The TGA has approved a dual immunotherapy regimen combined with limited chemotherapy for the frontline treatment of some advanced non-small cell lung cancers (NSCLC).

The combination of nivolumab (Opdivo), a PD-1 inhibitor, plus ipilimumab (Yervoy), a CTLA-4 inhibitor, with two cycles of platinum-doublet chemotherapy received TGA registration last week following US FDA approval in May.

The TGA approved the combination as a first-line therapy for patients with metastatic NSCLC whose tumours do not have EGFR or ALK aberrations.

The indication is based on findings from the phase 3 CheckMate-9LA trial, which compared the chemo-dual-immunotherapy regime with the then standard therapy of chemotherapy alone in 719 treatment-naive patients with stage IV/recurrent NSCLC and no known sensitising EGFR or ALK alterations.

Some 361 patients were randomised to receive nivolumab dosed at 360 mg once every three weeks in combination with ipilimumab dosed at 1 mg/kg once every six weeks and two cycles of chemotherapy. Immunotherapy treatment continued for 2 years, or until disease progression or unacceptable toxicity.

Median overall survival was 15.6 versus 10.9 months (HR 0.69; 95% CI: 0.55–0.80; P = 0.0006) and a higher percentage of patients assigned the nivolumab-ipilimumab regimen survived at least 1 year (63% vs. 47%). The benefit in overall survival was seen in the majority of investigated subgroups, including those based on the various levels of PD-L1 expression.

Early differences

Speaking to the limbic, Associate Professor Tom John, Medical Oncologist at the Peter MacCallum Cancer Centre, said the survival curve for the treatment group separated early on.

“In this study the curves began to separate from around the three month mark and they stayed separated throughout and this is reassuring that using the combination chemo-immunotherapy is worthwhile,” he said.

He also highlighted the prolonged tail observed in the survival curve.

“What’s really intriguing is what’s going to happen further down; if those patients who’ve done really well actually end up plateauing and effectively are cured.”

Professor John noted that the toxicity is ‘relatively’ manageable, although the number of people who stopped treatment due to toxicity was higher in the dual immunotherapy arm compared to chemotherapy alone.

The most common adverse reactions included fatigue (49%), musculoskeletal pain (39%), nausea (32%), diarrhoea (31%) and rash (30%). The most frequent serious adverse events included pneumonia, diarrhoea, febrile neutropenia, anaemia, acute kidney injury, musculoskeletal pain, dyspnoea, pneumonitis and respiratory failure.

Meanwhile seven patients (2%) experienced fatal adverse events. These included hepatic toxicity, acute renal failure, sepsis, pneumonitis, diarrhoea with hypokalaemia and massive haemoptysis in the setting of thrombocytopenia.

Subgroup analysis

Determining the role of upfront dual immunotherapy within the NSCLC treatment paradigm is difficult, says Professor John, because the comparator of chemotherapy alone that was beaten by the nivolumab/ipilimumab/chemo combination, is an old standard not often used. But there are patients he would preference the new regimen in, he explains.

“There are definitely a group of patients that I think look like they would derive greater benefit from this regimen compared to others but it’s actually impossible to know if this is better than our current standard of care because chemo-immune therapy wasn’t the control arm of this study.”

“The benefit with this regimen was seen across the board – all patients who received the chemo immunotherapy do better and if you then start to look at subsets there are some groups that seem to do better than others,” he said.

A caveat is that subgroup analyses were not necessarily powered to look for overall survival outcomes.

“If I had the option to use this regimen it would be particularly in a squamous cell patient – the survival curves look very different in the squamous cell population – and we know that squamous cell patients do worse in general compared to non squamous patients,” he said.

Other subgroups of interest were younger patients, those with low or negative PD-L1 expression and heavy smokers.

“Heavy smokers tend to have very high mutations in their tumours, and the more mutational burden that tumours have the more antigens arise that can be presented to the immune system. And so we think of high mutational burden tumours as being immunogenic, so its certainly not surprising that smokers seem to do better.”

Overall survival in patients with less than 1% PD-L1 expression did ‘surprisingly well’ on the therapy, with a hazard ratio in that group of 0.62.

“So they do seem to do a lot better than what you would generally expect with single agent immunotherapy and chemotherapy. And that also speaks to that group of patients who we know are heavy smokers but are PD-L1 low or PD-L1 negative – you treat them with single immuno-chemotherapy and they do OK but this trial would suggest that using dual agent immunotherapy they could potentially do better.”

Treatment decisions

Deciding which of the approved regimens to use upfront in individual patients is becoming increasingly nuanced, said Professor John.

“Going in with your best agent makes a big difference in this group of patients – if you treated with single agent immunotherapy in someone who was PD-L1 high – greater than 50% – five years ago, versus frontline chemotherapy then immunotherapy, 30% of the patients treated with single agent immunotherapy upfront are alive at five years, which is astounding.”

But for those who started chemotherapy upfront and then went to immunotherapy that number is halved, he noted.

“So you compromise their treatment – they eventually got to the immunotherapy but you’ve changed something in the tumour and they haven’t done as well by doing that so there’s a lot of nuance and I think we’re going to struggle with this over time.”

“It will be interesting to see going forward how we deal with all of this but our current thinking is to go in with your best shot so CheckMate-9LA sort of supports that by saying, well we’re giving everything upfront that is our best shot at this point in time.”

While he welcomes the regimen’s TGA approval of the costly treatment, Professor John said the next question is reimbursement.

“Hopefully it’s another option that we will have available to us because there are definitely a group of patients that I would preference this regimen for but if it’s not reimbursed I would struggle to see how it would be used.”