Necitumumab (Portrazza)

Number: 0898

Policy

Aetna considers necitumumab (Portrazza) medically necessary for treatment of individuals with metastatic squamous non-small cell lung cancer (NSCLC) in combination with gemcitabine and cisplatin.

Aetna considers continued use of necitumumab medically necessary when there is no evidence of unacceptable toxicity or disease progression while on the current regimen.

Aetna considers combined necitumumab and abemaciclib for the treatment of NSCLC experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers combined necitumumab and pembrolizumab for the treatment of NSCLC experimental and investigational because the effectiveness of this approach has not been established.

Aetna considers necitumumab experimental and investigational for the treatment of other solid tumors (not an all-inclusive list):

• Colorectal cancer
• Head and neck squamous cell carcinoma
• Non-squamous NSCLC.

Dosing Recommendations

Necitumumab is available as Portrazza in 800 mg/50 mL vials for injection.  The recommended dose of necitumumab (Portrazza) is 800 mg (absolute dose) as an intravenous infusion over 60 minutes on days 1 and 8 of each 3-week cycle.  Portrazza is indicated to be given in combination with gemcitabine and cisplatin.

Source: Prescribing Information. Portrazza (necitumumab) injection, for intravenous use. 2015

Background

Portrazza (necitumumab) is a recombinant human lgG1 monoclonal antibody that binds to the human epidermal growth factor receptor (EGFR), a protein commonly found on squamous non-small cell lung cancer (NSCLC)., and blocks the binding of EGFR to its ligands. Expression and activation of EGFR has been correlated with malignant progression, induction of angiogenesis, and inhibition of apoptosis. Binding of necitumumab induces EGFR internalization and degradation in vitro. In vitro, binding of necitumumab also led to antibody‐dependent cellular cytotoxicity (ADCC) in EGFRexpressing cells.

The U.S. FDA approved Portrazza (necitumumab) in combination with gemcitabine and cisplatin, for the first‐line treatment of patients with metastatic squamous NSCLC.

Squamous Non-Small Cell Lung Cancer (NSCLC)

Takeda and Nakagawa (2015) stated that dysregulation of EGFR signaling due to receptor over-expression or activating mutation is associated with cancer cell proliferation, metastasis, and survival.  They noted that EGFR has become an important therapeutic target for NSCLC, and several EGFR-targeted agents, such as tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAbs), have been developed.  The EGFR-TKIs afatinib, erlotinib, and gefitinib have been approved by the Food and Drug Administration (FDA) for the treatment of advanced NSCLC, and sensitivity to these drugs has been shown to be associated with the presence of EGFR mutations.  Various mAbs to EGFR have also been evaluated in pre-clinical and clinical studies.  In particular, phase III clinical trials have shown a clinically significant survival benefit for addition of the anti-EGFR mAbs cetuximab or necitumumab to a platinum doublet in chemotherapy-naive patients with advanced NSCLC. 

Sacco et al (2015) noted that over the past 2 decades, progress in the treatment of patients with metastatic squamous NSCLC has been limited.  The EGFR is involved in tumor progression and invasion and therefore it has become the target of several studies in lung cancer.  Strategies to block this pathway are focused on the development of small molecule (TKI) and mAbs.  Some mAbs have been studied in patients with advanced NSCLC.  For the first time, a fully human immunoglobulin G (IMC-11F8), subclass 1 (IgG1) mAb targeting the EGFR, in combination with standard chemotherapy (cisplatin + gemcitabine), has been shown to increase overall survival (OS) in chemo-naive patients with confirmed metastatic squamous cell histology.

