Could All Patients With Advanced NSCLC Go Chemo-Free?

Liam Davenport

September 28, 2019

BARCELONA, Spain — Treatment with combination immunotherapy showed improved overall survival when compared with chemotherapy in patients with untreated advanced non-small cell lung cancer (NSCLC), even in the absence of programmed death ligand 1 (PD-L1) expression.

This offers hope for chemotherapy-free treatment for all comers, say investigators.

The new data come from the part 1 final analysis of the CheckMate 227 trial, conducted in more than over 1700 patients with stage IV or recurrent NSCLC. Patients were randomly assigned to receive either the combination of the nivolumab (Opdivo, Bristol-Myers Squibb) plus ipilimumab (Yervoy, Bristol-Myers Squibb); or chemotherapy alone; or nivolumab alone; or the combination of nivolumab with chemotherapy.

The results show that in patients with PD-L1 expression ≥1%, median overall survival was improved by 21%, from 15 months to 17 months, with combined immunotherapy vs chemotherapy.

Furthermore, the results showed that the combination of nivolumab plus low-dose ipilimumab was associated with a survival benefit in patients with PD-L1 expression <1% and all patients combined, with the effect lasting beyond the 2-year treatment period.

Crucially, there were no new safety signals, with fewer patients experiencing grade 3/4 treatment-related adverse events than those given chemotherapy, commented lead investigator Solange Peters, MD, PhD, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.

She presented the findings here at the European Society of Medical Oncology annual meeting, and the results were simultaneously published online in the New England Journal of Medicine.

Peters said that, in her opinion, the results are "practice changing," as it is the first trial to show that combined nivolumab and ipilimumab prolongs survival over chemotherapy in treatment-naïve metastatic NSCLC.

"We already have several front-line treatment options for these patients, including chemotherapy combined with an anti-PD-1 agent or an anti-PD-L1 agent alone, and now we have a chemotherapy-sparing option of nivolumab plus ipilimumab," she said in an ESMO statement.

Peters emphasized, however, that "the important step now is to develop an algorithm to select the best front-line treatment for each patient."

"We need to wait for a little more time to see which treatment really gives rise to improved long-term survival. The 5-year survival from trials with these treatments will teach us if any of the options are better than others," she said.

"The second critical point will be to compare toxicities. We can then have an informed discussion with our patients," she added.

Commenting on the new data at an ESMO press briefing, Marina C. Garassino, MD, head of thoracic medical oncology at the National Cancer Institute of Milan, Italy, said that although the results "show we have a new treatment option for the first-line treatment of metastatic NSCLC...we don’t yet know if the findings are practice changing."

The "promise" of the current results from CheckMate 227, she said, is that patients could having "long-lasting responses, and that means a long life, with a chemotherapy-sparing regimen."

"But at the same time we have to go back to the bench and to the bedside and act as scientists to understand who are the right patients to be treated with immunotherapy plus immunotherapy, with a combination of chemotherapy and immunotherapy, or just with a single agent," she said.

This process could take several years, Garassino noted, but the "good news" is there are now multiple ways in which patients can be treated.

This, she believes, will mean that patients will play an increasingly important role in deciding which treatments to use.

"We are in the time of patient empowerment," she said, adding she is sure that patients "will play a fundamental role in the decision over the first line treatment."

Pembrolizumab Monotherapy

The current results with combination immunotherapy complement recent findings with single agent pembrolizumab (Keytruda, Merck) in 550 patients with NSCLC in the KEYNOTE-001 trial, results from which were presented at ASCO earlier this year. They showed that 23% of treatment-naïve patients given immunotherapy were still alive at 5 years, as were 16% of those who had been previously treated.

Among patients with PD-L1 expression of 50% or more, survival rose to almost 30% of treatment-naïve patients and 25% of those who were previously treated.

Peters, the lead investigator, told the press conference that, taken together, these two studies raise the question of, "Who should receive what treatment?"

"Who should receive [nivolumab/ipilimumab], who should receive chemo, who should receive only pembrolizumab?" she elaborated. 

"This discussion will start today, and I’m looking forward to having it."

Complementary Modes of Action

Peters began her presentation by pointing out that ipilimumab and nivolumab have "distinct but complementary mechanisms of action." Ipilimumab is a CTLA-4 inhibitor which induces de novo anti-tumor T-cell responses, while nivolumab is a PD-1 inhibitor that restores anti-T cell function and enhances the preexisting T-cell response.

This, she said, "creates a biological rationale for why we try to combine both compounds in many disease entities."

Peters emphasized that "we would like to give immunotherapy to all patients in the frontline," but chemotherapy-sparing regimens with immunotherapy alone are typically "restricted to a very small subset of patients" with high PD-L1 expression.

Therefore, the idea behind combining immunotherapies in CheckMate 227 was "to try to understand if, by reinforcing the immunotherapy, we can have [some] more patients benefiting from an immunotherapy-only strategy" and spare more patients from having to undergo chemotherapy.

The researchers recruited patients with stage IV or recurrent NSCLC who were treatment naïve and had no sensitizing EGFR mutations or known ALK mutations.

Patients with tumor PD-L1 expression ≥1% were randomly assigned in a 1:1:1 fashion to nivolumab plus low-dose ipilimumab, chemotherapy, or nivolumab alone, while those with expression <1% were randomly assigned to combination immunotherapy, chemotherapy, or nivolumab plus chemotherapy, again in a 1:1:1 fashion.

Treatment was continued until disease progression, the development of unacceptable toxicity, or for 2 years in the case of immunotherapy.

Working from contemporaneous findings, the researchers chose the coprimary endpoints of progression-free survival (PFS) in patients with high tumor mutation burden and overall survival in those with PD-L1 expression ≥1%.

