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


Joachim Aerts

Dr Aerts begins by asking the attendees, “do you screen for genetic abnormalities in stage IV patients with non-squamous NSCLC?”

  1. No, because I do not think this is of additional value
  2. No, because it is not possible at my institute
  3. Yes, with next-generation sequencing
  4. Yes, but only for EGFR and ALK

The majority do testing and responses were divided between options 3 and 4.

Should every patient be treated with a PD-1/PD- L1 checkpoint inhibitor as second-line treatment?

  1. Yes, regardless of PD-L1 status
  2. No, only in patients who have PD-L1- positive tumours

The attendees were divided in their response.

The ESMO clinical practice guidelines for diagnosis, treatment and follow-up of metastatic NSCLC were updated in 2016. The field is evolving quickly and Dr Aerts reviews these updates, which state that clinicians must incorporate histology, molecular pathology, age and performance status of the patient, comorbidities and patient preferences.

The guidelines for 1 st -line treatment of Stage IV non-squamous NSCLC are to treat with crizotinib in the case of an ALK translocation and to treat with gefitinib, erlotinib + bevacizumab, or afatanib with an EGFR mutation. In the case of no EGFR/ALK mutation, treatment is based on age and performance status using: platinum combinations ± bevacizumab if under 70 years of age with PS 0-1, using a carboplatin-based doublet or single-agent chemotherapy if under 70 years of age and PS 2, or of over 70 years of age and PS 0-2, and providing best supportive care if PS 3-4, regardless of age.

Following 1 st -line treatment, if PS 0-1 with a partial response or stable disease, maintenance treatment can be given using pemetrexed (switch or continuation), or erlotinib (with an EGFR-activating mutation) ± bevacizumab (if given before). In summary, in the ESMO guidelines in the 1 st -line setting there has been no major change in chemotherapy-treatment options and no evidence for the best combination-chemotherapy choice, however there are rapid developments in the number of targeted therapies, the number of targets and in targeted treatment options. We don’t know how to sequence these different agents, and there are cost considerations in determining sequencing using clinical trials, so perhaps other methods need to be developed.

Dr Aerts reviews several clinical trials using targeted therapies. A comparison of osimertinib versus platinum+pemetrexed as a 2 nd -line therapy in EGFR-mutated patients treated at progression showed osimertinib outperformed chemotherapy. Another trial comparing ceritinib to chemotherapy following crizotinib therapy showed ceritinib outperformed chemotherapy. The question now is to figure out the sequence of these types of therapy.

In the KEYNOTE-024 study, patients with untreated Stage IV NSCLC, high PD-L1 expression, PS 0-1, no activating EGFR mutation or ALK translocation were administered either pembrolizumab for 2 years or platinum-doublet chemotherapy for 4-6 cycles until progression and then switched to pembrolizumab for 2 years. The primary endpoint of median progression-free survival was met, with 10.3 months for pembrolizumab versus 6.0 months for chemotherapy followed by pembrolizumab.

At progression of Stage IV non-squamous NSCLC, the ESMO guidelines recommend best supportive care for patients with PS 3-4. For those with PS 0-2, there are many treatment options: pemetrexed, docetaxel, nivolumab, pembrolizumab, ramucirumab + docetaxel, nintedanib + docetaxel or erlotinib.

Dr Aerts illustrates choice of treatment using several case studies. Case 1 is a 66-year old female, PS 1, never smoker, diagnosed with an adenocarcinoma which was K-ras+ by next generation sequencing. No PD-L1 determination was performed. In January 2015, she had a lobectomy of the left lower lobe which was a T1N0M0 NSCLC. In July 2015 she developed multiple lung lesions and was treated with cisplatin + pemetrexed for 4 cycles. She showed progression after 2 cycles of maintenance treatment, had PS 1 and suffered with fatigue.

What would be your treatment, except for re-evaluation of the mutation status?

  1. Docetaxel
  2. Docetaxel and anti-angiogenic agents
  3. Nivolumab
  4. Pembrolizumab
  5. Atezolizumab
  6. Erlotinib
  7. No further treatment
  8. Prefer immunotherapy, but no reimbursement at my institute

The majority selected nivolumab, followed by docetaxel and anti-angiogenic agents and docetaxel.

