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Paul A. Bunn, Jr.
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P3.03 - Chemotherapy/Targeted Therapy (ID 719)
- Event: WCLC 2017
- Type: Poster Session with Presenters Present
- Track: Chemotherapy/Targeted Therapy
- Presentations: 1
- Moderators:
- Coordinates: 10/18/2017, 09:30 - 16:00, Exhibit Hall (Hall B + C)
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P3.03-007 - LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor (ID 8338)
09:30 - 16:00 | Author(s): Paul A. Bunn, Jr.
- Abstract
Background:
The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.
Method:
904 patients with centrally confirmed stage IV lung adenocarcinomas who were candidates for therapy had at least one of 14 oncogenic drivers assessed in a CLIA-compliant laboratory using genotyping, FISH, massively parallel sequencing (NGS), and immunohistochemistry (IHC) analyses.
Result:
Among 423 patients tested for all 14 targets, we found a driver in 65%. Mutated KRAS was found in 31%, sensitizing EGFR in 14%, MET amplification in 5%, ALK rearrangements in 4%, BRAF V600E in 3%, and HER2 in 3%. Rearrangements in RET and ROS1 were each found in 2% (CI 1 to 3%). Using IHC, PTEN loss was found in 8% (CI 6 to 11%) and MET expression in 58% (CI 55 to 61%). Use of targeted therapies in patients with EGFR, HER2, or BRAF mutations, ALK, ROS1, or RET rearrangements, and MET amplification was associated with a gain in overall survival of 1.5 years relative to those with the same drivers not receiving targeted therapy and a gain of 1 year relative to those without an actionable driver. Current and former cigarette smokers derived a survival benefit from targeted therapies similar to never smokers (p=0.975). Among 154 patients who had all drivers assessed and NGS testing in addition, any TP53 mutation was associated with poorer survival among those with EGFR, ALK, or ROS1 (p=0.014). STK11 was detected in 11%, all in patients with KRAS mutations.
Conclusion:
Using an expanded testing panel, LCMC2 demonstrates the survival benefit of matching targeted treatments to oncogenic drivers in patients with lung adenocarcinomas, identifies additional prognostic factors, and supports the performance of multiplex molecular testing on specimens from all individuals with lung adenocarcinomas irrespective of clinical characteristics. We detected either MET amplifications or HER2 mutations in 7%, together more than the 4% with ALK. A targeted drug is available in the United States for 35% of patients with lung adenocarcinomas. The routine use of massively parallel sequencing (NGS) detects both targetable drivers and tumor suppressor genes that have significance for therapy selection and prognosis. Supported by Free to Breathe
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PL 04 - Closing Plenary: Where We Are Now, and Where We Will Be in 10 Years (ID 587)
- Event: WCLC 2017
- Type: Plenary Session
- Track:
- Presentations: 1
- Moderators:H. Kato, Rafael Rosell
- Coordinates: 10/18/2017, 16:30 - 17:45, Main Hall
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PL 04.01 - Where We Are Now, and Where We Will Be in 10 years: From North American Perspective (ID 7841)
16:30 - 17:45 | Presenting Author(s): Paul A. Bunn, Jr.
- Abstract
- Presentation
Abstract:
Stage 4 NSCLC 1[st] line Rx: In addition to complete staging, all patients with any histology should have PD-L1 testing of their tumor. In addition patients with an adenocarcinoma histology and never smokers should have molecular testing that would include at least EGFR, ALK, ROS1 and BRAF. If NGS testing is selected that additional genes can be tested including MET,RET, HER2,and NTRK. Patients with a PD-L1 tumor proportion score (TPS) >49% who do not have a molecular driver can be treated with pembrolizumab as their first therapy. This therapy is continued for 2 years or until progression or unacceptable toxicity. For those with a TPS score of 1-49, concurrent chemotherapy plus pembrolizumab may be considered based on the results of a small phase II trial. However, larger phase III trials are in progress and may alter this choice. Patients with a molecular alteration in EGFR, ALK, ROS1, or BRAF are treated with the appropriate TKI or TKI combination in the case of v600E BRAF. Although all of the randomized trials comparing these new therapies to chemotherapy included only PS 0-1 patients, there is clear evidence that patients with PS 2 and even PS 3 and elderly patients may benefit from these therapies and should thus be tested. For patients with a lower TPS score or no molecular abnormality and PS0-1, the standard therapy is a platinum doublet chemotherapy with or without bevacizumab. For patients with adenocarcinoma, the most frequently used regimen is pemetrexed with platinum. In North America the platinum is most often carboplatin because of its preferred toxicity profile. PS 0-1 adenocarcinoma patients may also receive bevacizumab if there are no comorbid conditions that would increase toxicity. A taxane doublet with or without bevacizumab is also acceptable. For patients with squamous carcinoma the platinum doublet usually contains gemcitabine or a taxane with carboplatin with or without bevacizumab. Patients receiving chemotherapy are restaged after 2 cycles. Those with progressive disease are offered second line therapy. Patients with stable disease or response receive 2 additional cycles and are then restaged again. Those with acceptable toxicity and continued response are offered 2 additional cycles for a total of 6. Those without further response or additional toxicity are offered maintenance therapy after the 4 cycles. Patients receiving 6 cycles are also offered maintenance therapy. Maintenance therapy may consist of continued pemetrexed or continued bevacizumab for those responding to these. Switch therapy to pemetrexed or to erlotinib or gemcitabine may be considered. 2[nd] Line Rx. For patients receiving 1[st] line pembrolizumab, 2[nd] line rx is first line chemotherapy as discussed above. For patients progressing on a 1[st] line TKI, the 2[nd] line therapy is most often a 2[nd] or 3[rd] generation TKI. When therapy with a TKI is exhausted, the next line of therapy is standard first line chemotherapy as described above. For patients who receive 1[st] line chemotherapy, the second line therapy is most often immunotherapy which can be any of the 3 approved agents for patients with a TPS score of >1 or nivolumab or atezolizumab for patients with a TPS score of 0. 3[rd] Line Rx: Patients who receive 1[st] line I/O followed by chemo or who receive gene specific TKIs followed by 1[st] line chemotherapy, the 3[rd] line treatment would be what was previously considered 2nl line chemo such as docetaxel +/- ramicirumab. Other chemotherapy agents can also be considered such as gemcitabline, other taxanes or irinotecan. Clinical trials may be substituted for any of these treatments in any lines of therapy. Unresectable Stage III. The standard approach is currently concurrent chemotherapy with chest radiotherapy. This is likely to change as positive results of a trial comparing CT/RT alone to CT/RT followed by immunotherapy with durvalumab were announced in mid-2017. The chest RT is generally about 60 Gy given over 6 weeks. The chemotherapy is generally a platinum doublet with etoposide, paclitaxel or pemetrexed. At the time of progression the algorhythm described for stage 4 above can be instituted. Resectable stage I-IIIA. For stage 1A standard therapy is lobectomy alone or stereotactic body radiotherapy (SBRT) for those who are medically inoperable. Patients with stage IB, especially with poor prognostic features such as large size or vascular invasion may receive neoadjuvant or adjuvant chemotherapy with a cisplatin doublet and surgery is standard while other smaller stage IB tumors are treated with lobectomy alone. Stage II and IIIA patients may be treated with neoadjuvant chemotherapy or neoadjuvant CT/RT followed by surgery. They may also receive surgical resection first followed by adjuvant CT or CT/RT. The future: It is highly likely that immunotherapy combinations will prove to be superior to single checkpoint inhibitors so that the majority of sage IV patients without a molecular driver are likely to receive an immunotherapy combination, likely irrespective of TPS score. For stage IV patients with a molecular driver, it is likely that initial therapy will consist of the TKI plus another agent that can affect the cells that persist after initial TKI therapy. It is likely that immunotherapy combinations and molecular combinations will be used in unresectable stage III disease before, after or during CT/RT and will improve cure rates. I believe that a large change in approach to early stage patients will occur with the development of neoadjuvant immunotherapy and molecular therapy. In these approaches we have the opportunity to improve cure rates as well as to more rapidly develop new therapies based on pathologic complete response rates as we now do in breast cancer. The future is also likely to see new ways to define risk in both smokers and non-smokers so that we can detect patients early and so that we can develop new prevention strategies for those at high risk. Figure 1
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