October 2019

By Tom Newsom-Davis, BTOG Vice-Chair

Treatment of RET-Fusion NSCLC: LIBRETTO-001

RET fusions are found in a number of different cancer and account for approximately 2% of NSCLC. Although rare, they are predominantly found in younger patients, non-smokers or ex-light smokers. Only recently identified, targeted inhibitors against RET are showing considerable clinical potential.

The Study
LIBRETTO-001 is a phase 1/2 study of Selpercatinib (previously known as LOXO-292) in a range of cancer types. Results from 105 NSCLC patients, previously treated with chemotherapy was presented, as well as 34 treatment naïve NSCLC patients. 60% of patients were female, median age was 61 years, and 20-35% had brain metastases at time of trial entry.

The Results
Selpercatinib showed an impressive level of activity. In patients who had previously received chemotherapy, Response Rate and Disease Control Rate were 68% and 98% respectively. The figures in treatment naïve patients were 85% and 97%. In the pre-treated cohort, median Duration of Response (DoR) was 20.3 months and median Progression Free Survival (PFS) was 18.4 months. In the treatment naïve group neither median DoR nor median PFS had been reached, partly reflecting the immaturity of the data with follow up less than 5 months.

Selpercatinib is well tolerated, with very low rates of grade 4 toxicities. There were more grade 3 toxicities, but still at a comparatively low rate. Side effects are principally hypertension, gastrointestinal or abnormal liver function. Rates of treatment discontinuation were low (<2%).

Interpretation
Selpercatinib is one of two RET targeting agents, the other being Pralsetinib (previously known as BLU-667). Although the data from the trials of these agents remains limited to early phase studies, and so caution is required when drawing conclusions, both drugs show significant clinical effectiveness with high response rates and a favourable side effect profile. These is also evidence for intra-cranial activity against brain metastases.

Both selpercatinib and pralsetinib continue to be tested in clinical trials, and as yet are not licensed in the UK. As such they are not yet available via NICE or the Cancer Drugs Fund. RET fusion testing is not part of routine molecular testing for NSCLC, but should be considered especially in patients without a significant smoking history in whom EGFR, ALK and ROS1 mutations have been excluded. RET testing can be undertaken as part of clinical trial screening, and such studies are open in the UK. RET fusion analysis is due to part of the standard panel for the forthcoming National Genomics Medicine platform.

Given the results above, it is highly likely in the future that RET will be added to our list targets to test and treat in lung cancer.

1st Line Chemo-immunotherapy in Extensive Stage SCLC: CASPIAN

One of the highlights of the WCLC 2019 Presidential Session was the first results from the CASPIAN study. This was a phase 3, open label trial of first line treatment of extensive stage small cell lung cancer (ES-SCLC) and was widely anticipated due to limited success in improving outcomes for patient with ES-SCLC over the past 3 decades.

The Study
CASPIAN was a 3-arm study which randomised 805 patients. The control arm – representing the international standard of care – was the combination of etoposide and platinum (cisplatin or carboplatin) chemotherapy, every 3 weeks, for up to 6 cycles. This was compared to the same chemotherapy with the addition of the anti-PD-L1 immunotherapy agent, durvalumab, for 4 cycles, followed by single-agent durvalumab every 4 weeks until disease progression. A third arm, in which 4 cycles of the CTLA-4 targeting agent tremelimumab was added to etoposide, platinum and durvalumab, was not reported. The primary end point was overall survival (OS) whilst secondary endpoints included progression free survival (PFS), overall response rate (OSS), safety and tolerability. Patients were stratified according to type of platinum chemotherapy.

The inclusion and exclusion criteria were fairly standard, but there were two aspects of note: Firstly, patients with brain metastases were allow to particulate so long as they were asymptomatic from these, or they had been treated and had been stable for at least 1 month. Secondly, patients were excluded if they had had thoracic radiotherapy, or if this was planned. Prophylactic cranial irradiation (PCI) was allowed in the control arm only.

Approximately 270 patients were randomised to each of the two arms reported. The majority (70%) were male, were smokers or ex-smokers (92-95%) and – reflecting the countries involved in the trial – approximately 85% were Caucasian. 10% of patients had brain metastases at the time of trial entry.

