The 24th round of Long March Difficult Tumor MTB Conference focused on the long-term benefits of precise diagnosis and treatment of MSS bowel cancer patients, and analyzed the characteristics, mechanism and treatment plan of rare EGFR19delins mutations

On October 19, the 24th round of Long March Molecular Tumor Board (MTB) was held
in Long March Hospital as scheduled.
MTB is a multidisciplinary model that integrates diverse patient information to discuss the treatment of patients with advanced tumors at the molecular level
.
The MTB Conference of Changzheng Hospital was initiated by the team of Director Zang Yuansheng, Department of Oncology, Changzheng Hospital Affiliated to Naval Military Medical University, featuring the discussion of the best treatment options for patients with difficult tumors, with the goal of
improving the long-term treatment effect of patients with difficult tumors and winning survival benefits for patients.
The two cases discussed in this MTB were brought by clinical experts Professor Wang Zhan and Professor Jiao Xiaodong, and participated in the discussion by molecular biology experts Dr.
Wen Fengcai and Dr.
Zhu Mingjun, bioinformatics expert Dr.
Zhang Ding, and many oncology clinicians
.

Case 1:

Basic condition of the patient:

The patient's female 71 years old, in July 2020, consciously felt cervical lymphadenopathy, CT showed multiple swollen lymph nodes in the left armpit, slightly larger lymph nodes in the mediastinum, and underwent left cervical lymph node resection, pathology suggests adenocarcinoma, metastasis is considered, and gastrointestinal origin may be
possible.
Colonoscopy in August showed "a new organism of giant ulcerative type in the sigmoid colon"
.
Biopsy pathology showed "sigmoid mucinous adenocarcinoma", PET-CT (2020-8-6) showed "sigmoid colon cancer, pelvic, retroperitoneal, mediastinum, left axillary, left suprinavicle, left neck lymph node metastasis"
.

On August 18, 2020, he was admitted to our department to complete the laboratory and baseline imaging examination, enrolled in the APICAL-CR clinical study, and was given anlotinib + sindilimab treatment from August 21 to May 13, 2021, q3w, a total of 13 cycles, during which the dose of anlotinib was reduced due to adverse reactions, the efficacy evaluation of 4 cycles was PR, and the efficacy evaluation of 10 cycles was SD;

From June 4, 2021 to November 19, 2021, anlotinib + sindilimab treatment was continued, and on December 14, the pathology of the left axillary mass biopsy showed metastatic adenocarcinoma, and the patient's imaging examination was performed, and the efficacy was evaluated as PD;

Switching to FOLFOX+ bevacizumab (q2w) for SD assessed as slowly progressing after 5 cycles from December 2021 to February 25, 2022, with 5-FU adjusted to raltitrexed as appropriate; Oxaliplatin + raltitrexed + bevacizumab was given on April 21;

On May 21, 2022, the treatment plan was adjusted, specifically irinotecan + raltitrexed + bevacizumab, Q3W, and then bevacizumab was suspended due to asymmetric swelling of the left forearm, and the adjustment plan was irinotecan + raltitrexed on June 2; On June 13, 2022, there was no obvious thromboembolism in the color ultrasound, so irinotecan + raltitrexed + bevacizumab was given on June 22 and July 13, Q3W;

On August 5, 2022, 08-26, 09-16, the examination and skin performance considered the progress, adjusted the plan, and gave irinotecan + raltitrexed + carrelizumab + regorafenib treatment
.
The patient's recent asymmetrical swelling of the left upper arm is similar to before, the skin temperature is normal, the left breast and left shoulder blade are flaky erythema, and there are multiple round-like soft tissue masses
on the skin surface.