In an open-label, phase III, multi-center, randomized controlled trial (RCT), Thatcher et al (2015) compared treatment with necitumumab plus gemcitabine and cisplatin versus gemcitabine and cisplatin alone in patients with previously untreated stage IV squamous NSCLC.  This study was carried out at 184 sites in 26 countries.  Patients aged 18 years or older with histologically or cytologically confirmed stage IV squamous NSCLC, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 and adequate organ function and who had not received previous chemotherapy for their disease were eligible for inclusion.  Enrolled patients were randomly assigned 1:1 to a maximum of six 3-week cycles of gemcitabine and cisplastin chemotherapy with or without necitumumab according to a block randomization scheme (block size of 4) by a telephone-based interactive voice response system or interactive web response system.  Chemotherapy was gemcitabine 1,250 mg/m(2) administered intravenously over 30 mins on days 1 and 8 of a 3-week cycle and cisplatin 75 mg/m(2) administered intravenously over 120 mins on day 1 of a 3-week cycle.  Necitumumab (800 mg), administered intravenously over a minimum of 50 mins on days 1 and 8, was continued after the end of chemotherapy until disease progression or intolerable toxic side effects occurred.  Randomization was stratified by ECOG performance status and geographical region.  Neither physicians nor patients were masked to group assignment because of the expected occurrence of acne-like rash -- a class effect of EGFR antibodies -- that would have unmasked most patients and investigators to treatment.  The primary end-point was OS, analyzed by intention-to-treat.  Between January 7, 2010, and February 22, 2012, these researchers enrolled 1,093 patients and randomly assigned them to receive necitumumab plus gemcitabine and cisplatin (n = 545) or gemcitabine and cisplatin (n = 548).  Overall survival was significantly longer in the necitumumab plus gemcitabine and cisplatin group than in the gemcitabine and cisplatin alone group (median of 11.5 months [95 % confidence intervals [CI] 10.4 to 12.6]) versus 9.9 months [8.9 to 11.1]; stratified hazard ratio (HR) 0.84 [95 % CI: 0.74 to 0. 96; p = 0.01]).  In the necitumumab plus gemcitabine and cisplatin group, the number of patients with at least 1 grade-3 or worse adverse event was higher (388 [72 %] of 538 patients) than in the gemcitabine and cisplatin group (333 [62 %] of 541), as was the incidence of serious adverse events (257 [48 %] of 538 patients versus 203 [38 %] of 541).  More patients in the necitumumab plus gemcitabine and cisplatin group had grade 3 to 4 hypomagnesaemia (47 [9 %] of 538 patients in the necitumumab plus gemcitabine and cisplatin group versus 6 [1 %] of 541 in the gemcitabine and cisplatin group) and grade 3 rash (20 [4 %] versus 1 [less than 1 %]).  Including events related to disease progression, adverse events with an outcome of death were reported for 66 (12 %) of 538 patients in the necitumumab plus gemcitabine and cisplatin group and 57 (11 %) of 541 patients in the gemcitabine and cisplatin group; these were deemed to be related to study drugs in 15 (3 %) and 10 (2 %) patients, respectively.  Overall, these researchers found that the safety profile of necitumumab plus gemcitabine and cisplatin was acceptable and in line with expectations.  The authors concluded that these findings showed that the addition of necitumumab to gemcitabine and cisplatin chemotherapy improved OS in patients with advanced squamous NSCLC and represented a new first-line treatment option for this disease.

On November 24, 2015, the FDA approved necitumumab (Portrazza) in combination with 2 forms of chemotherapy to treat patients with metastatic squamous NSCLC who have not previously received medication specifically for treating their advanced lung cancer based on the findings of the phase III clinical trial by Thatcher et al (2015).  However, necitumumab was not found to be an effective treatment in patients with non-squamous NSCLC.  The most common side effects of necitumumab are skin rash and hypomagnesemia, which can cause muscular weakness, seizure, irregular heartbeats and can be fatal.  Portrazza includes a boxed warning to alert health care providers of serious risks of treatment with necitumumab, including cardiac arrest and sudden death, as well as hypomagnesemia.

In the clinical trial which led to FDA‐approval, Portrazza was given in combination with gemcitabine (1250 mg/m2, Days 1 and 8) plus cisplatin (75 mg/m2, Day 1) every 3 weeks (1 cycle). Gemcitabine and cisplatin were administered for a maximum of 6 cycles in the absence of disease progression or unacceptable toxicity. Portrazza (800 mg by intravenous infusion on Days 1 and 8 of each 3‐week cycle) was administered prior to gemcitabine and cisplatin. Patients demonstrating at least stable disease on Portrazza plus gemcitabine and cisplatin were to continue Portrazza as a single agent in the absence of disease progression or unacceptable toxicity after completion of 6 planned courses of chemotherapy or if chemotherapy was discontinued for toxicity.

