Immunotherapy in earlier stage non small cell lung cancer (NSCLC) has the potential to make the biggest impact on improving overall survival outcomes, says a leading lung cancer expert who is pushing for a shift in research priorities and regulatory approval in the setting.

Medical oncologist and NSCLC specialist Professor Nick Pavlakis says that immunotherapy has revolutionised lung cancer management in the metastatic and advanced lung cancer setting but optimising it’s use in early phases, before the disease returns or spreads, represents a significant opportunity and unmet need.

“In metastatic disease immunotherapy has become part of the treatment paradigm – we’ve moved from second line to first line therapy and we’re also using it in stage three disease as well as in extensive stage small cell lung cancer – it’s across the spectrum but not in early stage disease and I think that’s the area that will have the biggest impact because survival with surgery and chemotherapy has been small, even though it’s been very real, it’s been small,” he tells the limbic in an interview. 

The senior staff specialist at Sydney’s Royal North Hospital says evidence is mounting for the safety, efficacy and durability of immunotherapy in patients with earlier-stage NSCLC in the adjuvant, neo-adjuvant and peri-operative settings.

“For the first time at ASCO this year we saw two studies presented demonstrating that it looks like immunotherapy has a big impact on early stage disease – the first was IMPOWER010 it evaluated atezolizumab after chemotherapy and the second was a CheckMate study that looked at the adding nivolumab  to chemotherapy preoperatively – taking it even earlier.”

In metastatic and later stage disease the overall survival outcome with these therapies is a significant leap ahead from the outcomes expected with chemotherapy alone he says. 

For some patients these can be durable long term and those with a PD-L1 immunohistochemistry (IHC) expression over 50% can obtain this benefit without the need for chemotherapy at all while others have the choice for lesser chemotherapy

Cost benefit

But for the therapy’s more widespread use in early stage disease Professor Pavlakis says several advancements need to be prioritised – as well as an overhaul of the drug approval process.

“The government, in terms of value for money, is going to have to look seriously at this – when you’re actually having cures that’s a very different ball game to the survivorship extension we see in advanced disease. I think the big impact [from earlier use] is what should drive a cost-benefit analysis.”

The need to become more precise about selecting which patients stand to benefit from the therapy also becomes critical if immunotherapy in NSCLC is to be approved for early stage disease.

“Biomarkers assisting patient selection for greater benefit from IO therapies are still currently limited to PD-L1 IHC, with the data on tumour mutational burden inconsistent,” he said writing in an editorial for the Journal of Oncology Practice.

“There is a need for better biomarkers for positive selection of patients or specific populations as well as identifying patients who will benefit less (negative selection).Many potential markers have been identified including comutations STK-11 and KEAP1 in KRAS-mutated NSCLC, which may act as negative selection biomarkers, but consistency in the evidence and prospective validation is required,” he said.

Resistance

Meanwhile research focusing on overcoming immunotherapy resistance that incorporates the new agents with the use of existing modalities of treatment such as radiotherapy and reintroduction of chemotherapy, should also be prioritised.

“The benefit of immunotherapy in stage III disease was demonstrated in the PACIFIC trial. Incorporating radiotherapy with IO in different disease stages is the subject of ongoing trials,” he notes

Other strategies that focus on overcoming resistance, like the addition of antiangiogenic therapies to immunotherapy, based on overcoming the immunosuppressive effect of angiogenesis in the tumour microenvironment, will also prove critical to moving the therapy to early stage disease.

Lung screening

Combined with these developments the biggest hope of improving overall lung cancer survival rates – which currently sit at 17% at five years – is the introduction of a national screening program.

Professor Pavlakis is hopeful that, despite its challenges and limitations, such a program will be a reality.

“Cancer Australia has made a recommendation that the government should look at a screening program in Australia – this is not imminent, its going to take time but we’ve now got very solid evidence from randomised trials that have demonstrated it’s an effective thing to do.”

Acknowledging the inherent challenges that come with population-based screening – the over investigation of nodules that aren’t cancerous for one as well as just how effectively public health campaigns will be able to target high risk groups to participate in screening – Professor Pavalakis maintains that its introduction will mark an improvement on overall survival rates.

“We have our challenges with this but if we can look at a screening program, if we can start applying the evidence for the use of some of these new immunotherapy agents early in the natural history of the disease combined with surgery then we have a chance of bigger impact overall and at getting that 17% five year survival up.”

As for what the treatment landscape will look like for those who relapse after early immunotherapy, Professor Pavalakis said that scenario opens up a lot of questions.

“Not everyone will be cured but more people, hopefully, will be if the evidence that we’ve seen so far is shown to be substantiated with longer follow up. Currently we have two trials  and our expectations are high. So the question then becomes, whats going to be the natural history of the people who do relapse – that will be the new challenge.

It’s not salvation for all not everyone benefits from immunotherapy and more work needs to be done to identify why and how we can turn a person who is a non responder to a responder by adding something else such as chemotherapy, radiotherapy or even a Tyrosine Kinase Inhibitor and there’s a lot of research going on in that area.”