Genetic test results (July 23, 2020):

ERBB2 T733I mutation, KRAS G13D mutation, FLT3 copy number increase, ZNF703 copy number increase, etc.
were measured

Discussion questions:

1.
The clinical significance of ERBB2, KRAS mutations and FLT3 copy number increase were detected this time

2.
Immunotherapy for colorectal cancer

Molecular biology analysis (molecular biologist Wen Fengcai):

1.
There is limited evidence for targeted therapy for colorectal cancer with HER2 mutations

HER2 is one of the important members of the human epidermal growth factor receptor family, which is involved in regulating cell proliferation, migration, differentiation and apoptosis, and is closely related to tumorigenesis ^{and development1-2}
.
In colorectal cancer, the proportion of HER2 gene abnormalities is 2-6%, of which point mutations account for about 3%³
.
The HER2 T733I variant carried by this patient is in the tyrosine kinase domain, which causes abnormal activation of the kinase
.
In the AACR GENIE database, the variant was detected in only 0.
03% of colorectal cancer patients, suggesting that the HER2 T733I variant is extremely rare
.

In terms of treatment, trastuzumab combined with pertuzumab or lapatinib for HER2-positive advanced colorectal cancer has become the standard of care recommended by NCCN ^{guidelines4-7}, however, neither tropa in combination nor monoclonal antibody combined with small molecule TKI has seen a particularly clear clinical benefit in advanced colorectal cancer with HER2 point ^mutation8-10
。 With the development of antibody conjugates, in a study of T-DXd (DS8201) in the treatment of HER2-mutant solid tumors, the best response to T-DXd in one patient carrying the HER2 T733I variant was SD, and the duration of disease stability maintenance is ^unknown11
.

2.
Simultaneous mutations of KRAS and HER2 may affect the efficacy of targeted therapy

The KRAS G13D mutation carried by this patient is one of the classic variants in the KRAS gene in colorectal cancer, and colorectal cancer patients who usually carry this mutation have a worse prognosis and shorter survival ^time12,13
.
In colorectal cancer, there are few studies or case reports of HER2 with KRAS mutations, and secondary mutations in KRAS genes are usually the key factors for failure of first-line anti-HER2 therapy14, so it is suggested that due to the presence of downstream KRAS ^G13D mutations, the efficacy of targeted therapy for HER2 variants may be affected, and caution and appropriate follow-up
should be strengthened when trying.

3.
FLT3 gene amplification is uncommon in colorectal cancer and usually predicts a poor prognosis

FMS-like tyrosine kinase 3 (FLT3), a member of the class III receptor tyrosine kinase family, is often expressed in hematopoietic progenitor stem cells and plays a key role
in controlling the proliferation and differentiation of hematopoietic precursors.
A large sample of colorectal cancer patients in Japan reported that FLT3 gene amplification accounted for about 3.
6%, and the median OS of FLT3 amplified bowel cancer patients was significantly shorter than that of patients with normal FLT3 ^gene15
.
In solid tumors, inhibitors that specifically target FLT3 amplification are still in the early stages of clinical development, and broad-spectrum tyrosine kinase inhibitors such as sorafenib and regorafenib have been reported to benefit colorectal cancer patients who have failed multi-line ^{chemotherapy16-17}
.
The progression-free survival of regorafenib monotherapy was 12.
4 months in one patient with sigmoid colon cancer with KRAS G12S and FLT3 amplification after standard therapy ^failure16
.

4.
Immunotherapy for colorectal cancer has shown initial efficacy

The REGONIVO study is an immune combined with anti-angiogenic inhibitors for advanced backline MSS colorectal cancer has achieved encouraging clinical efficacy, with an ORR of up to 30% and an mPFS of 7.
9 ^months18, which has triggered many attempts and explorations on anti-PD-1 immunotherapy combined with anti-angiogenic drugs at home and abroad, although the overall ORR is between 0-20%, and the results of the REGONIVO study have not been ^{replicated19-23} , but subgroup analysis showed that bowel cancer patients without liver metastases were more likely to benefit
from immunotherapy combined with TKI.
Just as in this case of sigmoid colon cancer with extensive metastases in multiple lymph nodes throughout the body but no tumor invasion of the liver, the patient achieved progression-free survival of up to 14 months from the combination of anlotinib + sindilimab
.

