Is Upfront Combo Therapy Better Than the Sum of Its Parts?

H. Jack West, MD


August 09, 2018

For all of the excitement around targeted therapies and immunotherapy today, and the hope that these treatments could potentially replace chemotherapy, one of the big surprises in the lung cancer field is that the interventions with the greatest impact to date have involved adding conventional chemo to first-line targeted therapy or immunotherapy. But is the timing of these treatments concurrently in the first-line setting adding anything beyond the assurance that patients will benefit from receiving what would otherwise be two separate lines of treatment, with potential attrition along the way?

Though they may not change practice due to the recent US Food and Drug Administration approval of osimertinib[1] following the positive results of the FLAURA trial,[2] the most impressive results at the recent 2018 annual meeting of the American Society of Clinical Oncology (ASCO) for patients with an activating EGFR mutation was the NEJ009 trial comparing gefitinib alone versus gefitinib with carboplatin-pemetrexed as first-line therapy.[3] It is important to note that patients assigned to start on gefitinib were transitioned to carboplatin-pemetrexed upon progression, in an attempt to dissociate timing from access to these treatments with established efficacy. Those who received the EFGR tyrosine kinase inhibitor (TKI)-chemotherapy combination had a significantly longer progression-free survival (PFS): 20.9 versus 11.2 months (hazard ratio [HR], 0.49).

Notably, even though patients who started on gefitinib went on to receive the same chemotherapy sequentially that the other arm received concurrently and achieved the same PFS with this sequential approach (20.9 vs 20.7 months for concurrent gefitinib-chemotherapy vs gefitinib followed by chemotherapy, respectively; HR, 0.97), the patients who started with the gefitinib-chemotherapy combination had a significantly longer overall survival (OS; 52.2 vs 38.8 months; HR, 0.70). Approximately a quarter of patients assigned to gefitinib monotherapy didn't end up receiving chemotherapy subsequently, while 15% went on to get it, with a performance status of 2, and 9% had a performance status of 3-4.

Not only has chemotherapy not lost its place in lung cancer treatment, but it also had a very strong ASCO.

In many ways, these results echo the findings of the TORCH trial conducted nearly a decade ago, which compared cisplatin-gemcitabine versus erlotinib as first-line therapy in an unselected patient population in Europe, presumably including few with an activating EGFR mutation and with a planned switch from one to the other treatment.[4] The trial was discontinued early after the Data Safety Monitoring Board noted far inferior results, in terms of response rate (RR), PFS, and OS, for the patients who started on erlotinib. The most striking finding was that the patients who received chemotherapy second-line demonstrated an RR of 10%, just one third the RR of the same regimen administered to patients who received it as first-line therapy on the other arm of the trial. There are other settings in which the same therapy administered earlier demonstrates a highly significantly better OS, such as docetaxel[5] or abiraterone-prednisone[6] in men with metastatic prostate cancer.

Arguably the most practice-changing trial for lung cancer was the KEYNOTE-407 trial, which compared chemotherapy doublet with placebo versus chemo-pembrolizumab as first-line treatment for patients with advanced squamous non–small cell lung cancer, which demonstrated a significantly higher RR, PFS, and OS in the chemo-pembrolizumab arm.[7] Though crossover to pembrolizumab was allowed for patients who demonstrated progressing disease on chemotherapy alone, only 50% of eligible patients actually crossed over to pembrolizumab. It is difficult for me to imagine how half of the patients became too debilitated to receive second-line immunotherapy, with its proven OS benefit. Nevertheless, for whatever reason, there was profound attrition along the way.

Though the concept of "give your best treatment up front" is a widely cited mantra in oncology, we need to assess whether and potentially why that is true, particularly if it involves compressing several lines of treatment into one in the first-line setting and losing treatment options that we would otherwise offer sequentially. How much of the greater effect is due to a lower tumor burden, better patient physiology earlier in the treatment setting, or simply more reliable delivery of effective treatment administered early versus late?

Despite the remarkable results of the NEJ009 trial, even a median PFS of nearly 21 months and median OS of well over 4 years is unlikely to lead US-based oncologists to favor unglamorous gefitinib and standard chemotherapy over osimertinib, especially with the latter providing very good tolerability and unmatched activity in the central nervous system. But these results should lead us to eagerly pursue clinical trials pairing osimertinib with chemotherapy as first-line treatment. Not only has chemotherapy not lost its place in lung cancer treatment, but it also had a very strong ASCO.


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