a, N2,3) disease following partial response or progression after primary treatment with concurrent chemoradiotherapy
    • stage IVA (cT4b, any N, M0; any T, any N, M1a) disease
    • stage IVB (any T, any N, M1b) disease
    • metastatic or local recurrence post cystectomy

• Urothelial Carcinoma of the Prostate
  
  Therapy for metastatic disease as a single agent for first-line systemic therapy (preferred) in cisplatin ineligible patients whose tumors express PD-L1 or who are not eligible for any platinum-containing chemotherapy regardless of PD-L1 expression; or second-line systemic therapy post-platinum (alternative preferred regimen) [2A].

Breast Cancer

• Invasive Breast Cancer
  
  Preferred therapy in combination with albumin-bound paclitaxel for PD-L1 positive triple negative recurrent or stage IV (M1) disease [2A].

Non-Small Cell Lung Cancer (NSCLC)

• Continuation maintenance therapy in combination with bevacizumab for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF negative and no contraindications to PD-1 or PD-L1 inhibitors in patients with performance status 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/paclitaxel/bevacizumab for nonsquamous cell histology [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 1 for all others].
• Continuation maintenance therapy for recurrent, advanced or metastatic disease for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF negative and no contraindications to PD-1 or PD-L1 inhibitors in patients with performance status 0-2 who achieve a response or stable disease following first-line therapy with atezolizumab/carboplatin/albumin-bound paclitaxel for nonsquamous cell histology [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for all others].
• Continuation maintenance therapy in combination with bevacizumab (if previously received first-line atezolizumab/carboplatin/paclitaxel/bevacizumab regimen) for recurrent, advanced or metastatic disease, performance status 0-2, and tumors of nonsquamous cell histology in patients who achieve tumor response or stable disease following initial systemic therapy [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 1 for all others]
• Continuation maintenance therapy (if previously received first-line atezolizumab/carboplatin/albumin-bound paclitaxel) for recurrent, advanced or metastatic disease, performance status 0-2, and tumors of nonsquamous cell histology in patients who achieve tumor response or stable disease following initial systemic therapy [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for all others]
• Preferred single agent as subsequent therapy for recurrent, advanced or metastatic disease in patients with performance status 0-2 and no prior progression on a PD-1/PD-L1 inhibitor [1 for first progression; 2A for subsequent progression; 2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease].
• Treatment for recurrent, advanced, or metastatic disease as first-line therapy for PD-L1 expression positive (≥1%) tumors that are EGFR, ALK, ROS1, BRAF negative and no contraindications to PD-1 or PD-L1 inhibitors and performance status 0-2 for nonsquamous cell histology [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for combination with carboplatin and albumin-bound pacilitaxel; 1 for all others]
  
  
  • in combination with bevacizumab, carboplatin and paclitaxel
  • in combination with carboplatin and albumin-bound paclitaxel
    
    
• Treatment for recurrent, advanced or metastatic disease in combination with carboplatin, paclitaxel, and bevacizumab, or in combination with carboplatin and albumin-bound paclitaxel for patients with performance status (PS) 0-1, no contraindications to PD-1 or PD-L1 inhibitors, and tumors of nonsquamous cell histology as [2B for locoregional recurrence or symptomatic local disease (excluding mediastinal lymph node recurrence with prior radiation therapy) with no evidence of disseminated disease; 2A for combination with carboplatin and albumin-bound paclitaxel; 1 for all others]
  
  
  • initial systemic therapy for EGFR, ALK, ROS1, BRAF negative and PD-L1 <1%
  • first-line (useful in certain circumstances) or subsequent therapy for BRAF V600E-mutation positive tumors
  • first-line (useful in certain circumstances) or subsequent therapy for NTRK gene fusion positive tumors
  • subsequent therapy for sensitizing EGFR mutation-positive tumors and prior erlotinib +/- (ramucirumab or bevacizumab), afatinib, gefitinib, osimertinib, or dacomitinib therapy
  • subsequent therapy for ALK rearrangement-positive tumors and prior crizotinib, ceritinib, alectinib, or brigatinib therapy
  • subsequent therapy for ROS1 rearrangement-positive tumors and prior crizotinib, entrectinib, or ceritinib therapy
  • subsequent therapy for PD-L1 expression-positive (≥1%) tumors and EGFR, ALK, ROS1, BRAF negative and no prior platinum-doublet chemotherapy and PD-1/PD-L1 inhibitor

Small Cell Lung Cancer

Preferred initial treatment in combination with etoposide and carboplatin followed by single agent maintenance for extensive stage disease in patients [1]

• without localized symptomatic sites or brain metastases and good performance status (PS 0-2)
• without localized symptomatic sites or brain metastases and poor PS (3-4) due to small cell lung cancer
• with localized symptomatic sites
• with brain metastases.

FDA-Approved Indications

1. Locally advanced or metastatic urothelial carcinoma
   
   
   1. Indicated for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma who:
      
      
      1. Are not eligible for cisplatin-containing chemotherapy, and whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells [IC] covering >5% of the tumor area), as determined by an FDA-approved test, or
      2. Are not eligible for any platinum-containing chemotherapy regardless of PD-L1 status, or
      3. Have disease progression during or following any platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant chemotherapy.
2. Metastatic non-small cell lung cancer (NSCLC)
   
   
   1. Indicated in combination with bevacizumab, paclitaxel, and carboplatin, for the first-line treatment, of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
   2. Indicated in combination with paclitaxel protein-bound and carboplatin for the first-line treatment of adult patients with metastatic non-squamous NSCLC with no EGFR or ALK genomic tumor aberrations.
   3. Indicated for the treatment of adult patients with metastatic NSCLC who have disease progression during or following platinum-containing chemotherapy. Patients with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving Tecentriq.
3. Unresectable locally advanced or metastatic triple-negative breast cancer (TNBC)
   
   Indicated in combination with paclitaxel protein-bound for the treatment of adult patients with unresectable locally advanced or metastatic TNBC whose tumors express PD-L1 (PD-L1 stained tumor-infiltrating immune cells (IC) of any intensity covering ≥ 1% of the tumor area), as determined by an FDA approved test.
   
