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How I optimize treatment for my patients with advanced squamous NSCLC: present options and future perspectives

LUIS PAZ-ARES

Luiz Paz-Ares

The prevalence of squamous-cell carcinoma is lessening globally, accounting for 11-28% and 27-46% of all NSCLCs in women and men respectively. These carcinomas frequently have genetic mutations in multiple pathways and have completely different molecular backgrounds than to non- squamous NSCLCs. With adenocarcinomas we often see mutations in oncogenes, but in squamous-cell carcinoma there are mutations in tumour-suppressor genes such as TP53. These are very difficult to target pharmacologically and it has hampered treatment progression.

Patient demographics differ, with adenocarcinoma more prevalent in women, patients tend to be non-smokers and younger, whereas squamous-cell carcinomas are more prevalent in men, is associated with smoking and patients are older. The tumour location is generally peripheral in adenocarcinomas, and adenocarcinomas tend to metastasize, with brain metastasis more common. The tumour location is generally central in squamous-cell carcinomas, are more prone to remain localized and brain metastasis is less common.

Overall, advanced squamous NSCLC is associated with a worse prognosis (median OS time of 9-11 months) than for advanced non-squamous NSCLC (median OS of 12-14 months).

Front-line treatments involve platinum-based chemotherapy, but have not improved survival much compared to supportive care alone. Typically in clinic, we choose one of a number of doublet chemotherapies based on the toxicity profile, patient characteristics such as PS and comorbidities, convenience of the therapy (for patients who are not close to a clinic for example), cost of therapy and local experience.

Clinical trial data shows that gemcitabine is slightly better than pemetrexed in squamous NSCLC. For cisplatin versus carboplatin, there is little difference in survival benefit. In Dr Paz-Ares’ clinic, he will select carboplatin over cisplatin due to the poor health and comorbidities he typically sees in his Stage IV squamous NSCLC patients.

For non-squamous NSCLC patients, maintenance therapy can offer benefit, but this is not the case in squamous NSCLC patients and is not recommended. Partly this is due to a lack of data and very small numbers in clinical trials attempting to look at OS and PFS endpoints.

Improvements in front-line treatments are emerging. For example in the Squire Trial, necitumumab was added to cisplatin + gemcitabine in squamous NSCLC patients, and improved OS rates were observed compared to cisplatin + gemcitabine alone (1 year OS of 48% versus 43% and 2 year OS of 20% vs 17%, hazard ratio = 0.84). Caution is advised for patients over 70 years of age, where toxicity associated with necitumumab administration can have an impact.

Very few new 1 st -line treatment options have been approved for patients with squamous NSCLC. One is a nanoparticle albumin-bound formulation of paclitaxel (nab-paclitaxel) + carboplatin, which significantly improved overall response rate (ORR), when compared with solvent-based paclitaxel + carboplatin.

Recently, pembrolizumab was approved in Europe for 1 st -line treatment of patients with both squamous and non-squamous metastatic NSCLC whose tumours had high PD-L1 expression with no EGFR or ALK aberrations. Approval was based on the KEYNOTE-024 data which interestingly showed a benefit that was higher for squamous than for non-squamous NSCLC.

Second-line treatment includes docetaxel, which has a benefit over best standard of care. There is trial data showing that afatanib may be better than erlotinib, however, there is a debate on erlotinib’s role as a standard of care—particularly for squamous NSCLC, which then casts a shadow over afatanib’s place in therapy. Docetaxel + ramucirumab versus docetaxel showed a small benefit in OS (10.5 months versus 9.1 months) when ramucirumab was added. PD-(L)1 inhibitors, such as nivolumab, are having a modest impact on OS in squamous NSCLC.

Dr Paz-Ares describes a case study involving a 60 year old male, smoker with arterial hypertension who presented with left thoracic pain and dyspnoea with an acute haemoptysis. Bronchoscopy revealed direct invasion of the left bronchial tree, and pathology was squamous NSCLC, CK 5/6 & p63+, CK 7/TTF-1- . PET-CT showed a left hiliar-mediastinal mass and multiple bone, liver and renal masses.

He was treated with cisplatin/gemcitabine + necitumumab (Phase 2 JFCK trial) × 6 cycles and had a nice partial response so he was then given necitumumab every 3 weeks. Toxicity was low, involving a Grade 1 rash, Grade 1 hypomagnesaemia, and Grade 1 paronychia. After 13 months, the disease progressed with new liver metastasis appearing. His PS was 1 and he was oligosymptomatic. He was given pembrolizumab and had a partial response and tolerated treatment well, with no G3 or G4 toxicity.

After 2.4 months of pembrolizumab he presented to hospital with dyspnoea and lung infiltrates that may have been toxic pneumonitis or infection. Pembrolizumab was delayed and levofloxacin given for 7 days. Three days later he had a breathless dry cough and wheezing, oxygen saturation of 93% and was diagnosed with Grade 2 pneumonitis and was given prednisolone p.o. and inhalers and improved in 48 hours. Over 6 weeks the steroids were tapered and pembrolizumab resumed. After 40 months of the initial diagnosis, the patient continues to do well. Dr Paz-Ares concludes by stating the even 10 years ago there would not have been an expected survival of 40 months for a patient with Stage IV squamous NSCLC.

In conclusion:

  • Squamous NSCLC is a distinct disease that affects each patient differently.
  • There continues to be an unmet clinical need in treating squamous NSCLC as the prognosis is still poor.
  • Front-line treatment:
    – Platinum-based chemotherapy is the keystone.
    – Added value of necitumumab (triplet therapy) and abraxane (doublet therapy).
    – Immuno-oncology is gaining ground: e.g., using pembrolizumab in tumours expressing high levels of PD-L1.
  • Some improvements in the second-line setting:
    – PD-(L)1 inhibitors are a standard of care in cases with no prior immuno-oncological treatment.
    – Ramucirumab plus docetaxel, and docetaxel monotherapy are alternatives (with aggressive disease or PD-L1- negative tumours).
    – Afatinib to be considered in further lines.

(At the 28.48 mark of this session, a question and answer period starts, which is not summarised here.)