The Portrazza/cisplatin/gemcitabine regimen was added to the NCCN NSCLC guidelines as a category 3 recommendation. In the opinion of the authors, the category 3 recommendation reflects the fact that the panel does not prefer the addition of Portrazza to the already established regimen based on toxicity, cost, and limited improvement in efficacy, relative to cisplatin/gemcitabine. The NCCN panel voted unanimously to delete the necitumumab/cisplatin/gemcitabine regimen from the NCCN guidelines on "Non-small cell lung cancer" (version 6.2018) per aforementioned.

Lack of efficacy of Portrazza in combination with pemetrexed and cisplatin for the treatment of patients with metastatic non‐squamous NSCLC was determined in the INSPIRE trial; a randomized, open‐label, multicenter trial. The study was closed prematurely after 633 patients were enrolled due to increased incidence of death due to any cause and of thromboembolic events in the Portrazza arm. The main efficacy outcome was OS. Progression‐free survival (PFS) and overall response rate (ORR) were also assessed. Addition of Portrazza to pemetrexed and cisplatin did not improve OS [HR=1.01; 95%CI (0.84, 1.21)]; PFS [HR=0.96; 95% CI (0.8, 1.16)] or ORR (31% in the Portrazza plus pemetrexed and cisplatin arm and 32% in the pemetrexed and cisplatin alone arm).

Black Boxed Warnings

• Cardiopulmonary arrest and/or sudden death occurred in 3.0% of patients treated with Portrazza in combination with gemcitabine and cisplatin. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, with aggressive replacement when warranted during and after Portrazza administration.
• Hypomagnesemia occurred in 83% of patients receiving Portrazza in combination with gemcitabine and cisplatin, and was severe in 20% of patients. Monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia prior to each dose of Portrazza during treatment and for at least 8 weeks following completion of Portrazza. Withhold Portrazza for Grade 3 or 4 electrolyte abnormalities. Replete electrolytes as medically appropriate.

Warnings and Precautions

• Venous and Arterial Thromboembolic Events
• Dermatologic Toxicities
• Infusion‐Related Reactions
• Embryo‐Fetal Toxicity

Experimental Indications

Necitumumab is also being investigated in the treatment of other solid tumors; however, its effectiveness for these indications has not been established.

Colorectal Cancer

Dienstmann and Tabernero (2010) stated that necitumumab (IMC-11F8) is a fully human IgG1 mAb targeting the EGFR for the potential  treatment of cancer, in particular NSCLC.  Pre-clinical studies indicated that the anti-tumor activity of necitumumab is either comparable with or superior to that of cetuximab (a chimeric anti-EGFR mAb).  In a phase I clinical trial in patients with advanced solid malignancies, necitumumab displayed non-linear pharmacokinetic behavior.  The toxicity profile of necitumumab is acceptable, with skin toxicity being the most frequently reported adverse event in the phase I and II clinical trials conducted to date.  The authors stated that preliminary data from a phase II clinical trial of necitumumab in combination with chemotherapy for the first-line treatment of advanced colon cancer are promising. 

Furthermore, a phase II clinical trial on the use of IMC-11F8 in combination with chemotherapy in the treatment of colorectal cancer has been completed (Last updated: January 22, 2014). 

Head and Neck Squamous Cell Carcinoma

Cohen (2014) stated that over-expression of the EGFR is a common characteristic of head and neck squamous cell carcinomas (HNSCC).  Cetuximab is a chimeric anti-EGFR mAb with multiple approved indications in HNSCC, including with radiation therapy (RT) for locoregionally advanced disease, as monotherapy after platinum progression, and with platinum/5-fluorouracil for recurrent or metastatic disease.  There remain, however, numerous unanswered questions regarding the optimal use of cetuximab in HNSCC, including patient selection, its mechanisms of action and resistance, the effect of human papillomavirus status on outcomes, its role when combined with induction chemotherapy or adjuvant radiation, and optimal management of skin toxicity and hypersensitivity reactions.  In addition, a variety of other anti-EGFR agents (the multi-targeted small molecule TKIs lapatinib, dacomitinib, and afatinib and the anti-EGFR mAbs zalutumumab, nimotuzumab, and panitumumab) are currently under investigation in phase II and III clinical trials in different HNSCC therapeutic settings.  The anti-EGFR TKI erlotinib is currently in phase III development for oral cancer prevention.  Numerous other drugs are in earlier stages of development for HNSCC treatment, including novel anti-EGFR mAbs (MEHD7945A, necitumumab, and RO5083945), small-molecule TKIs (vandetanib, icotinib, and CUDC-101), EGFR anti-sense, various add-on therapies to radiation and chemotherapy (bevacizumab, interleukin-12, lenalidomide, alisertib, and VTX-2337), and drugs (temsirolimus, everolimus, OSI-906, dasatinib, and PX-866) intended to overcome resistance to anti-EGFR agents.  Overall, a wealth of clinical trial data is expected in the coming years, with the potential to modify significantly the approach to anti-EGFR therapy for HNSCC.

