1. Stinchcombe, Tom MD

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The oral presentations at this year's ASCO meeting demonstrated continued progress in the treatment of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC).

Tom Stinchcombe, MD.... - Click to enlarge in new windowTom Stinchcombe, MD. TOM STINCHCOMBE, MD, is with the Thoracic Oncology Program at UNC-Chapel Hill.

There were several presentations on treatment of anaplastic lymphoma kinase (ALK) rearranged NSCLC. A phase III trial in Japan compared alectinib 300 mg twice daily to crizotinib. Patients assigned to the alcetinib arm compared to criztoinib arm experienced a higher objective response rate (ORR) (85% versus 70%, respectively), a statistically significant longer progression-free survival (PFS) (HR of 0.34; p< 0.0001; median PFS of not reached and 10.2 months, respectively) and lower rate of grade 3 or 4 adverse events (26% and 52%, respectively) (Abstract 9008).


A randomized phase II trial investigated brigatinib at 90 mg daily or 90 mg daily for 7 days followed by 180 mg daily in patients previously treated with crizotinib. The ORR and median PFS observed in the 90 mg daily arm were 45 percent and 9.2 months, and in the 90 mg daily followed 180 mg daily arm were 54 percent and 12.9 months (Abstract 9007). Preliminary results of a phase II trial of lorlatinib in patients who were previously treated with an ALK TKI revealed an ORR and PFS of 46 percent and 11.4 months (Abstract 9009). The ORR and PFS in patients who had received one prior ALK TKI were 57 percent and 13.5 months, and the ORR and median PFS in patients who had received >= 2 ALKT TKIs were 42 percent and 9.2 months.


Small Cell Lung Cancer

Recent improvements in SCLC have come from improvements in radiation therapy (RT), and a previous trial in limited stage SCLC revealed an improvement in OS with twice daily compared to once daily RT to 45 Gy. Data from a phase III trial of twice daily compared to once daily RT to 60 Gy in patients with limited-stage SCLC was presented at ASCO (Abstract 8504). All patients received cisplatin (25 mg/m2 days 1-3 or 75 mg/m2 on day 1) and etoposide (100 mg/m2 on days 1-3), and the primary endpoint of overall survival (OS). Patients assigned to twice daily RT had a similar survival to patients assigned to once daily RT (median OS of 30 and 25 months, respectively; p=0.15). Patients assigned to both arms had a better OS than historical controls, and the increased use of PET scan staging may have contributed to the better OS (57% of patients underwent PET scan staging). The rate of grade 3-5 esophagitis and pneumonitis were similar in the two arms.


Chemotherapy has been the mainstay of treatment for extensive stage SCLC, and previous trials of newer chemotherapies have not yielded clinical improvements. Given the revolutionary impact of immunotherapy, there is significant interest in investigating immunotherapy in SCLC. A phase II trial investigated nivolumab alone, and two different nivolumab and ipilimumab combinations in patients who had progressed after platinum-based therapy (Lancet Oncol 2016:17;883-895). The ORR and median OS observed with single agent nivolumab were 10 percent and 4.4 months. In the combination arms the ORR were 23 percent and 19 percent, and the median OS were 7.7 and 6.0 months. The rate of grade 3-4 treatment related adverse events in the nivolumab alone was 13 percent, and in the two combination arms were 30 percent and 19 percent.


A phase I trial with expansion cohorts investigated rovalpituzumab tesirine (Rova-T), an antibody drug conjugate that targets the delta-like protein 3 (DLL-3) (Abstract LBA8505). Two-thirds of patients had DLL-3 expression of >= 50 percent. The ORR among patients with over-expression of the DLL-3 of >= 50 percent was 31 percent; Rova-T had similar activity in second and third-line patients. The most common grade >= 3 adverse events were thrombocytopenia, skin reactions, serosal effusions (pleural or pericardial effusions, ascites, or capillary leak syndrome).


The Future of Lung Cancer

Perhaps the most provocative study presented at ASCO was a randomized phase II trial of local consolidative therapy, defined as surgery or radiation to primary and metastases, or physician's choice for standard therapy or maintenance in patients with oligiometastatic NSCLC after induction systemic therapy (Abstract 9004). Induction system therapy was defined as >= 4 cycles of platinum-doublet chemotherapy, and >= 3 months of epidermal growth factor receptor TKI for EGFR mutant NSCLC or ALK TKI for ALK rearranged NSCLC. Patients were required not to have progressive disease on induction therapy, and have <= 3 metastatic sites (N1-N3 considered as a single site) after induction therapy. Of the 74 patients enrolled in the induction phase, 49 patients were randomized, and the majority of patients received RT as their local therapy. In patients assigned to the local therapy and no local therapy arms, the median PFS observed were 11.9 and 3.9 months, respectively (p=0.005).


The importance of molecular testing has been well-established, but obtaining sufficient tumor tissue for molecular testing can be problematic. There is interest in utilizing blood-based molecular testing of circulating tumor DNA. A study investigated the EGFR genotyping using matched urine, plasma, and tumor tissue (Abstract 9001). The tumor tissue was tested using real-time PCR, plasma digital PCR followed flow cytometry, and urine using mutation enrichment next-generation sequencing. Urine testing required 100 mL urine and could be stable at room temperature for 2 weeks. The plasma and urine sensitivity for detection of T790M resistance mutation were 81 percent with tissue as the reference, and both testing methods detected the T790M mutation in patients with inadequate tumor samples and tumor samples that are negative for the T790M mutation. Patients received rociletinib and the ORR and PFS were similar in patients with the T790M detected by plasma, tissue, and urine.

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Of the presentations at ASCO, the first-line trial of alectinib is most likely to influence current treatment paradigms. Studies of brigatinib and lorlatinib in ALK rearranged NSCLC, and Rova-T and immunotherapy in SCLC revealed promising activity. For patients with limited stage-SCLC both once daily and twice radiotherapy to 60 Gy are options. The concept of consolidative local therapy is appealing in patients with olgiometastatic NSCLC, but the promising results will need to be confirmed in a larger trial. The further development of blood and urine-based mutation testing will facilitate the detection of the T790M resistance mutation.