The treatment options for post-platinum progression are numerous; chemotherapy (docetaxel or pemetrexed if not given previously) EGFR TKI (erlotinib or afatinib), anti-angiogenics (nintedanib or ramucirumab, both + docetaxel if not given previously) or immune checkpoint inhibitors (nivolumab, pembrolizumab or atezolizumab). Note that erlotinib may be inferior to chemotherapy in wild-type patients, afatinib is only approved for squamous NSCLC, nintedanib is only approved for adenocarcinoma and pembrolizumab is only approved for patients with PD-L1 expression.

Dr Aerts reviews the endpoints for several clinical trials for 2 nd -line treatments, including the LUME- lung 1 and REVEL studies. For PD-(L)1, data for 2 nd -line therapy compared docetaxel to a PD-(L)1 checkpoint inhibitor, with a primary endpoint of overall survival (OS). The first trial compared nivolumab to docetaxel in non-squamous NSCLC and showed an increase in OS of nivolumab (hazard ratio = 0.73). Another trial in PD-L1+ tumours showed pembrolizumab OS was superior to docetaxel. In the atezolizumab (PD-L1 antibody) versus docetaxel study, the hazard ratio (0.73) favoured atezolizumab.

For the case-study patient, she was started on nivolumab, 3 mg/kg q2wk in December. In February the CT scan showed an increase in nodule size.

What would you do?

  1. Stop treatment and refer for best supportive care
  2. Stop treatment and docetaxel with/without anti-angiogenic agents
  3. Continue treatment, this may be pseudoprogression?

About 2/3 would continue treatment. Dr Aerts continued nivolumab and by May 2016 there was a response. By January 2017 she showed a complete response. She was one of the rare incidences of pseudoprogression (which is thought to occur in <10% of patients).

Case study 2 was a 66-year old male, PS 1, NSCLC, adenocarcinoma, negative for EGFR, ALK, PD-L1

expression negative and was a smoker with myocardial infarction. He had T2N3M1c NSCLC and was treated with cisplatin + pemetrexed every 21 days. Disease was stable after 2 cycles and progressed after 4 cycles. Performance status was 1 and the patient wanted ‘whatever is best for me’.

What would be your treatment?

  1. Docetaxel
  2. Docetaxel and anti-angiogenic agents
  3. Nivolumab
  4. Pembrolizumab
  5. Erlotinib
  6. No further treatment
  7. Prefer immunotherapy, but no reimbursement at my institute
  8. Decide on PD-L1 status

Most attendees chose docetaxel and anti-angiogenic agents followed by nivolumab. The patient was started on nivolumab, 3 mg/kg q2wk and progressed after 3 cycles, deteriorated in general condition, was unable to be treated further and died a few weeks later.

There remain issues regarding immunotherapy treatment—it is not the ‘magic bullet’. For example, nivolumab treatment (in patients with <1% PD-L1 expression level), showed worse overall survival in the first 6 months of treatment compared to docetaxel before it surpassed docetaxel and improved OS.

Where to from here? New developments in immunotherapy include immuno-oncology (I-O) drugs in combination with each other, I-O and chemotherapy, I-O and anti-angiogenic agents, and I-O and targeted agents (EGFR, ALK). For example, a trial of carboplatin + pemetrexed with or without pembrolizumab as 1 st -line therapy for advanced NSCLC showed improved progression-free survival rates for the combination with pembrolizumab.

Dr Aerts predictions for next ESMO guideline changes for 1 st -line treatment of Stage IV non-squamous NSCLC include incorporating PD-L1 status; when PD-L1 expression is >50%, then treat with pembrolizumab. Also testing for ROS1, BRAF, HER2, RET and MET for should be included.

For 2 nd and 3 rd -line treatments, he predicts that more data will be available on PD-(L)1 testing with different cut-off levels.

Dr Aerts ends his session with a table summarizing how he optimizes treatment in patients with advanced non-squamous NSCLC.

Patient characteristics Disease characteristics Treatment considerations
Age Histology Prior treatments received
Gender Mutational status Response to 1st line
Ethnicity Metastases Specific toxicity considerations
ECOG PS Brain metastases Corticosteroids
Comorbidities Rate of progression Doctor and patient preference
Contraindication to immune CP inhibitors Eligibility for anti-angoinenic agents Cost
Smoking status PD-L1 expression (standardization?)