Non-Squamous Non-Small-Cell Lung Cancer

In an open-label, randomized, controlled phase-III clinical trial, Paz-Ares and colleagues (2915) compared necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated, stage IV, non-squamous non-small-cell lung cancer (NSCLC).  This phase-III study was carried out at 103 sites in 20 countries.  Patients aged 18 years or older, with an ECOG performance status of 0 to 2 and adequate organ function, were randomly assigned 1:1 to treatment with a block randomization scheme (block size of 4) via a telephone-based interactive voice-response system or interactive web-response system.  Patients received either cisplatin 75 mg/m(2) and pemetrexed 500 mg/m(2) on day 1 of a 3-week cycle for a maximum of 6 cycles alone, or with necitumumab 800 mg on days 1 and 8. Necitumumab was continued after the end of chemotherapy until disease progression or unacceptable toxic effects.  Randomization was stratified by smoking history, ECOG performance status, disease histology, and geographical region.  Patients and study investigators were not masked to group assignment.  The primary end-point was OS.  Efficacy analyses were by intention-to-treat.  Between November 11, 2009, and February 2, 2011, these researchers randomly assigned 633 patients to receive either necitumumab plus pemetrexed and cisplatin (n = 315) or pemetrexed and cisplatin alone (n = 318).  Enrolment was stopped on February 2, 2011, after a recommendation from the independent data monitoring committee.  There was no significant difference in OS between treatment groups, with a median OS of 11·3 months (95 % CI: 9.5 to 13.4) in the necitumumab plus pemetrexed and cisplatin group versus 11.5 months (10.1 to 13.1) in the pemetrexed and cisplatin group (HR 1.01 [95 % CI: 0.84 to 1.21]; p = 0·96).  The incidence of grade 3 or worse adverse events (AEs), including deaths, was higher in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group; in particular, deaths regarded as related to study drug were reported in 15 (5 %) of 304 patients in the necitumumab group versus 9 (3 %) of 312 patients in the pemetrexed and cisplatin group.  Serious AEs were like-wise more frequent in the necitumumab plus pemetrexed and cisplatin group than in the pemetrexed and cisplatin group (155 [51 %] of 304 versus 127 [41 %] of 312 patients).  Patients in the necitumumab plus pemetrexed and cisplatin group had more grade 3 to 4 rash (45 [15 %] of 304 versus 1 [less than 1 %] of 312 patients in the pemetrexed and cisplatin alone group), hypo-magnesemia (23 [8 %] versus 7 [2 %] patients), and grade 3 or higher venous thrombo-embolic events (VTE; 23 [8 %] versus 11 [4 %] patients) than did those in the pemetrexed and cisplatin alone group.  The authors concluded that these findings showed no evidence to suggest that the addition of necitumumab to pemetrexed and cisplatin increased survival of previously untreated patients with stage IV non-squamous NSCLC.  Moreover, they stated that unless future studies identify potentially useful predictive biomarkers, necitumumab is unlikely to provide benefit in this patient population when combined with pemetrexed and cisplatin.

