Good drugs first, drug-resistant worry-free ositinib first-line treatment of drug resistance-histological transformation coping strategies

*For medical professionals only

How should EGFR mutation-positive lung adenocarcinoma be converted into small cell lung cancer or lung squamous cell cancer after oxintinib treatment?

For advanced non-small cell lung cancer (NSCLC) with EGFR mutation positive, ositinib has become the first-line treatment standard and even the preferred solution
recommended by authoritative guidelines at home and abroad.

However, in clinical practice, there are still many clinicians who have concerns: if the third-generation weapon is used first, what should be done after the drug resistance occurs? In the series of articles "Good drug first, no worries about drug resistance", we have previously introduced the coping strategy for the mutation of the drug-resistant target after first-line treatment of oxitinib, and this article will explain the occurrence of resistance caused by histological transformation and the corresponding coping strategies
.

Review of FLAURA research data:

The advantages of first-line treatment of oxitinib are prominent

The phase III FLAURA study established the "king" status
of ositinib in the first-line treatment of EGFR mutation-positive advanced NSCLC.

In terms of progression-free survival (PFS), the median PFS in patients treated with ositinib reached 18.
9 months, which was significantly longer than that of the first generation of EGFR-TKI^[1]; In terms of overall survival (OS), the median OS in the ositinib group was 38.
6 months, a significant increase of 6.
8 months compared to the first generation of EGFR-TKI, refreshing the PFS and OS history ^[2].

Figure 1: PFS and OS outcomes of first-line treatment of oshitinib

In addition, osirtinib has a powerful ability to penetrate the blood-brain barrier, significantly reducing the risk of CNS progression or death in patients with cardionervous system (CNS) metastases at baseline, and may reduce the appearance of new CNS ^[3,4
].

At the same time, oxitinib has good safety ^[1,2,5
].

In the first-line treatment of advanced NSCLC with EGFR mutation positive, ositinib has obtained the highest level of recommendation from authoritative guidelines at home and abroad, and has a very high clinical treatment status
.

Figure 2: Current status of domestic and foreign guidelines for first-line treatment of oxitinib

Histology transformation is

Important mechanisms of EGFR-TKI resistance

There is no doubt that oxitinib as a first-line therapy for patients with advanced NSCLC with EGFR mutation positive can maximize the survival time of patients and highlight the clinical value
of targeted therapy.

However, like other targeted therapies, ositinib eventually develops resistance problems
.

Histological transformation is one of the important mechanisms of EGFR-TKI drug resistance, including transformation into small cell lung cancer (SCLC), squamous cell carcinoma, etc
.

1

SCLC conversion

The mechanism by which histological transformation occurs has not been fully elucidated, and studies suggest that coexisting mutant genes such as TP53, Rb1, and PIK3CA may be detected prior to histological transformation ^[6-8].


The risk of SCLC transformation may be higher in patients with complete inactivation of TP53 and Rb1, as well as other genetic alterations such as high APOBEC ^{alterations [7,8}
].

In addition, one retrospective study found that pre-treatment Rb1 deletion was significantly associated with SCLC conversion, while patients with pre-treatment TP53 and Rb1 deletions generally had a poorer prognosis ^[9
].

In patients with EGFR mutation-positive lung adenocarcinoma, SCLC conversion may occur after drug resistance, regardless of several generations of EGFR-TKI, with a incidence of 5% to 14% ^[6,10-14].


Recent studies have shown that the incidence of histological transformation in patients with acquired resistance to first- and second-line oshitinib is 15 percent and 14 percent, respectively ^[15].


SCLC conversion typically occurs 14 to 26 months after TKI treatment, with a median time of 18 months ^[11].


Although most SCLC-transformed patients still retain the original EGFR mutation, EGFR expression levels decrease after transformation, which may be the reason why post-transformed tumors are not sensitive to EGFR-TKI therapy ^[16,17].

2

Squamous cell carcinoma transformation

The incidence of squamous cell carcinoma transformation after first-line oxitinib first-line therapy is 7%, and 9%
after post-treatment.

As with SCLC transformation, patients with squamous cell carcinoma transformation usually retain the original EGFR mutation, but the molecular pattern after transformation is currently unclear ^[15].

Histological transformation occurs after EGFR-TKI drug resistance,

How to deal with it?

1

SCLC conversion

There is currently no evidence for randomized controlled studies on the treatment of translational SCLC, but there have been some retrospective studies that have explored it, including chemotherapy, chemotherapy combined with EGFR-TKI; At the same time, several clinical trials such as immunotherapy combined with PARP inhibitors, ositinib combined with mammalian rapamycin
target protein (mTOR) inhibitors are underway.

Etoposide + platinum (EP regimen) is the classic protocol
for conversion SCLC therapy.

One retrospective study included 67 patients with translational SCLC, 30% of whom had received ositinib
.

Among these patients, the EP regimen was the most commonly used treatment option, with results showing an objective response rate (ORR) of 54% and a median OS of 10.
9 months after conversion ^[6
].

Studies have shown that chemotherapy in combination with EGFR-TKI or bevacizumab is more
effective in SCLC-transformed EGFR mutation-positive lung adenocarcinoma.

