Do not use these combination cancer treatments

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Do not use these combination cancer treatments

Do not use these combination cancer treatments! Survival time not rising but falling? !

Due to the complexity of tumors, drug combination therapy with different mechanisms and different targets is still an important means to improve efficacy and overcome drug resistance.

For a long time, the combination of tumor drugs with different mechanisms of action is reflected in the combination of cytotoxic chemotherapy drugs, including cell cycle non-specific drugs + specific drugs ; chemotherapy combined with anti-vascular drugs ; chemotherapy combined with immunotherapy drugs , and different targets of tumor immunity association between etc.

However, reasonable combination therapy can bring better treatment options for tumor patients, while inappropriate combination regimens will increase the risk of subjects.

This article will discuss which combinations are inappropriate!

Do not use these combination cancer treatments

Non-small cell lung cancer

EGFR/ALK mutation aNSCLC, can TKI combined with immunotherapy work a miracle?

Let’s take a look at the joint plan of EGFR TKI+ICIs first, is it a “strong combination” or a ” positive positive wins negative “?

EGFR TKI+ICIs

In the CheckMate 057 study , patients with EGFR mutations ( previously or currently receiving TKI therapy) received nivolumab treatment, and there was no OS benefit compared to cetaxel . The KEYNOTE 010 study had similar results.

In the KEYNOTE 021 study , EGFR mutation-positive patients (4 patients with PD-L1 expression ≥ 50%) received erlotinib (n = 12) or gefitinib (n = 7) combined with pembrolizumab , Pablo The safety of bolizumab + erlotinib is the same as that of single drug, but the incidence of G3/4 liver toxicity of pembrolizumab + gefitinib is as high as 71.4%! The ORR was 41.7% . The study did not observe the additional benefit of the double drug combination .

Will switching to PD-L1 monocXlonal antibody improve safety?

In the NCT02088112 study , EGFR mutation-positive aNSCLC patients (TKI- naïve ) received gefitinib + durvalumab combination therapy concurrently , 35% of the patients had elevated transaminases until drug withdrawal, and the final ORR was 63.3% , mPFS and mDOR 10.1 and 9.2 months respectively .

Higher toxic and side effects, no obvious gain in curative effect , simultaneous use of PD-L1 monoclonal antibody + gefitinib in the treatment of TKI-naïve EGFR mutant NSCLC should be avoided clinically .

After reading these research results, do you feel surprised? ! It seems that inappropriate combination will be counterproductive, so how effective is the combination of ALK TKI+ICIs?

In the NCT02013219 study , ALK-positive aNSCLC patients received first-line alectinib + atezolizumab combination therapy. The incidence of grade 3 adverse events was 66.7% , the ORR was 85.7% , and the mPFS was 21.7 months. The long-term follow-up data is to be published.

Regarding these research results, the author can’t help feeling: The feasibility of TKI+ICI combination therapy in patients with ALK mutation-positive aNSCLC is still a question mark .

Osimertinib + anti-vascular double drug combination does not necessarily improve survival

Let’s take a look at osimertinib + anti-angiogenic drugs, how effective is this combination program?

NEJ-026 , CTONG-1509 and other studies have confirmed that EGFR-TKIs + anti-angiogenic drugs can improve the survival of patients . In particular, the combination regimen has shown impressive strength in the treatment of Exon21 L858R mutation.

The FLAURA study confirmed the great advantages of the third-generation TKI osimertinib, but osimertinib + anti-angiogenic targeted drugs cannot achieve a “strong combination” (Below overview 1).

The failure of WJOG-8715L and BOOSTER research made the idea of this combination drug confusing .

Overview 1 of combined drug data of osimertinib + anti-angiogenic targeted drugs:

WJOG-8715L

Patients with advanced lung adenocarcinoma who failed first-line EGFR-TKI therapy and were positive for T790M mutation received osimertinib + bevacizumab/osimertinib monotherapy as second-line therapy.
ORR: 68% vs 54%; mPFS: 9.4 vs 13.5 months; mos: notreached vs 22.1 months.
Osimertinib + bevacizumab combined with second-line treatment of T790M-positive patients cannot improve PFS.

BOOSTER

Patients with 790M mutation-positive aNSCLC who failed previous EGFR-TKI therapy received osimertinib plus bevacizumab/osimertinib monotherapy.
mPFS: 15.4 vs 12.3 months mos: 24.0 vs 24.3 months Safety: The incidence of 2G3 TRAEs was 47% vs 18%, respectively.
Osimertinib + bevacizumab combined with second-line therapy did not improve survival, and 2G3 treatment-related side effects were more common.