In addition to immunization plus TKI, PD-1 + CTLA-4 dual immunization has also shown some efficacy, and in the CCTG CO.
26 study, durvalumab plus Tremelimumab+ optimal supportive care (BSC) in patients with advanced colorectal cancer who are not responsive to all treatments was compared with BSC, with overall survival extended by 2 months (6.
6 vs 4.
1 months), but no improvement in PFS and ^ORR24
。

Clinical team analysis and protocol selection (Prof.
Wang Zhan):

The results of genetic testing showed that the patient carried mutations or amplifications of HER2, KRAS, FLT3 and other genes at the same time, indicating that the tumor heterogeneity was high and the prognosis was poor, so it was difficult for a single type of drug to inhibit the progression
of the disease.
Although there is no particularly strong evidence of targeted therapy for the ERBB2 T733I point mutation carried by patients, due to the high abundance of this mutation, it indicates that its tumor drive ability is strong and needs to be specifically inhibited
。 In addition, in view of the case reports of FLT3 amplification patients benefiting from regorafenib, after full communication with patients, the treatment group began to add pyrrotinib on September 17, 2022, that is, irinotecan + raltitrexed + carrelizumab + regorafenib + pyrotinib five-drug combination "cocktail" treatment regimen; At present, 2 courses of treatment have been completed, waiting for the efficacy evaluation
.

Other clinical expert views:

Professor Qin Baodong: This case is a patient with sigmoid colon cancer, it is worth noting that the tumor metastasis site is not the liver and lung metastasis common in bowel cancer, but the extensive metastasis of axillary and supraclavicular lymph nodes.

At the therapeutic level, immune combined with anti-angiogenic drugs have been long-lasting and effective in controlling tumors in the first line, and I personally believe that it is feasible to consider immune restart when multi-line chemotherapy fails and almost no drugs are available, but it is recommended to use different PD-1 antibodies or PD-1/CTLA-4 dual antibodies to try
.

Professor Jiao Xiaodong: The patient's follow-up treatment options are mainly based on the NGS test results in July 2020, which were sampled by the patient without systemic treatment, and after a variety of chemotherapy, targeted, immunological and other drug treatments, the patient's tumor mutation status may have changed, if feasible, it is recommended to re-detect the patient's new lesion tissue or ctDNA to better guide subsequent medication
.

Professor Zang concluded:

1.
Personalized treatment and timely protocol adjustments for patients to survive longer

In the case of patients whose initial physical condition is poor and they cannot tolerate first-line chemotherapy, the treatment group preferentially recommends patients to enroll in the clinical study of anlotinib combined with sindilimab, which brings patients lasting disease control and is conducive to the gradual recovery
of patients' physical strength.
After the failure of first-line treatment, the treatment group gave chemotherapy in a timely manner, and continuously fine-tuned and optimized the treatment plan according to the actual situation of the patient to reduce the adverse effects
of chemotherapy.
Up to now, this elderly colon cancer patient has won 27 months of survival, which is a very successful case of refined treatment, which is not easy
.

2.
Innovative treatments for difficult tumors need to be targeted

Innovative treatments for difficult tumors are mainly aimed at patients
with advanced late-line tumors without standard treatment regimens.
In the process of carrying out innovative treatment, patients' willingness to treat and economic affordability, and how to choose clinically accessible, efficient and low-toxicity treatment regimens are all key factors
for clinicians to consider.
Returning to this patient, clinicians should actively seek better and innovative treatment options for the patient, such as retesting to find new targets or trying new drugs such as PD-1/CTLA4 dual antibodies
, provided that her willingness to treat and affordability permit.

