Back Back
Necitumumab in Squamous NSCLC
My Thoughts on Necitumumab for Patients With Newly Diagnosed Squamous NSCLC

Released: March 02, 2016

Expiration: March 01, 2017

Activity Information

Activity

Progress
1
Course Completed
Continue

Case Report
A 68-year-old man with a heavy smoking history who hasn’t smoked in 20 years presented with a cough and mild hemoptysis. A PET/CT scan showed a right‑upper lobe lesion and mediastinal lymphadenopathy, as well as an adrenal metastasis and multiple bony metastases. A biopsy confirmed squamous non-small-cell lung cancer (NSCLC). The patient is a recently retired executive, fully functional with an excellent performance status.

He is interested in the best available options for first-line therapy. Considering the currently approved treatments available in this setting, he was determined to be a prime candidate for necitumumab in addition to chemotherapy.

At Long Last, a New Option
There have been no major advances in first‑line therapy for advanced squamous NSCLC for more than 20 years, in contrast to the expanding options for nonsquamous NSCLC. Multiple phase III trials have evaluated the addition of new targeted agents to chemotherapy regimens in squamous NSCLC and failed to show clinical benefit. So new effective therapies for squamous NSCLC represent an unmet need. In addition, some effective agents for nonsquamous NSCLC are contraindicated in squamous NSCLC, either due to toxicity (eg, bevacizumab) or reduced efficacy (eg, pemetrexed). Necitumumab, a new anti-EGFR monoclonal antibody, was recently approved in combination with chemotherapy by both the FDA and the EMA as first-line therapy for patients with squamous NSCLC based on results from the phase III SQUIRE trial (N = 1093) that demonstrated improved response, PFS, and OS. This is the only advance for first-line therapy of squamous NSCLC in 20 years, and this point cannot be overemphasized.

Why would a drug like necitumumab be effective in squamous NSCLC? Compared with adenocarcinoma, squamous NSCLC is much more likely to demonstrate EGFR protein expression, present in > 90% of cases. Although EGFR isn’t mutated, as in adenocarcinomas, the EGFR pathway is still important in cell proliferation, and it is still a valid therapeutic target. Many studies have demonstrated that EGFR-directed therapy is effective in squamous NSCLC, such as BR21, which showed that the TKI erlotinib improves survival in lung cancer with wild-type EGFR. In fact, the HR for erlotinib therapy was even higher in squamous cancer than it was in adenocarcinoma. Erlotinib was approved based on these data. The rationale here is that despite a low response rate, there is improved disease control, and that slowing growth results in improved survival in patients with wild-type EGFR.

With anti-EGFR monoclonal antibodies, there are additional mechanisms of activity in wild-type EGFR cancers, such as receptor internalization and ADCC. The data from SQUIRE showed that adding necitumumab to gemcitabine/cisplatin chemotherapy increased PFS and OS. Median OS was 11.5 months with the combination vs 9.9 months without necitumumab (P = .01) (Figure). Aside from rash, which is the primary adverse event of necitumumab, there was very little added toxicity in the combination arm, with nearly identical rates of grade 3/4 toxicities. Patients do need to be monitored for electrolyte abnormalities, and replacement needs to be given when appropriate. The SQUIRE data also showed that adding necitumumab to chemotherapy did not adversely affect quality of life.

A current hot topic is the value of cancer therapy. ASCO, ESMO, the NCCN, and healthcare providers all assess the value of new drugs and have recommended at least a 2‑month improvement in median OS as a parameter of effectiveness. Frankly, this is problematic because the median doesn’t reflect the overall Kaplan‑Meier curve and, therefore, is a poor way to assess efficacy. We now have many studies in lung cancer, where median PFS or OS do not reflect the true benefit. Of most importance, these value assessments do not reflect the impact of therapies on an individual patient basis. For the last several years, I have used cetuximab plus chemotherapy in many such patients and would now consider necitumumab in first-line therapy for squamous NSCLC.

Figure. SQUIRE: Median OS.



Addressing Hypomagnesemia Concerns
There exists concern that necitumumab could create electrolyte problems, in particular hypomagnesemia, which rarely might result in cardiac arrhythmia and sudden death. This risk is highlighted in a black‑box warning. But in my opinion, this concern stems from the SQUIRE trial design, which did not require replacement of electrolytes and resulted in some patients experiencing profound hypomagnesemia that was not addressed by replacement therapy. Cetuximab, which has been in used safely for decades, is associated with a similar hypomagnesemia. Every clinical trial of cetuximab takes this into account, and every oncologist who uses cetuximab knows that replacement magnesium is needed. The SWOG 0819 study of the addition of cetuximab to standard therapies in stage IV NSCLC did not show problems like cardiac arrhythmia and sudden death because the electrolytes were replaced as needed, including calcium and potassium. If the SQUIRE trial had mandated electrolyte replacement, I personally don’t think this concern over hypomagnesemia would have arisen.

Can We Increase the Benefit Through Better Patient Selection?
Lastly, is there a subset of patients with squamous NSCLC who would be most likely to benefit from a drug like necitumumab? The emerging data suggest that the answer is yes. In the FLEX trial of cetuximab, patients with squamous histology and a higher EGFR protein level in their tumor were most likely to benefit. In the SQUIRE trial of necitumumab, those patients with EGFR overexpression by FISH showed a trend for longer survival (median OS: 12.6 vs 9.2 months; HR: 0.70; P = .066). The HR for OS was 0.84 for all patients, but 0.75 in those with high EGFR expression, representing an increase in median OS of approximately 3.5months. Note that this analysis was retrospective rather than prospective and was not part of the FDA approval.

In a similar fashion, SWOG 0819 is a recently completed phase III trial, in all histologies of advanced NSCLC, of the addition of cetuximab to chemotherapy (with or without bevacizumab). Results showed no benefit for cetuximab in the overall population but, as in the SQUIRE trial, a subset analysis showed a positive effect in the squamous‑cell subset, in patients with cancers positive for EGFR by FISH. In this group, the HR for survival was 0.56, which is highly statistically significant and represents > 5-month difference.

Based on these consistent observations, I think that further prospective studies are needed and warranted to better define which patients will obtain the most benefit from anti-EGFR monoclonal antibodies.

Please let me know in the comments how you would treat this patient or if you have used necitumumab in your own clinical practice.

Continue

Poll

1.
What would you recommend for the patient described in this post?
2.

Die Ergebnisse der CAPTIVATE- und GLOW-Studien unterstützen welche der folgenden Kombinationen im Erstlinien-Setting für CLL?
3.

Welche der folgenden BTK-Inhibitoren der nächsten Generation haben bei Patienten mit CLL und Progression der Erkrankung bei Einnahme von Ibrutinib aufgrund einer BTK-C481-Resistenzmutation eine Wirkung ausgelöst?
4.

Welcher der folgenden Patienten mit MCL würde sich für die Aufnahme in die Phase-III-BRUIN-MCL-321-Studie qualifizieren?
Submit