The Results
The headline result was that the trial met its primary end point, with an increase in median OS from 10.3 months in the control arm, to 13.0 months in the chemo-immunotherapy arm (Hazard Ratio = 0.73, p-value = 0.0047). 12-month survival increased from 39.8% to 53.7%. Benefits were seen in all sub-groups, with no particular subset benefitting significantly more or less. There was no difference in median PFS, although there was an increase in 12-month PFS (4.7% vs. 17.5%). The chemotherapy-immunotherapy arm saw a higher response rate (57.6% vs. 67.9%) and a high proportion of patients still responding after 12 months (6.3% vs. 22.7%).

With respect to safety and side effects, there was little increase in toxicity in the experimental arm. The overall rates of grade 3/4 adverse events, serious adverse events and treatment discontinuation were similar. There was an increase in immunotherapy related adverse events however it should be remembered that this as an open-label study and so both the patient and the treating doctor knew whether immunotherapy had been given.

Interpretation
CASPIAN demonstrated that adding immunotherapy to chemotherapy improves overall survival in the first line treatment of ES-SCLC. It follows, and indeed closely mirrors, the results of the IMpower-133 trial which was presented at WCLC in October 2018. IMpower-133 also involved the first-line treatment for ES-SCLC, comparing etoposide and carboplatin chemotherapy to etoposide, carboplatin and the PD-L1 agent, atezolizumab. IMpower-133 also showed an improvement in median OS (10.3 months vs. 12.3 months). The fact that both CASPIAN and IMpower-133 have shown a survival benefit of chemo-immunotherapy over chemotherapy confirms the role of immunotherapy in this setting.

There are important comparisons to be made between CAPSIAN and IMpower-133 trial designs when considering their respective results. Patient demographics were very similar in both studies. However, CAPSIAN was an open-label study whereas IMpower-133 was placebo controlled, patients with untreated brain metastases were excluded from IMpower-133, PCI was only allowed in the control arm of CASPIAN but was permitted in any arm of IMpower-133, and CASPIAN included any platinum agent whereas IMpower-133 only involved carboplatin.

With these differences in mind, the OS benefits of chemo-immunotherapy over chemotherapy are similar, with a slight numerical advantage of CASPIAN over IMpower133 for median OS, but slight advantage for IMpower-133 for OS Hazard Ratio. In both studies the Kaplan-Meir curves for OS and PFS are initially identical, with divergence after approximately 6 months. This suggests that the benefit of chemoimmunotherapy is less likely to be due to improving response rates, but perhaps more related to improving duration of response to treatment. This theory is supported by the fact that there is a ‘tail’ on the PFS and Duration of Response Kaplan-Meir curves. Subsets analyses from these two trials, and other studies, has failed to find a subset of patients (for example based one PD-L1 expression or Tumour Mutational Burden) who particularly benefit from chemo-immunotherapy.

A further similarity between CASPIAN and IMpower-133 is that the chemo-immunotherapy arm was well tolerated with no clinically significant difference in grade 3-4 toxicities. Although there are higher rates of immune-related adverse events in the experimental arm of both studies, these were predominantly low grade (1-2) and there was only a small increase in grade 3-4 immune-related adverse events.

Conclusion
In the discussion after presentation of the CASPIAN data at WCLC, chemo-immunotherapy was described as the new standard of care for ES-SCLC. The survival benefit is modest, and less than that seen in other lung cancer types, however this needs to be seen in the context of the lack of any improvement in the prognosis of ES-SCLC for 30 years. However whether either the CASPIAN or IMpower-133 regimens will be sufficiently cost-effective to achieve approval by either the Cancer Drug Fund or NICE remains to be seen. Identifying which patients are benefiting from adding immunotherapy to chemotherapy, and focussing treatment on these, would make therapy more cost effective. Results of the KEYNOTE-604 study are awaiting (chemotherapy +/- pembrolizumab) as well as the 3rd arm from CASPIAN.

CASPIAN Lancet Oncology publication