NCT02789345

Patients with T790M mutation-positive aNSCLC who failed previous EGFR-TKI therapy received osimertinib+remoglut for 2 months in the second line. Monoclonal antibody combination therapy.
ORR: 76%, mPFS: 11.0 months
Osimertinib + Ramucirumab Shows Promising Safety and Anticancer Activity in Phase 1 Study

What is the effect of anti-PD-1/PD-L1 + anti-CTLA4 double antibody in the treatment of aNSCLC ?

When it comes to joint programs, how can we miss the high-profile The “double immunity” therapy of CTLA-4 and PD-1/PD-L1 , let’s see if this combination can be successful?

In the CheckMate 227 study (part 1b), aNSCLC patients with PD-L1 <1% were enrolled and received nivolumab + ipilimumab , or nivolumab + chemotherapy , or chemotherapy.

The novelty of CheckMate 227 is that the double-immune treatment successfully improved the OS of the PD-L1 <1% population , and the median OS and 3-year survival rate of PD-L1-positive and PD-L1-negative patients receiving double-immune therapy were similar. PD-L1-negative patients received double-immune therapy, which significantly improved OS compared with chemotherapy (17.2 vs 12.2 months).

Although comparative studies are lacking, the above data suggest that for PD-L1 negative patients, double immunization may be more appropriate than single immunization .

But unfortunately :

In the MYSTIC study , durvalumab ± CTLA4 inhibitor tremelimumab failed to improve OS in PD-L1-positive (≥ 25%) patients compared with chemotherapy .

In the KEYNOTE 598 study , patients with aNSCLC with high PD-L1 expression received pembrolizumab + ipilimumab , or pembrolizumab monoimmunization, there was no significant benefit in efficacy (mOS: 21.4 vs 21.9), but poor The reaction is heavier .

In KEYNOTE 021 research cohorts D and H, previously treated aNSCLC patients (n=44) received combination therapy of pembrolizumab 2 mg/kg + ipilimumab 1 mg/kg, the ORR was 30% , and the mPFS and mOS were respectively For 4.1 , 10.9 months. The incidence of G3-5 TRAEs was 29% . The combination regimen showed anticancer activity in the later-line treatment of aNSCLC, but the adverse reactions were also significant .

The results of the three studies, MYSTIC study, KEYNOTE 598 study, and KEYNOTE 021 study, can basically be summed up in one sentence: After combined medication, the toxicity does not increase.

PD-L1 low expression (1-49%) aNSCLC use PARPi + anti-PD-1 monoclonal antibody has no additional benefit

Laboratory studies have shown that PARP inhibitors (PARPi) can increase tumor mutation load and increase PD-L1 expression to enhance the response rate of ICIs, so there is a synergistic effect between PARPi and anti-PD-1/PD-L1 monoclonal antibodies .

The classic MEDIOLA study ( olaparib + durvalumab ) and the TOPACIO study ( niraparib + pembrolizumab ) both showed that PARPi combined with ICIs can achieve the effect of 1+1>2 .

Does the PARPi+immune combination regimen have the potential to improve the survival of aNSCLC patients? The JASPER study (Phase 2) aimed to explore this question (Overview 2).

Overview 2 of JASPER study data (data source: Reference 1)

JASPER study (NCTO4475939)

PD-L1 TPS >50% (cohort 1) and 1-49% (cohort 2) of aNSCLC patients (n=38) were treated with niraparib (200mg qd) and pembrolizumab (200mg g3w). Primary endpoint: ORR; secondary endpoints: DOR, PFS, OS, safety, etc.

Queue 1

PD-L1 expression: more than 50%
Curative effect: ORR: 56.3% (9/16), including 2 cases of CR. DCR: 87.5%; mDOR: 19.7 months, mPFS: 8.4 months, mos: NE
Adverse reactions: The incidences of more than G3 treatment-related toxic and side effects were 88.2% and 85.7%, respectively. The most common adverse reactions were fatigue, nausea, and loss of appetite, and the incidence rates of the two cohorts were similar

Queue 2

PD-L1 expression: 1-49%
Curative effect: ORR: 20.0% (4/20), DCR: 70.0%. mDOR: 9.4 months, mPFS: 4.2 months, mos: 7.7 months
Adverse reactions: The incidences of more than G3 treatment-related toxic and side effects were 88.2% and 85.7%, respectively. The most common adverse reactions were fatigue, nausea, and loss of appetite, and the incidence rates of the two cohorts were similar

The JASPER study explored the efficacy of PARPi+immune first-line treatment of aNSCLC for the first time, and confirmed the anti-tumor activity of this combined regimen in NSCLC, especially in the population with high expression of PD-L1 (TPS ≥ 50%) , the treatment response was more significant (ORR: 56.3%), while the ORR achieved by pembrolizumab in the KEYNOTE 024 study was 44.8% .