A study conducted by Chinese scholars retrospectively collected patients with SCLC transformation confirmed by tissue biopsy after the previous advancement of TKI treatment in Guangdong Provincial People's Hospital, and the analysis found that compared with chemotherapy alone, chemotherapy combined with EGFR-TKI or bevacizumab may have better ORR (25% vs 50%) and post-transformation PFS (3.
9 months vs 6.
4 months), and the post-transformation OS also showed a prolonged trend (7.
1 months vs).
10.
7 months)^[18].

At present, translational SCLC therapy is also recommended
in domestic and foreign guidelines/consensus.

The 2022 edition of the Chinese Society of Clinical Oncology (CSCO) SCLC guidelines for the diagnosis and treatment of SCLC states that the corresponding translational SCLC treatment strategy can be selected according to the post-EGFR-TKI post-treatment progression mode
.

For translational SCLCs with systematic and rapid progression following EGFR-TKI resistance, standard SCLC chemotherapy regimens can be selected; Translational SCLC with isolated lesion progression can be treated with the original EGFR-TKI/or standard SCLC chemotherapy regimen in combination with topical therapy; Patients with systemic slow-progression of SCLC may be treated with standard SCLC chemotherapy regimens ± EGFR-TKI ^[19
].

Table 1.
Translational SCLC therapy is recommended in the 2022 edition of the CSCO SCLC guidelines

In addition, the 2022 edition of the European Society for Internal Oncology (ESMO) EGFR mutation NSCLC treatment expert consensus states that for patients with SCLC transformation after EGFR-TKI resistance, it is recommended to use etoposide plus platinum chemotherapy; It is unclear whether continued use of ositinib is necessary during chemotherapy; For immunotherapy, participation in clinical trials is recommended ^[20].

2

Squamous cell carcinoma transformation

There is a lack of research evidence on treatment strategies for patients with squamous cell carcinoma translation, and the 2022 edition of ESMO EGFR mutant NSCLC treatment recommends the use of histological type chemotherapy ^[20].

Here is a case of squamous cell carcinoma transformation after the acquired resistance of EGFR mutation-positive lung adenocarcinoma: a 44-year-old male non-smoking patient who visited the hospital for "right back pain for 2 months" was diagnosed with EGFR 19 exon deletion mutation (19del) lung adenocarcinoma with bone metastasis
.

After 10 months of gefitinib treatment, the primary lesion of the upper lobe of the right lung enlarges
.

Genetic testing revealed that the patient had 19del and T790M mutations, which were switched to ositinib after 6 cycles of treatment with cisplatin + pemetrexed
.

After 15 months of sustained remission, patients develop mild disease progression and elevated carcinoembryonic antigen (CEA) levels, so chemotherapy
is added.

However, the primary tumor in the upper lobe of the right lung progresses rapidly and new L3 vertebral metastases
occur.

Pathological testing of resected bone and soft tissue specimens revealed squamous cell carcinoma with gene mutations 19del and T790M mutations
.

The patient was then treated with docetaxel and remained stable until the case was published ^[21].

Figure 3.
Treatment timeline as well as chest and bone scan pictures

Expert comments: See the tricks, calmly deal with the histological transformation after EGFR-TKI drug resistance

Histological transformation is one of the important resistance mechanisms of EGFR-TKI therapy, which may occur not only after ositinib resistance, but also after the first/second generation of EGFR-TKI resistance, so it is important
to understand the corresponding solution.

SCLC and squamous cell carcinoma are the more common types
of histological transformation.

For SCLC conversion, EP regimens are the more commonly used treatment regimen, and the addition of EGFR-TKI or anti-angiogenic therapy to chemotherapy may bring better efficacy; The efficacy of immunotherapy is still uncertain, and a number of studies are currently being explored, hoping that these studies will bring more treatment options
to the clinic in the future.

There is currently a lack of research on squamous cell carcinoma transformation, and when this situation is encountered clinically, it can be treated
according to the recommendations of the guidelines for squamous cell carcinoma.

In short, in the face of histological transformation caused by EGFR-TKI resistance such as ositinib, clinicians should see tricks and calmly deal with them
.

Professor Yu Yao

The First Affiliated Hospital of Xi'an Jiaotong University

Director of the Department of Oncology, Chief Physician, Doctoral Supervisor

Deputy Leader of the Chinese Cancer Rehabilitation Support Therapy Group, Director of the Chinese Society of
Clinical Oncology (CSCO).

Member of the Lung Cancer Quality Control Committee of the National Cancer Quality Control Center

Member of the Anti-Tumor Surveillance Committee of the National Center for Cancer Quality Control

Vice Chairman of the Tumor Chemotherapy Committee of the Chinese Medical Education Association

Vice Chairman of the Tumor Metastasis Committee of the Chinese Medical Education Association

Member of the Standing Committee of the CSCO Malignant Melanoma Professional Committee

Member of the Standing Committee of the CSCO Lung Cancer Professional Committee

Member of the Standing Committee of Wu Jieping Tumor Multidisciplinary Diagnosis and Treatment Committee

Standing Director of Shaanxi Anti-Cancer Association, Chairman of
Chemotherapy Professional Committee of Shaanxi Anti-Cancer Association

Chairman of the Oncology Branch of Xi'an Medical Association

Member of the Standing Committee of the Medical Oncology Committee of Shaanxi Medical Association

Secretary General of Xi'an Anti-Cancer Society

JCO Chinese Editorial Board Member

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