Pembrolizumab with pemetrexed and platinum chemotherapy for untreated, metastatic, non-squamous non-small-cell lung cancer

In the original appraisal pemetrexed with carboplatin or cisplatin chemotherapy and pembrolizumab monotherapy were considered appropriate comparators. Chemotherapy using docetaxel, gemcitabine, paclitaxel or vinorelbine as monotherapy is rarely used in NHS clinical practice for treating non-squamous metastatic NSCLC. NICE's technology appraisal guidance on pembrolizumab for untreated PD-L1-positive metastatic NSCLC recommends pembrolizumab monotherapy only for people whose tumours express at least a 50% PD‑L1 tumour proportion score. Since the original appraisal was published, NICE has recommended atezolizumab combination for metastatic non-squamous NSCLC for people whose tumours express less than a 50% PD‑L1 tumour proportion score. In line with NICE's guide to the methods of technology appraisal, the original scope was not changed for this Cancer Drugs Fund review. Therefore, atezolizumab was not considered as a comparator because it was recommended after the original guidance was published. The committee concluded that the appropriate comparators are:

• pemetrexed with carboplatin or cisplatin (referred to as pemetrexed platinum chemotherapy), with or without pemetrexed maintenance therapy

• pembrolizumab monotherapy for people whose tumours express at least a 50% PD‑L1 tumour proportion score (referred to as the high PD‑L1 subgroup).

There were additional data from KEYNOTE‑189, which was a randomised controlled phase 3 trial. The trial included 616 people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score who were randomised to pembrolizumab combination or pemetrexed platinum chemotherapy. Two thirds of the trial population had tumours with a PD‑L1 tumour proportion score of at least 50% while the rest had tumours with a PD‑L1 tumour proportion score below 50%. The results showed that pembrolizumab combination was associated with a statistically significant improvement in overall survival compared with pemetrexed platinum chemotherapy (hazard ratio 0.56, 95% confidence interval 0.46 to 0.69). The committee concluded that for the intention-to-treat (ITT) population, that is, people with untreated advanced or metastatic non-squamous NSCLC regardless of PD‑L1 tumour proportion score, pembrolizumab combination was clinically effective compared with pemetrexed platinum chemotherapy.

Pembrolizumab monotherapy is standard care in clinical practice in the NHS for people with untreated NSCLC and at least a 50% PD‑L1 tumour proportion score (see section 3.1). The company presented updated results for this subgroup from an indirect treatment comparison based on data from:

• KEYNOTE‑189 (see section 3.2)

• KEYNOTE‑021 Cohort G, a trial including 267 people comparing pembrolizumab combination with platinum‑based chemotherapy

• KEYNOTE‑042, a trial including 1,274 people with PD‑L1 positive tumours comparing pembrolizumab monotherapy with platinum-based chemotherapy

• KEYNOTE‑024, a trial including 305 people with high PD‑L1 tumour proportion score comparing pembrolizumab monotherapy with platinum-based chemotherapy.
  
  Although the point estimate suggested better overall survival for pembrolizumab combination compared with pembrolizumab monotherapy, the 95% credible interval showed that this was not statistically significant. The exact results were academic in confidence so cannot be reported here. The committee concluded that overall survival was similar for people with at least a 50% PD‑L1 tumour proportion score who had pembrolizumab combination compared with pembrolizumab monotherapy.

The company used a log-logistic distribution to extrapolate overall survival for both pemetrexed platinum chemotherapy and pembrolizumab combination in the model for the ITT population. This is because for the comparator arm this distribution gave the most clinically plausible estimates for overall survival at 5 years and had the best statistical fit. The ERG used a generalised gamma distribution for both arms because this distribution fitted the pembrolizumab combination arm better. Both the log-logistic and the generalised gamma distributions gave clinically plausible 5‑year survival estimates for the comparator arm of between 5% and 11%. The clinical experts explained that people who have immunotherapy such as pembrolizumab second line have a 5‑year survival rate of approximately 13%. They reasoned that people who have pembrolizumab combination earlier in the pathway will benefit from this treatment, so the 5‑year survival rate is likely to be greater than 13%. They agreed that the overall survival in the pembrolizumab combination arm could be somewhere between what was predicted in the generalised gamma and log-logistic extrapolation (the estimates are confidential and cannot be reported here). The committee concluded that the ERG's overall survival estimates for the ITT population were pessimistic but the company's estimates were too optimistic.

Some people in the pembrolizumab combination arm of KEYNOTE‑189 were still having treatment after 2 years. It was not clear, however, how many people were still having combination therapy and how many were having pemetrexed platinum chemotherapy only. The Cancer Drugs Fund clinical lead explained that people could have pembrolizumab for up to 35 cycles, which could extend beyond 2 years. The company confirmed that some people did have further treatment with pembrolizumab alone or in combination with other therapies. From the data presented by the company it was unclear how many people this was. Retreatment with pembrolizumab is not NHS clinical practice. The committee noted that the overall survival curves for the pembrolizumab combination arm included the effect of retreatment. Therefore, the potential survival benefits in the trial might not be seen in NHS practice. The clinical experts explained that retreatment with pembrolizumab or similar drugs could improve survival prospects in this population, especially if they had a good response to initial treatment. The committee noted that retreatment with pembrolizumab could affect the overall survival outcome for the pembrolizumab combination arm. Also, it was aware that the costs of retreatment were not included in the model. The committee concluded that results from the trial might not be generalisable because retreatment with pembrolizumab is not NHS clinical practice.

To estimate overall survival for the comparison with pembrolizumab monotherapy in the high PD‑L1 subgroup the company used the same approach as for the ITT population (see section 3.4). Therefore, the committee could not establish whether the company's approach was the most appropriate approach, because no alternatives were provided by the company and ERG. The committee recalled that results from the indirect treatment comparison showed no statistically significant difference in the overall survival estimates for pembrolizumab combination compared with monotherapy (see section