In all, 1189 patients with PD-L1 expression ≥1% were randomly assigned to the three treatment groups, alongside 550 patients with expression <1%. The groups were well-balanced in terms of baseline characteristics.

The minimum follow-up to assess the primary endpoint was 29.3 months, while that required to assess the objective response rate was 28.3 months.

Among patients with tumor PD-L1 expression ≥1%, median overall survival was significantly longer with combined immunotherapy than chemotherapy, at 17.1 months vs 14.9 months, at a hazard ratio [HR] of 0.79 (P = .007).

Differences between the treatment group began to emerge at around 9 months, with 63% of combined immunotherapy and 56% of chemotherapy patients alive at 12 months and 40% and 33%, respectively, alive at 24 months.

The treatment benefit continued beyond the 2-year treatment period, with the gap between the survival curves for combined immunotherapy and chemotherapy continuing to widen even at 36 months.

Overall survival for patients treated with nivolumab alone lay between that for combined immunotherapy and chemotherapy, at a median of 15.7 months and a hazard ratio vs chemotherapy of 0.88.

At 12 months, 57% of patients given nivolumab alone were alive, falling to 36% at 24 months.

The median duration of treatment response was 23.2 months for combined immunotherapy, 15.5 months for nivolumab alone, and just 6.2 months for chemotherapy alone.

At 12 months, 64% and 63% of patients treated with combined immunotherapy and nivolumab alone, respectively, were still responding to treatment vs 28% of those given chemotherapy.

By 24 months, 49% of combined immunotherapy patients and 40% of nivolumab alone patients were still responding to treatment vs just 11% of those in the chemotherapy group.

Benefit in "All Comers"

Peters showed that the survival benefit with combined immunotherapy was not limited to patients with tumor PD-L1 expression ≥1%.

Even in patients with PD-L1 expression <1%, nivolumab plus ipilimumab was associated with a median overall survival of 17.2 months vs 12.2 months with chemotherapy [HR, 0.62].

This exploratory analysis showed that, at 12 months, 60% of combined immunotherapy patients were alive vs 51% of those treated with chemotherapy, whereas 40% and 23%, respectively, were alive at 24 months.

Again, the survival benefit with combined immunotherapy continued to accrue after the treatment period.

The combination of nivolumab and chemotherapy in patients with tumor PD-L1 expression <1% was, similarly to nivolumab alone in higher expressors, between that of the two other treatment groups.

Median survival with this treatment was 15.2 months, at a hazard ratio of 0.78 vs chemotherapy alone, with 59% of patients alive at 12 months and 35 alive at 24 months.

When the team compared combined immunotherapy with chemotherapy alone across all patients, regardless of PD-L1 expression, they found that median overall survival was 17.1 months with nivolumab and ipilimumab vs 13.9% for chemotherapy [HR, 0.73].

This unplanned, exploratory analysis revealed that, at 12 months, 62% of all combined immunotherapy patients were alive vs 54% of chemotherapy patients, with 40% and 30%, respectively, alive at 24 months.

Peters said that there were no new safety signals, with 33% of all combined immunotherapy patients experiencing grade 3/4 treatment-related adverse events, compared with 19% of those given nivolumab alone, and 26% of those given chemotherapy.

Biomarkers Not Predictive

Following her presentation, Peters explained that all first-line immunotherapy trials, not just CheckMate 227, have had to adapt in the light of accumulating evidence from other studies, which has been a "learning process."

The result is that trials have become "very complex," with changes in endpoints and strategies.

She said that PFS was measured based on tumor mutation burden (TMB) in the current study because results from earlier CheckMate studies suggested that the benefit with anti-CTLA-4 immunotherapy was stronger in patients with a higher burden.

The overall survival data from CheckMate 12 also suggested that patients with PD-L1-positive tumors were responding better than those whose tumors were not expressing PD-L1.

"Unfortunately, midway through this trial, we saw a larger dataset showing that PD-L1 probably is not predictive any time you have a CTLA-4 component," Peters said.

Peters said that it is now understood that "no biomarker is able to select for the patients who will respond" to combined immunotherapy.

She said that, in the lung cancer field, "we still struggle a little bit" with tumor mutation burden and PD-L1 expression as biomarkers.

That was why she presented the results in the PD-L1 negative cohort. "It was not the primary endpoint," she said, "but it completes the picture."

She added that the biological explanation for the benefit in patients with PD-L1 negative tumors is that CTLA-4 inhibition "strongly" induces PD-L1 expression, which raises the preexisting immunity to "kind of an average level."

The result, Peters said, is that "you don’t have to test for PD-L1 expression" in tumor tissue if you are using combined nivolumab and ipilimumab in advanced treatment-naïve NSCLC.

CheckMate 227 was sponsored by Bristol-Myers Squibb, manufacturer of both nivolumab and ipilimumab.

Peters reports relationships with AbbVie, Amgen, AstraZeneca, Bayer, Biocartis, Bioinvent, Blueprint Medicines, Boehringer Ingelheim, Bristol-Myers Squibb, Clovis, Daiichi Sankyo, Debiopharm, Eli Lilly, F. Hoffmann-La Roche, Foundation Medicine, Illumina, Janssen, and Merck Sharp and Dohme. Other authors also report numerous potential conflicts of interest. The full list can be found with the original article. Garassino reports relationships with many pharmaceutical companies and is a member of the ESMO Press Committee.

European Society for Medical Oncology (ESMO) 2019 Annual Meeting: LBA4_PR. Presented September 28, 2019.

NEJM. Published online September 28, 2019. Abstract

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