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At this year's meeting of the American Society of Clinical Oncology (ASCO 2019), held May 31 to June 4 in Chicago, investigators discussed the latest findings in cancer research. The editors of NEJM Journal Watch Oncology and Hematology were on hand to report highlights of the conference. Here, Associate Editor, Anne S. Tsao, MD, reviews key presentations on new treatments for patients with non–small-cell and small-cell lung cancer. All meeting abstracts can be viewed in the ASCO meeting library.
For patients with metastatic non-squamous non–small-cell lung cancer (NSCLC), it is standard practice to administer maintenance therapy with pemetrexed. But whether to give monotherapy or doublet maintenance therapy to patients receiving a triplet combination is unknown. To address this issue, Ramalingam colleagues conducted the phase III ECOG-ACRIN 5508 trial (abstract 9002) involving 1516 non-squamous NSCLC patients who initially received triplet therapy with carboplatin, paclitaxel, and bevacizumab. Patients who did not progress were then randomized 1:1:1 to maintenance therapy with bevacizumab, pemetrexed, or a combination of the two agents.
At a median follow-up of 50.6 months, progression-free survival (PFS) was longer with combination bevacizumab and pemetrexed maintenance therapy than with bevacizumab alone (7.5 vs. 4.2 months; P<0.001), and PFS trended longer with combination maintenance than with pemetrexed alone (7.5 vs. 5.1 months; P=0.06). However, overall survival (OS; the primary endpoint) was similar between combination maintenance and bevacizumab (16.4 and 14.4 months, respectively) and between combination maintenance and pemetrexed (16.4 and 15.9 months).
ECOG-ACRIN 5508 shows that in patients who receive the triple regimen of carboplatin, paclitaxel, and bevacizumab, doublet maintenance therapy with pemetrexed and bevacizumab does not improve OS versus single-agent maintenance therapy with pemetrexed or bevacizumab. In these patients who are eligible for maintenance therapy, it would be recommended to give them continuation bevacizumab or switch them to pemetrexed maintenance. Although this study is a definitive trial, it has limited applicability at this time, since most non-squamous NSCLC patients are receiving front-line immunotherapy or chemoimmunotherapy treatment. In immunotherapy-ineligible non-squamous NSCLC patients, this study may provide guidance for therapy.
Garon and colleagues updated OS results of the phase Ib KEYNOTE-001 trial (abstract LBA9015) of pembrolizumab in 550 metastatic NSCLC patients, including 449 pretreated patients, with positive PD-L1 IHC expression ≥1%.
OS at 5 years was 15.5% in pretreated patients and 23.2% in treatment-naive patients. Among patients with PD-L1 IHC ≥50%, the 5-year OS rate was 25% in pretreated patients and 29.6% in treatment-naive patients. The immune RECIST response rate was 23% in pretreated patients and 42% in treatment-naive patients.
This 5-year update of KEYNOTE-001 provides hope for patients with metastatic NSCLC, given that the prior historical 5-year OS rates were less than 5%. The long-term safety data showed no difference in immune-related toxicity rate of 17% reported from the 3-year update, which suggests that there is no detrimental cumulative toxicity from being on long-term checkpoint inhibition. Current trials are ongoing to explore the use of checkpoint inhibitors for various durations of therapy in the metastatic setting.
Although treatment paradigms have shifted in front-line metastatic NSCLC to immunotherapy-based regimens, it remains unknown whether there is a benefit to adding immunotherapy in the early-stage resectable setting. Provencio and colleagues report the results of the phase II NADIM trial (abstract 8509) involving 41 patients with resectable stage IIIA NSCLC treated with neoadjuvant nivolumab, paclitaxel, and carboplatin. After resection (90% lobectomy, 10% pneumonectomy), patients were given adjuvant nivolumab for 1 year.
A major pathologic response was seen in 83% of patients, and a complete pathologic response was see in 71%. Downstaging was seen in 90% of cases. Radiographic evaluation by RECIST showed a 71% partial response and 7% complete response.
This study was important for three main reasons. First, the response rates to neoadjuvant chemoimmunotherapy by both pathologic and radiographic criteria were very high and unprecedented in early-stage NSCLC, and the high rate of downstaging is highly promising. Second, the trial showed that neoadjuvant chemoimmunotherapy did not induce adverse toxicity and did not prevent surgical resections. Third, because this was a multicenter study that was conducted throughout Spain, it showed that this treatment strategy is feasible and can be performed in the community. The NADIM trial of neoadjuvant carboplatin, paclitaxel, and nivolumab may herald a paradigm shift in early-stage resectable NSCLC. However, it remains to be seen if these early markers of response will translate into a survival benefit. Additional survival outcomes should be reported within the next year. We hope they will show that the high responses translate into higher cure rates.
In NSCLC, RET fusions are identified in 2% of NSCLC patients. BLU-667 is a small-molecule oral agent that targets RET alterations. To test the activity and safety of BLU-667, Gainor and colleagues conducted the ARROW study (abstract 9008) involving 79 advanced pretreated NSCLC RET-altered patients. The RET alterations included 44 KIF5B, 16 CCDC6, and 19 others; 39% of patients had baseline brain metastases, and the median number of prior therapies was 2.
In 57 response-eligible patients, the response rate was 56%, and the disease control rate was 91%. In 30 patients who received the recommended phase II dose of 400 mg daily and who had prior platinum chemotherapy, the response rate was 60%. The responses were seen in all RET-fusion genotypes, and intracranial activity was seen. Grade ≥3 toxicity (increased liver function tests, hypertension, fatigue, decreased neutrophils, and constipation) was seen in 28% of patients, and 3% discontinued treatment due to toxicity.
BLU-667 has efficacy in advanced RET-fusion NSCLC and targets the most common RET-fusion partners seen in NSCLC. The toxicity profile is reasonable and manageable, and it is anticipated that once expansion cohort data are complete, registration approval will occur if the response rate holds.
There are few options for patients with refractory small-cell lung cancer (SCLC). Lurbinectedin is a novel agent that induces DNA double-strand breaks with apoptosis. Paz-Ares and colleagues conducted a phase II basket trial (abstract 8506) involving patients with multiple malignancies, including 115 with SCLC who were given lurbinectedin.
The median chemotherapy-free interval was 3.5 months; the response rate was 35.2%, with a median duration of response of 5.3 months; and median OS was 10.8 months. Patients with “sensitive disease,” defined as ≥90-day chemotherapy-free interval, had a 46.6% response rate, with a median duration of response of 6.2 months, and a median OS of 15.2 months. Five of 8 patients who had prior immunotherapy had a confirmed response. The most common adverse effect was myelosuppression (22.0% grade 3, 23.8% grade 4); 3.8% had grade 3 or 4 febrile neutropenia, and 6.6% had grade 3 or 4 thrombocytopenia. Only 3.8% of patients required treatment discontinuation.
Lurbinectedin demonstrated some activity in second-line SCLC and may ultimately be a reasonable therapeutic option. However, additional studies are needed to better identify which patients would benefit from this agent; those with sensitive disease appear to have the greatest survival benefit. What was interesting in this trial was that the cohort of patients who had prior immunotherapy appeared to respond well to lurbinectedin. In terms of toxicity, it is likely that patients will require growth-factor support to counteract the myelosuppression. Overall, the agent appears to be well tolerated with low rates of grade <2 fatigue, nausea, and vomiting. Additional studies are ongoing.