3.
Accurate treatment plans are inseparable from accurate diagnosis

The genetic testing of this patient was first diagnosed two years ago, and under the pressure of the choice of multiple therapeutic drugs, the molecular characteristics and microenvironment of the patient's tumor may have undergone major changes, and this change cannot be predicted by our clinicians, and must rely on the latest genetic test results to provide a basis
for subsequent treatment.
In addition, we can also use new technologies such as organoid models and CAR-T to explore the follow-up treatment direction
for patients.
Regarding the follow-up treatment plan of this patient, from the perspective of HER2-targeted therapy, although the efficacy of DS8201 seems to be better than trastuzumab and small molecule TKI, the level of evidence is still insufficient, and the potential safety issues of DS8201 also require our vigilance
.
Given that patients have benefited from immune combined with antiangiogenic drugs, I personally believe that PD-1/CTLA-4 dual antibody combined with low-dose chemotherapy is a relatively safe and effective option
.

Case 1 Details:

Swipe right to see more

Case 2:

Basic condition of the patient:

patient Xue, male, 61 years old; Chest CT in December 2018 showed that the lower lobe of the right lung showed a lobulated mass, 48*28mm in size, which was significantly strengthened, stretched pleura, and considered malignant lesions; There was no obvious enlarged lymph node shadow in both hilos and mediastinum; local thickening of the pleura on both sides; On the 20th, the right lung lesion was biopsied, and the results of the puncture report showed that: (right lung needle biopsy) malignant tumor, combined with immunohistochemistry consistent with poorly differentiated non-small cell lung cancer, predisposed to adenocarcinoma; Genetic test results showed that EGFR19 exon mutation;

Oral Iressa-targeted therapy from January 2019 to March 2021, during which it was assessed as stable;

Repeat CT in March 2021 showed that the right lower lung mass was slightly enlarged compared with the previous one, pericardial effusion, and genetic testing showed that EGFR T790M mutation;

On March 24, 2021, the protocol was adjusted to osimertinib targeted therapy, during which the condition was assessed as stable;

In March 2022, the patient began to experience blurred vision and double vision, dizziness, no headache, vomiting, and no further examination
due to the epidemic.
On July 27, 2022, the MR enhancement of the head of the outer hospital showed multiple small strengthening foci of the right frontal lobe and the left frontopietal lobe, excluding metastatic tumors combined with the medical history
.
Assess for PD.

Repeat blood genetic testing: EGFR T790M;

On August 2, 2022, the third-line protocol was replaced, specifically: albumin-bound paclitaxel 400mg intravenous d1 + carboplatin 400mg intravenous d1 + avastin 500mg intravenous d1, q3w; After 1 week, the patient developed fatigue, increased visual ghosting, headache, worsening dizziness, and loss of appetite with nausea and vomiting
.
After admission, the symptoms did not improve significantly after active dehydration, cranial pressure reduction, antiemetic, and analgesia treatment, and meningeal metastasis was considered in combination with imaging findings;

Final diagnosis: 1.
Lung cancer right lower lobe adenocarcinoma cTxNxM1 (bone, brain) stage IV ECOG 3 2.
Meningeal secondary malignant tumor

Summary of genetic test results:

Discussion questions:

Special type of EGFR 19del: How is EGFR T751_I759delinsN different from the common 19del mutation?

2.
What is the progress in the treatment of meningeal metastasis in lung cancer?

Molecular biology analysis (molecular biologist Mingjun Zhu):

EGFR 19delins is a rare and specific 19del subtype that can benefit from a generation of EGFR TKI for a longer period of time

With the increasing accuracy of molecular detection methods, more and more EGFR mutations have been discovered, which also confirms that NSCLC with EGFR mutations is a highly heterogeneous ^disease25
.
Taking EGFR exon 19 deletion as an example, there are more than 50 mutation types, including simple amino acid deletion, deletion and combination point mutation, deletion and insertion, etc
.
The EGFR T751_I759delinsN variant measured in this patient was a 19delins mutation, accounting for only 0.
13%
of lung cancer.
This variant, located in the C-helix domain of the EGFR protein kinase domain, activates the kinase by changing the position of the C-helix, thereby affecting the sensitivity of TKI therapy26
.
Previous studies have found that patients with rare EGFR 19delins mutations have a better prognosis than classic EGFR 19del (e.
g.
, E746_A750del), with significantly longer PFS times on first-line EGFR ^TKIs27
.
EGFR T751_I759delinsN in a 65-year-old woman with lung adenocarcinoma was treated with eclitinib, with PR and PFS for up to 22 months28
.
This is also consistent
with the PFS time of nearly 26 months obtained from Iressa in this case.

Current studies have confirmed that when a patient's first-generation TKI resistance progresses, whether it is the common EGFR 19del variant or the rare EGFR 19delins variant, the T790M mutation is the main resistance mechanism
.
When T790M resistance mutations appeared, the PFS of osimertinib received in the second line of patients with the rare variant of 19delins was significantly shortened compared with the classic 19del (5.
0m vs 12.
0m, p<0.
0001, except L747_A750delinsP)²⁷
.

2.
Patients with EGFR TKI-resistant advanced NSCLC may benefit from immunotherapy

With the in-depth understanding of the immunomodulatory role of targeted drugs and the continuous generation of clinical evidence, immunotherapy is expected to bring new hope for driver-positive non-small cell lung ^cancer28
.
A number of clinical studies have explored different models of immunotherapy regimens, providing effective evidence and guidance for immunotherapy in patients with drug-resistant EGFR-mutant NSCLC:

1) Immunotherapy and antiangiogenic therapy: IMpower150 Study ²⁹ and ORIENT-31 Study ³⁰ explored the efficacy and safety of different immunocombination chemotherapy and antiangiogenic therapy in NSCLC patients who failed EGFR-TKIs, respectively, and the two studies consistently confirmed the effectiveness of this combination therapy strategy and significantly prolonged overall survival.
The serious adverse reactions of the four-drug combination were also significantly higher than those in the three-drug combination group and the chemotherapy control group
alone.

2) Immunotherapy combined with chemotherapy: BGB-A317-2001-IIT study ³¹, CT18 study ³² and pembrolizumab combined with pemetrexed and carboplatin all confirmed that ICIs combined with chemotherapy for the treatment of resistant EGFR mutation NSCLC in patients with EGFR mutation or ALK fusion NSCLC who have previously received TKIs have good efficacy and safety
.

3) Immune combined antivascular therapy: A clinical study of carrelizumab combined with apatinib in the treatment of driver gene positive NSCLC for disease progression after receiving at least two systemic therapies showed that the ORR of 43 patients was 18.
6%, the median PFS was 2.
8 months, and the ORR of PD-L1-positive patients was better than that of negative patients (27.
3% and 7.
7%, respectively)³⁴
.

4) Immunomonotherapy: ATLANTIC findings suggest that ICIs monotherapy may also be an effective option
for PD-L1-positive patients resistant to EGFR/ALK-TKIs.

In summary, there is growing evidence that driver gene-positive NSCLC targeted therapy can still benefit from immunotherapy even after progression, but which combination regimen to adopt will be an important question
to explore next.