   
4. Small cell lung cancer (SCLC)- Indicated in combination with carboplatin and etoposide, for the first-line treatment of adult patients with extensive-stage small cell lung cancer (ES-SCLC).

Source: Genentech, 2019

Appendix

Atezolizumab must be withheld for diagnoses listed below and must be permanently discontinued for diagnoses listed below (Genentech,  2019).

Diagnoses for which atezolizumab must be withheld
Grade 2 pneumonitis
Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) greater than 3 and up to 8 times upper limit of normal (ULN) or total bilirubin greater than 1.5 and up to 3 times ULN
Grade 2 or 3 diarrhea or colitis
Grade 2, 3 or 4 endocrinopathies (e.g., hyophysitis, adrenal insufficiency, hyperthyroidism, and type 1 diabetes mellitus)
Grade 3 other immune-mediated adverse reactions involving a major organ
Grade 3 or 4 infection

Diagnoses for which atezolizumab must be permanently discontinued
Grade 3 or 4 pneumonitis
AST or ALT greater than 8 times ULN or total bilirubin greater than 3 times ULN
Grade 4 diarrhea or colitis
Grade 4 other immune-mediated adverse reactions involving a major organ
Grade 3 or 4 infusion – related reactions
Persistent Grade 2 or 3 adverse reaction that does not recover to Grade 0 or 1 within 12 weeks after last Tecentriq dose
Inability to taper corticosteroid to less than or equal to prednisone 10 mg per day (or equivalent) within 12 weeks after last Tecentriq dose
Recurrent Grade 3 or 4 (severe or life-threatening) adverse reaction

Table: CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Information in the [brackets] below has been added for clarification purposes.   Codes requiring a 7th character are represented by "+" :
Other CPT codes related to the CPB :
81235	EGFR (epidermal growth factor receptor) (eg, non-small cell lung cancer) gene analysis, common variants (eg, exon 19 LREA deletion, L858R, T790M, G719A, G719S, L861Q)
96413 - 96415	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met :
J9022	Injection, atezolizumab, 10 mg
Other HCPCS codes related to the CPB:
J8560	Etoposide; oral, 50 mg
J8565	Gefitinib, oral, 250 mg
J9035	Injection, bevacizumab, 10 mg
J9045	Injection, carboplatin, 50 mg
J9060	Injection, cisplatin, powder or solution, 10 mg
J9181	Injection, etoposide, 10 mg
J9263	Injection, oxaliplatin, 0.5 mg
J9264	Injection, paclitaxel protein-hyphenbound particles, 1 mg
J9267	Injection, paclitaxel, 1 mg
J9271	Injection, pembrolizumab, 1 mg
J9299	Injection, nivolumab, 1 mg
Q5107	Injection, bevacizumab-awwb, biosimilar, (mvasi), 10 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung
C50.011 - C50.929	Malignant neoplasm of breast
C61	Malignant neoplasm of prostate [not covered for prostate adenocarcinoma]
C65.1 - C65.9	Malignant neoplasm of renal pelvis
C66.1 - C66.9	Malignant neoplasm of ureter
C67.0 - C67.9	Malignant neoplasm of bladder
C68.0	Malignant neoplasm of urethra
ICD-10 codes not covered for indications listed in the CPB (not all inclusive):
C15.3 - C20	Malignant neoplasm of esophagus, stomach, small intestine (including duodenum), colon, rectosigmoid junction and rectum
C22.0 - C22.9	Malignant neoplasm of liver, primary and intrahepatic bile ducts [cholangiocarcinoma]
C25.0 - C25.9	Malignant neoplasm of pancreas [pancreatic adenocarcinoma]
C43.0 - C43.9	Malignant neoplasm of skin
C45.0 - C45.9	Mesothelioma
C48.0 - C48.8	Malignant neoplasm of retroperitoneum and peritoneum
C49.0 - C49.9	Malignant neoplasm of other connective and soft tissue
C53.0 - C55	Malignant neoplasm of uterus
C56.1 - C56.9	Malignant neoplasm of ovary
C57.00 - C57.02	Malignant neoplasm of fallopian tube
C64.1 - C65.9	Malignant neoplasm of kidney and of renal pelvis [renal cell carcinoma]
C69.30 - C69.32	Malignant neoplasm of choroid [uveal melanoma]
C69.40 - C69.42	Malignant neoplasm of ciliary body [uveal melanoma]
C71.0 - C71.9	Malignant neoplasm of brain [glioblastoma]
C72.0 - C72.9	Malignant neoplasm of central nervous system [glioblastoma]
C73	Malignant neoplasm of thyroid gland
C81.00 - C81.99	Hodgkin lymphoma
C82.00 - C91.92	Malignant neoplasm of lymphoid, hematopoietic and related tissue [non-Hodgkin's lymphoma]
C90.00 - C90.02	Multiple myeloma [asymptomatic myeloma, smoldering multiple myeloma]
C90.20 - C90.32	Extramedullary/solitary plasmacytoma
C91.10 - C91.12, C91.9 - C91.91	Chronic lymphoid leukemia [chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL)]
C92.00 - C92.02	Acute myeloid leukemia
C93.10 - C93.12	Chronic myelomonocytic leukemia
D45	Polycythemia vera
D46.0 - D46.9	Myelodysplastic syndrome
D75.81	Myelofibrosis [primary]

The above policy is based on the following references: