If you are unfortunate enough to have non-small cell lung cancer (NSCLC) and have missed your chance at a cure, don’t lose heart. As medicine advances and new drugs become available, more and more people with advanced NSCLC are surviving beyond 5 years and enjoying a good quality of life.
On April 26, 2018, the National Comprehensive Cancer Network (NCCN) updated its NSCLC guidelines to bring some new approaches and ideas to patients with advanced disease. This article will help you sort through them.
Before we get into the topic, it is important to introduce: the “Level of Evidence” after the recommendation indicates the strength of the evidence supporting the recommendation. There is little controversy (2B).
I. Targeted therapy
1. With EGFR-sensitive mutations, oseltinib is initially available
Oxitinib is a third-generation EGFR-targeted agent that is effective against the EGFR-resistant mutation, T790M, in addition to the sensitive mutations targeted by first- and second-generation drugs.
Older guidelines already recommended: after resistance to a first-generation EGFR-targeted drug, if a T790M mutation is found, you can use axitinib.
Based on this, the new guidelines recommend:
1) As long as there is an EGFR-sensitive mutation, you can go directly to axitinib (2A) regardless of the combination of T790M.
2) After resistance develops with oseltinib, depending on the symptoms, physicians may choose to respond as follows: a. Continue oseltinib therapy, which can be combined with local therapy; b. Switch to chemotherapy.
3) If resistance to oxitinib occurs, switching to a first- or second-generation drug is not currently supported.
4) If there are cerebrospinal metastases, with or without the T790M mutation, pulsed therapy with oseltinib or erlotinib can be considered (with regard to pulsed therapy, the clinic generally uses extended intervals with an increased single dose).
2. With ALK fusion genes, discontinuation may not be necessary after resistance to first-line targeted therapy
1) After resistance to an ALK-targeted drug, physicians need to consider the next step in treatment based on the presence or absence of symptoms. Some patients who continue to benefit from targeted therapy do not need to discontinue the drug and combine it with local therapy (e.g., head radiation if brain metastases are present); however, if local therapy fails, or if the disease progresses extensively, systemic chemotherapy should be used.
2) Some patients with rapid disease progression after hastily discontinuing targeted agents may resume ALK-targeted agents.
3) Crizotinib, ceritinib, and erlotinib can all be used as initial agents for targeted therapy, with erlotinib (Alectinib) being better.
3. Ado-trastuzumab emtansine is recommended in the presence of HER-2 gene mutations
If there is a HER-2 gene mutation, the new guidelines no longer recommend afatinib or trastuzumab and now recommend Ado-trastuzumab emtansine (a new drug that targets the HER-2 molecule, trade name KADCYLA).
4. About target testing
The new guidelines add testing for EGFR exon 20 insertional mutations and also recommend testing for BRAF mutations in patients with NSCLC.
II. Immunotherapy
1. The old guidelines used to recommend pembrolizumab (a new immunotherapy drug known as Keytruda) for patients with sensitive mutations who have failed targeted therapy if they test for more than 50% PD-L1 expression in cancer cells. However, the new guidelines remove this recommendation.
This is because several studies have confirmed that patients with sensitive genetic mutations are not better off than chemotherapy when given a new immunotherapy drug after resistance to targeted therapy.
2. In patients with advanced NSCLC, the initial treatment can be pembrolizumab in combination with chemotherapy. In non-squamous cancers, pemetrexed + carboplatin + pembrolizumab; in squamous cancers, paclitaxel + carboplatin + pembrolizumab.
In addition, given the results of the latest study reported this year (KEYNOTE-042), it is expected that US guidelines may soon recommend that patients with advanced NSCLC with PD-L1 expression greater than 1% who cannot be treated with targeted agents may initially be treated directly with pembrolizumab.
3. Patients with locally advanced NSCLC who are inoperable can receive consolidation therapy with Durvalumab (a new immunotherapy drug, trade name Imfinzi) after concurrent radiotherapy, unless they experience a serious adverse reaction after taking the drug.
This recommendation is based on a clinical study (the PACIFIC study) that showed an 11.2-month extension in progression-free survival and a significant increase in objective remission rates after consolidation with Durvalumab in this group of patients.
III. Radiotherapy
1. In patients with stage III NSCLC, radical radiotherapy should use IMRT, which is superior to 3D-CRT.
IMRT (Intensity-modulated radiation therapy) and 3D-CRT (3-dimensional conformal radiation therapy) are both relatively advanced radiotherapy techniques available today. The study (code RTOG 0617) showed that IMRT had similar efficacy compared with 3D-CRT, while significantly reducing the incidence of severe radiation pneumonia (from 7.9% to 3.5%).
2. After the development of limited oligometastases, aggressive local therapy, including surgery or radical radiotherapy, can be considered for oligometastatic lesions, provided the disease is stabilized with systemic therapy.
Oligometastases are defined as three to five metastases in a few organs. Studies have shown that in such patients, if the disease is stable after systemic therapy, local treatment (radiation therapy or surgery) given to the metastases can lead to longer survival.
3. For whole-brain radiotherapy in patients with limited brain metastases, the guidelines have reduced the recommendation because it may lead to neurocognitive decompensation.
In addition, the guidelines place special emphasis on controlling radiation dose and protecting normal organs surrounding the lesion. The use of new, more precise radiotherapy techniques can help achieve this.
To summarize, the new US guidelines on the treatment of mid- to late-stage NSCLC convey some new ideas, but the US guidelines are based on US realities and some are not appropriate for our patients. However, the U.S. guidelines are based on the actual situation in the U.S., and some of them are not suitable for patients in China. Moreover, your doctor will not copy the guidelines when treating you, but will consider various factors. Therefore, this article is not a substitute for your doctor’s opinion, and you should follow your doctor’s instructions regarding your specific condition.
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