Combined Necitumumab and Abemaciclib for the Treatment of NSCLC

In a 2-part, single-arm, multi-center, phase-Ib clinical trial, Besse and colleagues (2019) examined the safety and efficacy of necitumumab and abemaciclib in patients with NSCLC.  This trial was carried out to test the safety and efficacy of necitumumab plus abemaciclib in patients with advanced NSCLC who had received less than or equal to 2 lines of chemotherapy, including a platinum-based one.  Part A was a dose-escalation phase for abemaciclib (100, 150, 200 mg, every 12 hours [Q12H]) in combination with necitumumab 800 mg Day 1 and 8 every 3 weeks (D1D8 Q3W) to determine the recommended dose for the expansion cohort.  Part B -- he primary end-point was PFS rate at 3 months.  A total of 66 patients entered the study: 71 % male, 41 % squamous histology, 15 % never-smokers.  In Part A (n = 15), the maximum tolerated dose (MTD) of abemaciclib was 150 mg Q12H in combination with necitumumab 800 mg.  In 57 patients treated at this dose level, the 3-month PFS rate was 32.3 % (95 % CI: 20.4 to 44.8); median PFS was 2.14 months (1.41 to 2.76).  The ORR was 5.3 % (1.1 to 14.6).  The median OS was 6.93 months (4.96 to 12.85).  In the exploratory subgroup analysis of EGFR expression-negative patients (n = 10), both the 3-month PFS and ORR were 0.0 %.  The most common grade-3 treatment-emergent AEs were fatigue (14 %), dyspnea (9 %), diarrhea (7 %), vomiting (7 %), and hypokalemia (7 %).  The authors concluded that abemaciclib 150 mg Q12H with necitumumab 800 mg did not produce an additive effect over single-agent activity in patients with stage IV NSCLC.  The safety profile was consistent with the individual study drugs.

Combined Necitumumab and Pembrolizumab for the Treatment of NSCLC

In a single-arm, multi-center, phase-Ib clinical trial, Besse and colleagues (2020) examined the safety and efficacy of necitumumab when combined with pembrolizumab in patients with stage IV NSCLC of squamous and non-squamous histology, who had progressed after treatment with a platinum-based doublet.  This trial had a dose-finding phase, in which escalating doses of necitumumab (600 mg and 800 mg IV) were administered on Day 1 and 8 every 3 weeks (Q3W) in combination with pembrolizumab (200 mg IV) on Day 1 Q3W, and expansion cohorts.  Patients were treated until progressive disease (PD), toxicity requiring cessation, protocol non-compliance, or withdrawal of consent.  Efficacy was evaluated by ORR.  In 64 treated patients (32 patients [50 %] were programmed death-ligand 1 [PD-L1] negative), confirmed ORR was 23.4 % (95 % CI: 13.8 % to 35.7 %).  Two patients (3.1 %) had complete response (CR), 13 patients (20.3 %) had partial response (PR), 26 patients (40.6 %) had stable disease (SD), 17 patients (26.6 %) had PD, and 6 patients (9.4 %) were not evaluable.  Regardless of histology or PD-L1 status, median PFS (mPFS) was 4.1 months (95 % CI: 2.4 to 6.9 months) and OS at 6 months was 74.7 % (61.5 % to 83.9%).  Confirmed disease control rate was 64.1 % (95 % CI: 51.5 to 75.7).  Patients with PD-L1 greater than or equal to 1 % had numerically improved ORR and mPFS when compared with patients with PD-L1 negative cancer.  No dose-limiting toxicities (DLTs) were recorded and the combination of necitumumab 800 mg with pembrolizumab 200 mg was considered tolerable.  The authors concluded that the findings of this study suggested modest benefits of 2nd-line necitumumab and pembrolizumab combination therapy in patients with stage IV NSCLC.  Safety profiles were consistent with class effects typical of EGFR inhibitors and immunotherapies with no additive toxicities.  These preliminary findings need further validated in phase-II/III clinical trials.

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 :
96413 - 96416	Chemotherapy administration, intravenous infusion technique
HCPCS codes covered if selection criteria are met:
J9295	Injection, necitumumab, 1 mg
Other HCPCS codes related to the CPB:
Abemaciclib - no specific code
J9060	Injection, cisplatin, powder or solution, 10 mg
J9201	Injection, gemcitabine HCl, 200 mg
J9271	Injection, pembrolizumab, 1 mg
ICD-10 codes covered if selection criteria are met:
C34.00 - C34.92	Malignant neoplasm of bronchus and lung [metastatic squamous non-small cell lung cancer (NSCLC)] [not covered for non-squamous small cell lung cancer]
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C19	Malignant neoplasm of rectosigmoid junction [colorectal cancer]
C76.0	Malignant neoplasm of head, face and neck [head and neck squamous cell carcinoma]

The above policy is based on the following references: