Clinical Challenges: Immunotherapy and Chemo in NSCLC



Several studies have shown that adding immune checkpoint inhibitors to chemotherapy is a superior approach to chemotherapy alone for treating patients with advanced or metastatic non-small cell lung cancer (NSCLC).

Does that mean, however, that patients with NSCLC will eventually be able to go chemo-free?

According to Philip Bonomi, MD, of Rush Medical College in Chicago, results from two recent clinical trials suggest that chemotherapy, in combination with immunotherapy, will continue to play a key role in the treatment of NSCLC patients.

In the phase III KEYNOTE-189 trial, 616 patients with metastatic nonsquamous NSCLC without sensitizing EGFR or ALK mutations who had received no previous treatment for metastatic disease, were assigned to receive pemetrexed (Alimta) and a platinum-based drug plus either pembrolizumab (Keytruda) or placebo.

The investigators in that trial found that the estimated rate of overall survival (OS) at 12 months was 69.2% in the pembrolizumab-chemotherapy group compared to 49.4% in the chemotherapy alone group (P<0.001).

"This showed an amazingly good hazard ratio of .49, and that is something that lung cancer doctors used to dream about," Bonomi told MedPage Today. "So the risk of death was reduced by 50%, and it worked across all levels of PD-L1 expression."

Median progression-free survival (PFS) was 8.8 months in the pembrolizumab-chemotherapy group compared to 4.9 months with chemotherapy alone (HR 0.52, 95% CI 0.43-0.64).

The phase III KEYNOTE-407 trial assigned 559 patients with untreated metastatic, squamous NSCLC to pembrolizumab plus carboplatin and either paclitaxel or nanoparticle albumin-bound [nab]-paclitaxel (Abraxane) or the chemotherapy regimen plus placebo.

The median OS was 15.9 months in the pembrolizumab-chemotherapy combination group and 11.3 in the placebo-combination group (HR 0.64, 95% CI 0.49-0.85). The investigators determined the OS benefit was consistent regardless of the level of PD-L1 expression.

Median PFS was 6.4 versus 4.8 months, respectively (HR 0.56, 95% CI 0.45-0.70).

"Right now the data are pretty good for chemo and immunotherapy," Bonomi said. However, he pointed out that in the KEYNOTE-407 trial the survival benefit with the combination in patients with tumor PD-L1 expression ≥50% was not significantly better than with chemotherapy alone (HR 0.64, 95% CI 0.37-1.10).

Bonomi noted that in both studies, toxicities were very similar. In the KEYNOTE-189 trial adverse events of grade 3 or higher occurred in 67.2% of the patients in the pembrolizumab-chemotherapy group and in 65.8% of those in the chemotherapy-alone group, while in the KEYNOTE-407 trial adverse events of grade 3 or higher occurred in 69.8% of the patients in the combination group and in 68.2% of those in the chemotherapy-placebo group.

In a recently published review looking at the combination of pembrolizumab and chemotherapy, Frank Weinberg, MD, and Shirish Gadgeel, MBBS, both of the University of Michigan, suggested that it is possible a combination of pembrolizumab and chemotherapy, compared to pembrolizumab alone, provides added survival benefits to nonsquamous NSCLC patients with PD-L1 expression ≥50%.

"Studies specifically assessing the role of combination chemotherapy in addition to pembrolizumab in patients with tumor PD-L1 expression ≥50% are warranted," they wrote.

"If you have less than 50% PD-L1 expression, the evidence indicates that you are going to do better with a combination of chemotherapy and immunotherapy," said Julian Molina, MD, of the Mayo Clinic Cancer Center in Rochester, Minnesota. "And the chemotherapy regimen will be very dependent on histology. There is a regimen for adenocarcinoma and that regimen usually has carboplatin and pemetrexed, and there is a regimen of chemotherapy for squamous cell carcinoma, and that usually has carboplatin and paclitaxel."

Why does the combination of chemotherapy and immunotherapy work as well as it does?

"We know that chemotherapy tends to shrink tumors very quickly," Molina told MedPage Today. "And there is also the sense that when chemotherapy starts destroying cancer cells, these cancer cells start releasing antigens that are recognized by the immune system, which mounts a more effective immune response against the tumor."

According to Bonomi, there is also the possibility that chemotherapy might be decreasing certain immune suppressive cells like myeloid, macrophages, and perhaps neutrophils that are in the tumor. "This is theoretical," he said. "But these could be reasons why we are seeing good results with chemo plus immunotherapy."

Bonomi did note that recently published results from the phase III CheckMate-227 trial showed that a combination of nivolumab (Opdivo) and low-dose ipilimumab (Yervoy) increased OS among patients with advanced NSCLC compared to chemotherapy.

In part 1 of the trial, patients with PD-L1 expression of at least 1% were randomized to three treatment options: nivolumab plus low-dose ipilimumab, nivolumab alone, or histology-based chemotherapy. Patients with PD-L1 below 1% were randomized to nivolumab plus low-dose ipilimumab, nivolumab plus chemotherapy, or chemotherapy.

The investigators found that patients treated with nivolumab plus ipilimumab compared to chemotherapy, had significantly longer OS. Patients with PD-L1 expression greater than 1% treated with nivolumab plus ipilimumab had a median OS of 17.1 months compared to 14.9 months in the chemotherapy group (HR 0.79, 97.72% CI 0.65-0.96, P=0.007).

"The hazard ratio in this study was .79, which is pretty good, but not as good as the hazard ratios for chemotherapy plus immunotherapy versus chemotherapy [as demonstrated in the KEYNOTE trials]," said Bonomi.

"The hope has always been that chemotherapy should just go away -- and I don't disagree with that, if there's something that's better," Bonomi said. "But the problem is we don't know what that is."

Bonomi said the field needs to see results from trials comparing a combination of nivolumab and ipilimumab to immunotherapy plus chemotherapy, as well as studies, as suggested by Weinberg and Gadgeel above, comparing chemotherapy plus pembrolizumab to pembrolizumab alone. "That's what we need to see to know clearly whether one is better," he said. "But I think for many patients it will be chemotherapy and immunotherapy."

Bonomi has received personal fees from AstraZeneca, Biodesix, Clovis Oncology, Imedex, Merck, Pfizer, Roche/Genentech, Spectrum Pharmaceuticals, and Trovagene.

Clinical Challenges: Immunotherapy and Chemo in nsclc



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