However, in patients with aNSCLC with low PD-L1 expression, the niraparib+pembrolizumab combination regimen is lackluster . There may be no additional benefit from the use of PARPi + anti-PD-1 monoclonal antibody in this population.

Be sure to understand the applicable population when combining medications !

Small Cell Lung Cancer

Exploration of second-line dual-immune therapy for small cell lung cancer

The same problem of double immunity, throwing it to the choice of second-line treatment for small cell lung cancer, what is the result?

In the CHECKMATE 032 study , previously treated ES-SCLC patients received nivolumab , or nivolumab + ipilimumab . result:
Patients receiving nivolumab 1 mg/kg + ipilimumab 3 mg/kg: ORR: 23% (14/61), mDOR: 7.7 months, mPFS: 2.6 months, mOS: 7.7 months, 1-year survival Rate: 43% .
Patients receiving nivolumab 3 mg/kg + ipilimumab 1 mg/kg: ORR: 19% (10/54), mDOR: 4.4 months, mPFS: 1.4 months, mOS: 6.0 months. 1-year survival rate: 35% .
The combination of nivolumab and ipilimumab has only modest anticancer activity in previously treated SCLC patients .
In the BALTIC study , tremelimumab + durvalumab was used in the treatment of platinum-refractory and platinum-resistant extensive-stage SCLC, and a similar treatment response was achieved: ORR: 9.5% , mOS: 6 months.
In the NCT02701400 study , patients with relapsed SCLC who previously received ≤ 2 lines of chemotherapy were randomized to receive durvalumab + tremelimumab , or SBRT (stereotactic radiotherapy) followed by durvalumab + tremelimumab.
Results: 9 patients in each of the two groups were included in the study. In the double-immune therapy group, ORR: 0%, mPFS: 2.1 months, and mOS: 2.8 months. In the SBRT treatment group, ORR: 28.6%, mPFS: 3.3 months, mOS: 5.7 months. Durvalumab + tremelimumab ± SBRT did not show satisfactory efficacy in relapsed SCLC .

It can be seen from the above that the combination of anti-PD-1+CTLA4 double antibody can be used as a potential option in the late-line treatment of extensive-stage small cell lung cancer, but the efficacy may be limited .

Small cell lung cancer PARPi + immune efficacy is not as expected

lthough SCLC has a high probability of TMB-H, the efficacy of immunosuppressants is very limited.

In Thomas A, et al’s study, relapsed SCLC patients (n=20; 60% relapsed with platinum resistance) were treated with durvalumab + olaparib , and the ORR was only 10.5% . In terms of adverse reactions, the most common TRAEs was anemia ( 80%), decreased lymphocytes (60%), and decreased white blood cells (50%).

The efficacy of durvalumab + olaparib did not meet expectations .

Maintenance immunotherapy for small cell lung cancer

In the CheckMate 451 study , ES-SCLC patients (n=834), after receiving 4 cycles of first-line induction chemotherapy, randomly received nivolumab 1 mg/kg + ipilimumab 3 mg/kg q3w for 12 weeks, followed by Nivolumab 240 mg q2w maintenance, or nivolumab 240 mg q2w maintenance, or placebo maintenance.

Results: Compared with the placebo control group, the double immune treatment group had no improvement in OS (9.2 vs 9.6 months). For patients with TMB ≥ 13 mutations per megabase, double-immune therapy showed a tendency to prolong OS. The incidence of G3-4 TRAEs in the double-immune group was as high as 52.2% .

Navolumab + ipilimumab maintenance therapy did not bring OS benefit to patients with ES-SCLC .

Small cell lung cancer PARPi + chemotherapy

SCLC tends to highly express DDR-related proteins, including PARP1. Preclinical studies suggest that PARP inhibitors (PARPi) may have a synergistic effect with drugs that mediate DNA damage, such as platinum and temozolomide .