3.
Progress in the treatment of meningeal metastasis in lung cancer

The proportion of meningeal metastasis in NSCLC is about 3.
4%, while the proportion of meningeal metastasis in NSCLC with EGFR mutation is significantly increased, up to 9.
4%³⁵
.
Current NCCN guidelines recommend that if oligoprogression or central nervous system lesions occur after treatment of EGFR TKIs resistance, the original EGFR TKIs can be continued in combination with local therapy
.
In terms of the selection of different EGFR TKIs, the permeability of different EGFR TKIs to the blood-brain barrier was different, and the third-generation osimertinib was significantly higher than that of the first- or second-generation TKI, so the effect on intracranial lesion control was ^better36
。 The BLOOM study confirmed that in NSCLC patients with meningeal metastases who had progressed to prior EGFR TKI treatment, after treatment with osimertinib 160 mg per day, the ORR assessed by neuroradiologists was 62%, the duration of treatment was 15.
2 months, the clearance of tumor cells in the cerebrospinal fluid was 28%, and the patient's neurological function was significantly ^improved37
.
For patients with negative driver genes, systemic chemotherapy including pemetrexed by intrathecal injection or through the Ommaya capsule is an effective ^option38-40
.
In addition, a multi-centre retrospective real-world study in Australia also found that the IMpower150 ABCP four-drug combination regimen showed good clinical efficacy in patients with CNS metastases after driver gene positive targeted therapy, and the overall survival of patients with brain metastases and meningeal metastases was 11.
4 months and 7.
1 months,
^{respectively.
41}

Clinical team analysis and protocol selection and evaluation (clinical expert Professor Jiao Xiaodong):

Because the patient has severe neurologic abnormalities due to intracranial lesions, conventional chemotherapy and macromolecular monoclonal antibody drugs have poor meningeal permeability, so subsequent priority is given to trying EGFR TKIs
with well-controlled intracranial lesions 。 At present, the three generations of EGFR TKI clinically accessible in China include osimertinib, ametinib and vometinib, and the effectiveness of the three for CNS metastases is different, among which the dose expansion study of vometinib in the 2021 WCLC conference showed that the CNS ORR of the 160mg group of vometinib was as high as 84.
6%, and the CNS DCR was 100%, which was significantly higher than the previously reported data
of osimertinib and ametinib 。 Therefore, the patient was given vometinib 160mg/day orally in time after admission, and Ommaya capsule placement was performed on August 22, 2022, and pemetrexed 50mg was injected
through Ommaya capsule on the 31st.
However, the patient died
on 2 September due to a sharp deterioration in his general condition.

Professor Zang concluded:

1.
EGFR 19delins rare mutation should be paid attention to in clinical practice

In the past, there was a lack of sufficient clinical understanding of deletion mutations occurring in EGFR 19 exon, and through literature combing, we found that compared with traditional EGFR 19del mutations, 19delins is a relatively special and rare type, and its response to a generation of EGFR TKI is more durable, and when T790M mutations occur, different EGFR 19delins mutations have different sensitivity to osimertinib
.

2.
Patients with drug-resistant EGFR mutations may benefit from immunotherapy

Preclinical studies have shown that EGFR TKI can not only inhibit the activation of EGFR signaling pathway, but also regulate the tumor immune microenvironment through a variety of pathways and induce anti-tumor immune response
.
Several studies have explored the efficacy and safety of different immune combination modalities in EGFR-resistant patients, such as immune combined antiangiogenic drugs and chemotherapy mode, immune combination chemotherapy mode, immune monotherapy, etc
.
For patients with EGFR TKI resistance progression, immunotherapy is recommended in the absence of effective targeted drug therapy, but the specific treatment regimen needs to be comprehensively judged
based on the patient's performance status and disease progression.

Case 2 Details:

Swipe right to see more

Conference Summary: This MTB seminar discussed two cases worthy of clinical consideration, one case is a colorectal cancer patient with HER2 with KRAS gene mutation, first-line immune combined with antiangiogenic drug treatment to permanently inhibit tumor growth, and then continuously fine-tune the treatment plan based on the actual situation of the patient, in order to actively seek a more effective follow-up treatment plan for the patient through MTB discussion; Case 2 is a case with a rare mutation of EGFR 19delins, a lung cancer patient with EGFR 19delins developed meningeal metastasis after two-line TKI treatment, although the current evidence for the back-line treatment of lung cancer patients with meningeal metastasis is limited, but through a large number of literature review and in-depth discussion, it also reflects the benevolence and ingenuity
of the difficult tumor MTB team of Changzheng Hospital.

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