Clinical studies have shown that temozolomide + veliparib achieved an ORR of 39% in patients with relapsed SCLC , which was significantly better than temozolomide alone (14%), although the PFS and OS of the two groups were similar. The ORR of temozolomide + olaparib in the treatment of relapsed SCLC reached 44% , and the mPFS and mOS reached 4.2 and 6.7 months, respectively.

On this basis, EP chemotherapy + veliparib entered the first-line treatment of untreated SCLC. Although mPFS was prolonged, unfortunately, there was no significant additional benefit in mOS .

Advanced Colorectal Cancer

Immune + anti-angiogenic combination therapy for MSS mCRC still needs further testing

Basic research has confirmed that : ICIs + anti-angiogenic drugs have a synergistic effect , and the latter has a significant regulatory effect on the tumor immune microenvironment, which helps to strengthen the anti-cancer effect of immunotherapy.

In clinical research , the combination of immune + anti-vascular targeted drugs has achieved amazing results in the treatment of multiple cancers , such as NSCLC (NCT03628521, etc.), ES-SCLC (PASSION study), unresectable/advanced liver cancer (IMbrave150 study, RESCUE research, etc.).

MSS advanced colorectal cancer (mCRC) is known as an “immune desert”, but the combination of immune + anti-angiogenic therapy has created hope in MSS mCRC .

The REGONIVO study included patients with MSS mCRC who had received second-line or above standard treatment, and received combined therapy with regorafenib + nivolumab. Results: ORR: 33.3% , mPFS: 7.9 months, and 1-year OS rate: 68.0% .

Nowadays, it is common for physicians to recommend targeted (regorafenib/fruquintinib) + immune combination therapy for MSS mCRC patients in the third line . However, in practice, the efficacy of this combined approach in MSS mCRC remains to be tested .

First , REGONIVO’s medication idea, in the North American data, the ORR is only 7% . Second , the combination of domestic camrelizumab + apatinib in the treatment of MSS mCRC, the ORR was 0% , and the incidence of treatment-related adverse reactions was 100% , the study ended in failure.

Sintilimab + fruquintinib (NCT03903705) achieved an ORR of 22.7% , and an mPFS of 5.6 months , achieving a certain curative effect.

In addition, the 2019 ASCO GI meeting reported that durvalumab + tremelimumab double immunity failed to improve the PFS and OS of MSS patients .

According to the 2020 ESMO meeting report, the ORR of avelumab + cetuximab in the treatment of MSS mCRC was only 7% .

Other treatments

Increased risk of fulminant cardiotoxicity with anti-PD-1 followed by anti-PD-L1 mAbs

Although there are reports that after the use of anti-PD-1 monoclonal antibody, the subsequent switch to PD-L1 monoclonal antibody has achieved curative effect, and the toxicity and side effects are lower than that of PD-1 monoclonal antibody, but anti-PD-1 sequential anti-PD-L1 monoclonal antibody , Still need to be cautious!

In the study by Shin-Yi Liu, et al, a patient with lung adenocarcinoma with brain metastases received atezolizumab 1000 mg once after receiving nivolumab q2w for 5 cycles. On the first day, the patient came to the emergency department due to dyspnea and fatigue.

The pulmonary examination showed consolidation shadows and elevated heart damage markers. Cardiac- related symptoms appeared 28 days after the administration, and cardiac arrest occurred 68 days after the administration .

The researchers subsequently administered anti-PD-1 and PD-L1 interventions simultaneously/sequentially in the mouse model, resulting in myocardial cell damage and patchy mononuclear cell infiltration in the myocardium .

When used sequentially, increased neutrophil infiltration in mouse cardiomyocytes was observed.

Although the tumor control effect is better, simultaneous/sequential administration of anti-PD-1 and PD-L1 drugs can cause fulminant cardiotoxicity, and caution should be exercised in this usage .

✩ This article is only for the reference of medical and health professionals
references:
1 Yang JC, Gadgeel SM, Sequist LV, et al. Pembrolizumab in Combination With Erlotinib or Gefitinib as First-Line Therapy for Advanced NSCLC With Sensitizing EGFR Mutation[J]. J Thorac Oncol. 2019 Mar;14(3):553- 559. doi: 10.1016/j.jtho.2018.11.028.
2 Dingemans AC, Früh M, Ardizzoni A, et al. ESMO Guidelines Committee. Electronic address: [email protected]. Small-cell lung cancer: ESMO Clinical Practice Gu idelines for diagnosis, treatment and follow-up☆[J]. Ann Oncol. 2021 Jul;32(7):839-853. doi: 10.1016/j.annonc.2021.03.207.
3 Creelan BC, Yeh TC, Kim SW, et al. A Phase 1 study of gefitinib combined with durvalumab in EGFR TKI-naive patients with EGFR mutation-positive locally advanced/metastatic non-small-cell lung cancer[J]. Br J Cancer. 2021 Jan;124(2): 383-390. doi: 10.1038/s41416-020-01099-7.
4 Spigel DR, Reynolds C, Waterhouse D, et al. Phase 1/2 Study of the Safety and Tolerability of Nivolumab Plus Crizotinib for the First-Line Treatment of Anaplastic Lymphoma Kinase Translocation – Positive Advanced Non-Small Cell Lung Cancer (CheckMate 370)[J]. J Thorac Oncol. 2018 May;13(5):682-688. doi: 10.1016/j.jtho.2018.02.022.
5 Akamatsu H, Toi Y, Hayashi H, et al. Efficacy of Osimertinib Plus Bevacizumab vs Osimertinib in Patients With EGFR T790M-Mutated Non-Small Cell Lung Cancer Previously Treated With Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitor: West Japan Oncology Group 8715L Phase 2 Randomized Clinical Trial[J]. JAMA Oncol. 2021 Mar 1;7(3):386-394. doi: 10.1001/jamaoncol.2020.6758.
6 Paz-Ares LG, Ramalingam SS, Ciuleanu TE, et al. First-Line Nivolumab Plus Ipilimumab in Advanced NSCLC: 4-Year Outcomes From the Randomized, Open-Label, Phase 3 CheckMate 227 Part 1 Trial[J]. J Thorac Oncol. 2022 Feb;17(2):289-308. doi: 10.1016/j.jtho.2021.09.010.
7 Boyer M, Şendur MAN, Rodríguez-Abreu D, et al; KEYNOTE-598 Investigators. Pembrolizumab Plus Ipilimumab or Placebo for Metastatic Non-Small-Cell Lung Cancer With PD-L1 Tumor Proportion Score ≥ 50%: Randomized, Double-Blind Phase III KEYNOTE-598 Study[J]. J Clin Oncol. 2021 Jul 20;39(21):2327-2338. doi: 10.1200/JCO.20.03579.
8 Ready NE, Ott PA, Hellmann MD, et al. Nivolumab Monotherapy and Nivolumab Plus Ipilimumab in Recurrent Small Cell Lung Cancer: Results From the CheckMate 032 Randomized Cohort[J]. J Thorac Oncol. 2020 Mar;15(3):426-435. doi: 10.1016/j.jtho.2019.10.004.
9 Ramalingam SS, Thara E, Awad MM, et al. JASPER: Phase 2 trial of first-line niraparib plus pembrolizumab in patients with advanced non-small cell lung cancer[J]. Cancer. 2022 Jan 1;128(1):65-74. doi: 10.1002/cncr.33885.
10 Owonikoko TK, Park K, Govindan R, et al. Nivolumab and Ipilimumab as Maintenance Therapy in Extensive-Disease Small-Cell Lung Cancer: CheckMate 451[J]. J Clin Oncol. 2021 Apr 20;39(12):1349-1359. doi: 10.1200/JCO.20.02212.
11 Fukuoka S, Hara H, Takahashi N, et al. Regorafenib Plus Nivolumab in Patients With Advanced Gastric or Colorectal Cancer: An Open-Label, Dose-Escalation, and Dose-Expansion Phase Ib Trial (REGONIVO, EPOC1603)[J]. J Clin Oncol. 2020 Jun 20;38(18):2053-2061. doi: 10.1200/JCO.19.03296.
12 Liu SY, Huang WC, Yeh HI, et al. Sequential Blockade of PD-1 and PD-L1 Causes Fulminant Cardiotoxicity-From Case Report to Mouse Model Validation[J]. Cancers (Basel). 2019 Apr 24;11(4):580. doi: 10.3390/cancers11040580

Do not use these combination cancer treatments

(source:internet, reference only)

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Important Note: The information provided is for informational purposes only and should not be considered as medical advice.

Do not use these combination cancer treatments

Do not use these combination cancer treatments

Non-small cell lung cancer